Mobile website
Volume 32,Issue 8,2025 Table of Contents
2025, 32(8):783-798.
DOI: 10.3872/j.issn.1007-385X.2025.08.001
Abstract:
[Abstract] Immune checkpoint inhibitors (ICIs) based immunotherapy can induce immune-related adverse events (irAEs) while activating T cells and relieving immunosuppression. With the wide application of ICIs in solid tumors, irAEs has become a common clinical issue, seriously affecting the continuous benefits of immunotherapy and quality of life of patients. Therefore, a baseline assessment of patients is required before applying ICIs, such as evaluating the benefits and risks for special groups like those with autoimmune diseases, organ transplants, and viral infections. Meanwhile, the prediction and early identification of irAEs are paramount. Integrating various factors is essential for this purpose, including clinical factors such as underlying diseases and treatment history, host factors like intestinal flora and genetic polymorphisms, and biomarkers including tumor mutational burden, inflammatory indicators, and autoantibodies. In addition, the early symptoms of irAEs, such as fatigue, cough, and elevated bilirubin and transaminase levels, need to be differentiated from infections, tumor progression and adverse events caused by non-ICI interventions. irAE is an exclusion diagnosis and still requires the use of imaging, pathological and multidisciplinary consultation for differentiation. Mechanism research on irAE and prospective clinical trials should be conducted to promote the development precise prediction and treatment of irAE.
[Abstract] Immune checkpoint inhibitors (ICIs) based immunotherapy can induce immune-related adverse events (irAEs) while activating T cells and relieving immunosuppression. With the wide application of ICIs in solid tumors, irAEs has become a common clinical issue, seriously affecting the continuous benefits of immunotherapy and quality of life of patients. Therefore, a baseline assessment of patients is required before applying ICIs, such as evaluating the benefits and risks for special groups like those with autoimmune diseases, organ transplants, and viral infections. Meanwhile, the prediction and early identification of irAEs are paramount. Integrating various factors is essential for this purpose, including clinical factors such as underlying diseases and treatment history, host factors like intestinal flora and genetic polymorphisms, and biomarkers including tumor mutational burden, inflammatory indicators, and autoantibodies. In addition, the early symptoms of irAEs, such as fatigue, cough, and elevated bilirubin and transaminase levels, need to be differentiated from infections, tumor progression and adverse events caused by non-ICI interventions. irAE is an exclusion diagnosis and still requires the use of imaging, pathological and multidisciplinary consultation for differentiation. Mechanism research on irAE and prospective clinical trials should be conducted to promote the development precise prediction and treatment of irAE.
2025, 32(8):799-805.
DOI: 10.3872/j.issn.1007-385X.2025.08.002
Abstract:
[Abstract] Objective: To investigate the impact of methionine restriction on the proliferation and apoptosis of lung adenocarcinoma (LUAD) cells, and the pentose phosphate pathway. Methods: LUAD cells H1299 and A549 were assigned to the Met+ (100 μmol/L methionine) and Met? (0 μmol/L methionine) groups and cultured continuously for 4 d. Cell counting was used to evaluate the effects of methionine treatment on the proliferation of H1299 and A549 cells. Cell-cycle distribution was detected by PI staining; Cell apoptosis by Annexin Ⅴ-PE/7AAD labeling; intracellular ROS level by DCFH-DA probe; intracellular NADPH and GSH levels by WST-8 and DTNB assays, respectively. The Cancer Genome Atlas (TCGA) was used to analyze the correlations between the expressions of glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) and the methioninemetabolic pathway. WB assay was employed to evaluate the effects of methionine restriction and supplementation of S-adenosylmethionine (SAM), a downstream methionine metabolic product, on the expressions of G6PD and 6PGD, key enzymes in the pentose phosphate pathway, in LUAD cells. Results: Methionine restriction significantly inhibited the proliferation of H1299 and A549 cells (both P < 0.01), arrested cells in G2/M phase (both P < 0.05), elevated total ROS levels (both P < 0.001), and induced apoptosis (both P < 0.001). Furthermore, methionine restriction significantly reduced NADPH and GSH levels (both P < 0.01) and suppressed DNA synthesis (both P < 0.01). TCGA analysis revealed positive correlations between G6PD/6PGD expression levels and the methionine metabolic pathway (both P < 0.001). Methionine restriction down-regulated the expressions of G6PD and 6PGD proteins (both P < 0.01), whereas SAM supplementation partially restored their expressions (both P < 0.01), suggesting that methionine regulated the pentose phosphate pathway through SAM. Conclusion: Methionine restriction suppresses LUAD cell proliferation by inhibiting the PPP, which provides experimental evidence for methionine-restriction therapy for LUAD.
[Abstract] Objective: To investigate the impact of methionine restriction on the proliferation and apoptosis of lung adenocarcinoma (LUAD) cells, and the pentose phosphate pathway. Methods: LUAD cells H1299 and A549 were assigned to the Met+ (100 μmol/L methionine) and Met? (0 μmol/L methionine) groups and cultured continuously for 4 d. Cell counting was used to evaluate the effects of methionine treatment on the proliferation of H1299 and A549 cells. Cell-cycle distribution was detected by PI staining; Cell apoptosis by Annexin Ⅴ-PE/7AAD labeling; intracellular ROS level by DCFH-DA probe; intracellular NADPH and GSH levels by WST-8 and DTNB assays, respectively. The Cancer Genome Atlas (TCGA) was used to analyze the correlations between the expressions of glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) and the methioninemetabolic pathway. WB assay was employed to evaluate the effects of methionine restriction and supplementation of S-adenosylmethionine (SAM), a downstream methionine metabolic product, on the expressions of G6PD and 6PGD, key enzymes in the pentose phosphate pathway, in LUAD cells. Results: Methionine restriction significantly inhibited the proliferation of H1299 and A549 cells (both P < 0.01), arrested cells in G2/M phase (both P < 0.05), elevated total ROS levels (both P < 0.001), and induced apoptosis (both P < 0.001). Furthermore, methionine restriction significantly reduced NADPH and GSH levels (both P < 0.01) and suppressed DNA synthesis (both P < 0.01). TCGA analysis revealed positive correlations between G6PD/6PGD expression levels and the methionine metabolic pathway (both P < 0.001). Methionine restriction down-regulated the expressions of G6PD and 6PGD proteins (both P < 0.01), whereas SAM supplementation partially restored their expressions (both P < 0.01), suggesting that methionine regulated the pentose phosphate pathway through SAM. Conclusion: Methionine restriction suppresses LUAD cell proliferation by inhibiting the PPP, which provides experimental evidence for methionine-restriction therapy for LUAD.
2025, 32(8):806-813.
DOI: 10.3872/j.issn.1007-385X.2025.08.003
Abstract:
[Abstract] Objective: To investigate the systemic anti-tumor effects and immune mechanisms of CpG oligonucleotide and OX40 agonist antibody in situ vaccine (CpG + OX40) combined with anti-angiogenic drug anlotinib in the treatment of mouse ovarian cancer. Methods: A bilateral (primary and metastatic) ID8 cell mouse ovarian cancer model was established. And tumor-bearing mice were treated with anlotinib, CpG + OX40, or CpG + OX40 + anlotinib (the triple treatment), respectively. The anti-tumor effects of different treatment groups were evaluated by monitoring tumor volume and survival time. The changes of immune cells and cytokines in the tumor microenvironment were detected using flow cytometry and ELISA. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative expression levels of molecules reflecting vascular density and maturity in tumor tissues. Results: Compared with other treatment groups, the CpG + OX40 + anlotinib treatment significantly inhibited tumors on the treatment side (primary side) and the untreated side (metastatic side) (P < 0.01), and significantly improved the survival time of tumor-bearing mice (P < 0.05). The flow cytometry analyses showed that the CpG + OX40 + anlotinib treatment significantly increased the proportion of tumor infiltrating CD4+ T and CD8+ T cells in tumors at both the treated and untreated sides (P < 0.05). Immune cell depletion confirmed that when CD4+ T, CD8+ T, or NK cells were depleted alone, there was no significant difference in the inhibitory effects of the triple treatment on primary-side tumors, while the anti-tumor effects on metastatic-side tumors were significantly weakened but were still stronger than those of the PBS group (P < 0.01). When all three types of immune cells were depleted simultaneously, there was no statistically significant difference in their tumor suppressive effects compared with the PBS group (P > 0.05). The ELISA results showed that compared with other treatment groups, the triple treatment group showed a significant increase in Th1-related cytokines in the primary-side and metastatic-side tumors (P < 0.05), and a significant decrease in the expression of Th2-related cytokines (P < 0.05). The qRT-PCR results showed that, compared with the control group, the triple treatment group exhibited significantly lower CD31 expression (P < 0.0001) and a significantly higher Ang-1/Ang-2 ratio (P < 0.001) in tumor tissues on both sides. Conclusion: The combination of CpG + OX40 in situ vaccine and anlotinib has stronger systemic anti-tumor effects. Adaptive immunity, innate immunity and vascular density regulation play a crucial role in its anti-tumor effects, which provide potential treatment options for advanced cancer patients.
[Abstract] Objective: To investigate the systemic anti-tumor effects and immune mechanisms of CpG oligonucleotide and OX40 agonist antibody in situ vaccine (CpG + OX40) combined with anti-angiogenic drug anlotinib in the treatment of mouse ovarian cancer. Methods: A bilateral (primary and metastatic) ID8 cell mouse ovarian cancer model was established. And tumor-bearing mice were treated with anlotinib, CpG + OX40, or CpG + OX40 + anlotinib (the triple treatment), respectively. The anti-tumor effects of different treatment groups were evaluated by monitoring tumor volume and survival time. The changes of immune cells and cytokines in the tumor microenvironment were detected using flow cytometry and ELISA. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative expression levels of molecules reflecting vascular density and maturity in tumor tissues. Results: Compared with other treatment groups, the CpG + OX40 + anlotinib treatment significantly inhibited tumors on the treatment side (primary side) and the untreated side (metastatic side) (P < 0.01), and significantly improved the survival time of tumor-bearing mice (P < 0.05). The flow cytometry analyses showed that the CpG + OX40 + anlotinib treatment significantly increased the proportion of tumor infiltrating CD4+ T and CD8+ T cells in tumors at both the treated and untreated sides (P < 0.05). Immune cell depletion confirmed that when CD4+ T, CD8+ T, or NK cells were depleted alone, there was no significant difference in the inhibitory effects of the triple treatment on primary-side tumors, while the anti-tumor effects on metastatic-side tumors were significantly weakened but were still stronger than those of the PBS group (P < 0.01). When all three types of immune cells were depleted simultaneously, there was no statistically significant difference in their tumor suppressive effects compared with the PBS group (P > 0.05). The ELISA results showed that compared with other treatment groups, the triple treatment group showed a significant increase in Th1-related cytokines in the primary-side and metastatic-side tumors (P < 0.05), and a significant decrease in the expression of Th2-related cytokines (P < 0.05). The qRT-PCR results showed that, compared with the control group, the triple treatment group exhibited significantly lower CD31 expression (P < 0.0001) and a significantly higher Ang-1/Ang-2 ratio (P < 0.001) in tumor tissues on both sides. Conclusion: The combination of CpG + OX40 in situ vaccine and anlotinib has stronger systemic anti-tumor effects. Adaptive immunity, innate immunity and vascular density regulation play a crucial role in its anti-tumor effects, which provide potential treatment options for advanced cancer patients.
2025, 32(8):814-822.
DOI: 10.3872/j.issn.1007-385X.2025.08.004
Abstract:
[Abstract] Objective: To investigate the effects of paeonol (Pae) on the proliferation, migration, and invasion abilities of lung cancer A549 cells by regulating the enhancer of zeste homolog 2/neurexophilin 4 /cyclin dependent kinase inhibitor 2A (EZH2/NXPH4/ CDKN2A) axis. Methods: A549 lung cancer cell lines were treated with Pae at gradient concentrations (0, 6.25, 12.5, 25, 50, 100, 200 μg/mL). CCK-8 assay was used to screen for suitable Pae concentrations. A549 cells were assigned into the control group (untreated A549 cells), the Pae group (12.5 μg/mL Pae), the Pae + siEZH2 group (transfected with siEZH2+12.5 μg/mL Pae), the Pae + siNC group (transfected with siNC+12.5 μg/mL Pae), the Pae + vectorNC group (transfected with vector NC + 12.5 μg/mL Pae), and the Pae + vectorEZH2 group (transfected with vector EZH2 + 12.5 μg/mL Pae). After the indicated treatments, the colony formation assay was applied to detect the number of cell clones. Cell cycle distribution was measured by flow cytometry. Transwell assay was used to detect changes in cell invasion ability. Scratch assay was employed to detect changes in cell migration ability. Flow cytometry was applied to detect cell apoptosis. WB assay was used to detect the protein expression levels of EZH2, NXPH4, CDKN2A, Bcl-2, and caspase-3. Only siEZH2 or only siNC were transfected into A549 cells. Cell apoptosis was measured by flow cytometry, and the expressions of Bcl-2 and caspase-3 proteins were detected by WB assay. AnA549-cell nude-mouse transplant model was established to evaluate the in vivo antitumor efficacy of Pae and its effects on the expressions of relevant proteins. Results: 12.5 μg/mL was chosen as the concentration for subsequent experiments. Compared with those in the control group, the cell clone number, the proportion of S phase cells, the migration ability, the invasion ability, and the expression levels of EZH2, NXPH4, and Bcl-2 proteins were significantly reduced in the Pae group, while the proportion of G0/G1 phase cells, the apoptosis rate and the expression levels of CDKN2A and caspase-3 proteins were significantly increased (all P < 0.05). Compared with those in the Pae + si NC group, the cell clone number, the proportion of S phase cells, the migration ability, the invasion ability, and the expression levels of EZH2, NXPH4, and Bcl-2 proteins decreased more markedly in the Pae + siEZH2 group, while the proportion of G0/G1 phase cells, the apoptosis rate and the expression levels of CDKN2A and caspase-3 proteins increased more markedly (all P < 0.05). Compared with those in the Pae+vector NC group, the cell clone number, the proportion of S phase cells, the migration and invasion abilities, and the expression levels of EZH2, NXPH4, and Bcl-2 proteins increased significantly in the Pae + vectorEZH2 group, while the proportion of G0/G1 phase cells, the apoptosis rate and the expression levels of CDKN2A and caspase-3 proteins decreased significantly (P < 0.05). After EZH2 knockdown, the apoptosis rate and caspase-3 expression of A549 cells increased significantly, while Bcl-2 expression decreased significantly (both P < 0.05). In vivo experiments showed that paeonol significantly reduced tumor volume and mass, and inhibited the activity of the EZH2/NXPH4/ CDKN2A pathway. Conclusion: Pae inhibits the proliferation, migration and invasion of A549 cells and induces apoptosis by down regulating the EZH2/NXPH4/CDKN2Apathway.
[Abstract] Objective: To investigate the effects of paeonol (Pae) on the proliferation, migration, and invasion abilities of lung cancer A549 cells by regulating the enhancer of zeste homolog 2/neurexophilin 4 /cyclin dependent kinase inhibitor 2A (EZH2/NXPH4/ CDKN2A) axis. Methods: A549 lung cancer cell lines were treated with Pae at gradient concentrations (0, 6.25, 12.5, 25, 50, 100, 200 μg/mL). CCK-8 assay was used to screen for suitable Pae concentrations. A549 cells were assigned into the control group (untreated A549 cells), the Pae group (12.5 μg/mL Pae), the Pae + siEZH2 group (transfected with siEZH2+12.5 μg/mL Pae), the Pae + siNC group (transfected with siNC+12.5 μg/mL Pae), the Pae + vectorNC group (transfected with vector NC + 12.5 μg/mL Pae), and the Pae + vectorEZH2 group (transfected with vector EZH2 + 12.5 μg/mL Pae). After the indicated treatments, the colony formation assay was applied to detect the number of cell clones. Cell cycle distribution was measured by flow cytometry. Transwell assay was used to detect changes in cell invasion ability. Scratch assay was employed to detect changes in cell migration ability. Flow cytometry was applied to detect cell apoptosis. WB assay was used to detect the protein expression levels of EZH2, NXPH4, CDKN2A, Bcl-2, and caspase-3. Only siEZH2 or only siNC were transfected into A549 cells. Cell apoptosis was measured by flow cytometry, and the expressions of Bcl-2 and caspase-3 proteins were detected by WB assay. AnA549-cell nude-mouse transplant model was established to evaluate the in vivo antitumor efficacy of Pae and its effects on the expressions of relevant proteins. Results: 12.5 μg/mL was chosen as the concentration for subsequent experiments. Compared with those in the control group, the cell clone number, the proportion of S phase cells, the migration ability, the invasion ability, and the expression levels of EZH2, NXPH4, and Bcl-2 proteins were significantly reduced in the Pae group, while the proportion of G0/G1 phase cells, the apoptosis rate and the expression levels of CDKN2A and caspase-3 proteins were significantly increased (all P < 0.05). Compared with those in the Pae + si NC group, the cell clone number, the proportion of S phase cells, the migration ability, the invasion ability, and the expression levels of EZH2, NXPH4, and Bcl-2 proteins decreased more markedly in the Pae + siEZH2 group, while the proportion of G0/G1 phase cells, the apoptosis rate and the expression levels of CDKN2A and caspase-3 proteins increased more markedly (all P < 0.05). Compared with those in the Pae+vector NC group, the cell clone number, the proportion of S phase cells, the migration and invasion abilities, and the expression levels of EZH2, NXPH4, and Bcl-2 proteins increased significantly in the Pae + vectorEZH2 group, while the proportion of G0/G1 phase cells, the apoptosis rate and the expression levels of CDKN2A and caspase-3 proteins decreased significantly (P < 0.05). After EZH2 knockdown, the apoptosis rate and caspase-3 expression of A549 cells increased significantly, while Bcl-2 expression decreased significantly (both P < 0.05). In vivo experiments showed that paeonol significantly reduced tumor volume and mass, and inhibited the activity of the EZH2/NXPH4/ CDKN2A pathway. Conclusion: Pae inhibits the proliferation, migration and invasion of A549 cells and induces apoptosis by down regulating the EZH2/NXPH4/CDKN2Apathway.
2025, 32(8):823-830.
DOI: 10.3872/j.issn.1007-385X.2025.08.005
Abstract:
[Abstract] Objective: To investigate the effect of pristimerin (PT) on doxorubicin (DOX) sensitivity of huamn breast cancer cell MCF-7 by regulating the protein kinase B (AKT)/glycogen synthase kinase-3β (GSK-3β) signaling pathway. Methods: MCF-7 cells were cultured in vitro and used to construct a DOX resistant cell line MCF-7/DOX. MCF-7 cells were separated into the NC group, the L-PT group (2 μmol/L PT), the M-PT group (4 μmol/L PT), the H-PT group (8 μmol/L PT), the H-PT+SC79 group (8 μmol/L PT + 10 μmol/L AKT/GSK-3β signaling pathway inhibitor SC79), and the H-PT + LY294002 group (8 μmol/L PT + 2.5 μmol/L AKT/GSK-3β signaling pathway activator LY294002). MCF-7/DOX cells were separated into the MCF-7/DOX group (untreated), the DOX group (50 nμmol/L DOX), PT + DOX group (8 μmol/L PT and 50 nμmol/L DOX), the PT + DOX + SC79 group (8 μmol/L PT + 50 nμmol/L DOX + 10 μmol/L SC79), and the PT + DOX + LY294002 group (8 μmol/L PT + 50 nμmol/L DOX + 2.5 μmol/L LY294002). MTT assay, plate cloning assay, scratch assay, Transwell assay, and WB assay were applied respectively to determine cell proliferation, colony formation, migration, invasion, and AKT/GSK-3β signaling pathway protein expression in each group. Establish a MCF-7 cell xenograft model in nude mice to observe the effects of PT on tumor growth and the protein expression of the AKT/GSK-3β signaling pathway in the tumor tissues. Results: Compared with the NC group, the proliferation rate, colony formation rate, scratch healing rate, invasive cell count, and the p-AKT, p-GSK-3β protein expressions of MCF-7 cells in the L-PT group, the M-PT group, and the H-PT group all showed a PT concentration dependent decrease (all P < 0.05). Compared with the H-PT group, the trend of changes in the above indicators of MCF-7 cells in the H-PT + SC79 group was opposite to the above, while the trend of changes in the above indicators of MCF-7 cells in the PT + DOX + LY294002 group was the same (all P < 0.05). There was no significant difference in the proliferation rate, colony formation number, scratch healing rate, invasive cell count, and expressions of p-AKT and p-GSK-3β proteins between the MCF-7/DOX group and the DOX group (all P > 0.05). Compared with the MCF-7/DOX group and the DOX group, the PT + DOX group showed a decrease in the above indicators of MCF-7/DOX cells (all P < 0.05). Compared with the PT + DOX group, the above indicators in the PT + DOX + SC79 group all increased, while the above indicators in the PT + DOX + LY294002 group all decreased (all P < 0.05). Transplant tumor experiment in nude mice showed that compared with those in the control group and the DOX group, the mass and volume of transplant tumors, p-AKT and P-GSK-3β protein expressions in the PT + DOX group all decreased (all P < 0.05). Conclusion: PT can inhibit the proliferation, migration, and invasion of BC cells, and enhance their sensitivity to DOX chemotherapy., Its mechanism is related to the inhibition of the AKT/GSK-3β signaling pathway.
[Abstract] Objective: To investigate the effect of pristimerin (PT) on doxorubicin (DOX) sensitivity of huamn breast cancer cell MCF-7 by regulating the protein kinase B (AKT)/glycogen synthase kinase-3β (GSK-3β) signaling pathway. Methods: MCF-7 cells were cultured in vitro and used to construct a DOX resistant cell line MCF-7/DOX. MCF-7 cells were separated into the NC group, the L-PT group (2 μmol/L PT), the M-PT group (4 μmol/L PT), the H-PT group (8 μmol/L PT), the H-PT+SC79 group (8 μmol/L PT + 10 μmol/L AKT/GSK-3β signaling pathway inhibitor SC79), and the H-PT + LY294002 group (8 μmol/L PT + 2.5 μmol/L AKT/GSK-3β signaling pathway activator LY294002). MCF-7/DOX cells were separated into the MCF-7/DOX group (untreated), the DOX group (50 nμmol/L DOX), PT + DOX group (8 μmol/L PT and 50 nμmol/L DOX), the PT + DOX + SC79 group (8 μmol/L PT + 50 nμmol/L DOX + 10 μmol/L SC79), and the PT + DOX + LY294002 group (8 μmol/L PT + 50 nμmol/L DOX + 2.5 μmol/L LY294002). MTT assay, plate cloning assay, scratch assay, Transwell assay, and WB assay were applied respectively to determine cell proliferation, colony formation, migration, invasion, and AKT/GSK-3β signaling pathway protein expression in each group. Establish a MCF-7 cell xenograft model in nude mice to observe the effects of PT on tumor growth and the protein expression of the AKT/GSK-3β signaling pathway in the tumor tissues. Results: Compared with the NC group, the proliferation rate, colony formation rate, scratch healing rate, invasive cell count, and the p-AKT, p-GSK-3β protein expressions of MCF-7 cells in the L-PT group, the M-PT group, and the H-PT group all showed a PT concentration dependent decrease (all P < 0.05). Compared with the H-PT group, the trend of changes in the above indicators of MCF-7 cells in the H-PT + SC79 group was opposite to the above, while the trend of changes in the above indicators of MCF-7 cells in the PT + DOX + LY294002 group was the same (all P < 0.05). There was no significant difference in the proliferation rate, colony formation number, scratch healing rate, invasive cell count, and expressions of p-AKT and p-GSK-3β proteins between the MCF-7/DOX group and the DOX group (all P > 0.05). Compared with the MCF-7/DOX group and the DOX group, the PT + DOX group showed a decrease in the above indicators of MCF-7/DOX cells (all P < 0.05). Compared with the PT + DOX group, the above indicators in the PT + DOX + SC79 group all increased, while the above indicators in the PT + DOX + LY294002 group all decreased (all P < 0.05). Transplant tumor experiment in nude mice showed that compared with those in the control group and the DOX group, the mass and volume of transplant tumors, p-AKT and P-GSK-3β protein expressions in the PT + DOX group all decreased (all P < 0.05). Conclusion: PT can inhibit the proliferation, migration, and invasion of BC cells, and enhance their sensitivity to DOX chemotherapy., Its mechanism is related to the inhibition of the AKT/GSK-3β signaling pathway.
2025, 32(8):831-838.
DOI: 10.3872/j.issn.1007-385X.2025.08.006
Abstract:
[Abstract] Objective: To investigate the effects of circular RNA fascin actin-bundling protein 1 (circFSCN1) on the malignant biological behaviors of gastric cancer cells by regulating the microRNA-429 (miR-429)/glycoprotein nonmetastatic melanoma protein B (GPNMB) axis and its mechanisms. Methods: The gastric cancer tissues and corresponding para-cancerous tissues of 54 patients who underwent surgical resection at the First Hospital of Hebei Medical University between September 2022 and September 2023 were collected. The expressions of circFSCN1, miR-429 and GPNMB mRNA in gastric cancer tissues were detected by qPCR. Gastric cancer MGC803 cells were routinely cultured and divided into the control group, the sh-NC group, the sh-circFSCN1 group, the sh-circFSCN1+anti-NC group, and the sh-circFSCN1 + anti-miR-429 group. The expressions of circFSCN1, miR-429 and GPNMB mRNA in MGC803 cells of each group were detected by qPCR. The proliferation, migration, invasion and apoptosis of MGC803 cells in each group were detected by CCK-8 method, colony formation assay, Transwell assay and flow cytometry, respectively. Immunofluorescence was used to detect the expressions of GPNMB protein in cells of each group. WB assay was used to detect the expressions of PCNA, MMP-2, GPNMB and Cleaved Caspase-3 proteins in MGC803 cells of each group. Dual luciferase reporter assay and RNA-binding protein immunoprecipitation (RIP) assay were used to verify the binding regulatory relationship between circFSCN1 and miR-429, and between miR-429 and GPNMB. Results: circFSCN1 and GPNMB mRNA were both highly expressed in gastric cancer tissues (both P < 0.05), while miR-429 was lowly expressed (P < 0.05). Knockdown of circFSCN1 could promote the expression of miR-429 and inhibit the expression of GPNMB mRNA. Inhibition of miR-429 could promote the expression of GPNMB mRNA. Knockdown of circFSCN1 could significantly inhibit the proliferation, migration and invasion abilities of MGC803 cells and promote their apoptosis. Inhibition of miR-429 could partially reverse the effect of circFSCN1 knockdown. Knockdown of circFSCN1 could inhibit the expressions of PCNA, MMP-2 and GPNMB proteins in MGC803 cells and inhibit the expression of cleaved caspase-3 protein. There was a targeted binding and negative regulatory relationship between circFSCN1 and miR-429 and between miR-429 and GPNMB mRNA. Conclusion: Knocking down circFSCN1 inhibits the malignant biological behaviors of gastric cancer cells through the miR-429/GPNMB axis, indicating that circFSCN1 is a potential therapeutic target for gastric cancer.
[Abstract] Objective: To investigate the effects of circular RNA fascin actin-bundling protein 1 (circFSCN1) on the malignant biological behaviors of gastric cancer cells by regulating the microRNA-429 (miR-429)/glycoprotein nonmetastatic melanoma protein B (GPNMB) axis and its mechanisms. Methods: The gastric cancer tissues and corresponding para-cancerous tissues of 54 patients who underwent surgical resection at the First Hospital of Hebei Medical University between September 2022 and September 2023 were collected. The expressions of circFSCN1, miR-429 and GPNMB mRNA in gastric cancer tissues were detected by qPCR. Gastric cancer MGC803 cells were routinely cultured and divided into the control group, the sh-NC group, the sh-circFSCN1 group, the sh-circFSCN1+anti-NC group, and the sh-circFSCN1 + anti-miR-429 group. The expressions of circFSCN1, miR-429 and GPNMB mRNA in MGC803 cells of each group were detected by qPCR. The proliferation, migration, invasion and apoptosis of MGC803 cells in each group were detected by CCK-8 method, colony formation assay, Transwell assay and flow cytometry, respectively. Immunofluorescence was used to detect the expressions of GPNMB protein in cells of each group. WB assay was used to detect the expressions of PCNA, MMP-2, GPNMB and Cleaved Caspase-3 proteins in MGC803 cells of each group. Dual luciferase reporter assay and RNA-binding protein immunoprecipitation (RIP) assay were used to verify the binding regulatory relationship between circFSCN1 and miR-429, and between miR-429 and GPNMB. Results: circFSCN1 and GPNMB mRNA were both highly expressed in gastric cancer tissues (both P < 0.05), while miR-429 was lowly expressed (P < 0.05). Knockdown of circFSCN1 could promote the expression of miR-429 and inhibit the expression of GPNMB mRNA. Inhibition of miR-429 could promote the expression of GPNMB mRNA. Knockdown of circFSCN1 could significantly inhibit the proliferation, migration and invasion abilities of MGC803 cells and promote their apoptosis. Inhibition of miR-429 could partially reverse the effect of circFSCN1 knockdown. Knockdown of circFSCN1 could inhibit the expressions of PCNA, MMP-2 and GPNMB proteins in MGC803 cells and inhibit the expression of cleaved caspase-3 protein. There was a targeted binding and negative regulatory relationship between circFSCN1 and miR-429 and between miR-429 and GPNMB mRNA. Conclusion: Knocking down circFSCN1 inhibits the malignant biological behaviors of gastric cancer cells through the miR-429/GPNMB axis, indicating that circFSCN1 is a potential therapeutic target for gastric cancer.
2025, 32(8):839-846.
DOI: 10.3872/j.issn.1007-385X.2025.08.007
Abstract:
[Abstract] Objective: To investigate the effects of changes in interleukin-37 (IL-37) expression on CD8+ T cell vitality in patients with breast cancers. Methods: Forty-six patients with breast cancers, twenty-four patients with benign breast tumors, and twenty controls enrolled at the First Affiliated Hospital of Xinxiang Medical University between July 2020 and September 2022 were included in the study. Peripheral blood was collected. Plasma and peripheral blood mononuclear cells (PBMC) were isolated. Tumor tissues and para-cancerous tissues were collected from breast cancer patients who received surgical treatment. Tumor infiltrating lymphocytes (TILs) were isolated and CD8+ T cells purified. IL-37 and the expressions of soluble single immunoglobin IL-1 receptor-related (SIGIRR) proteins were detected by enzyme-linked immunosorbent assay (ELISA). IL-37 mRNA in the tissue was measured by real time PCR. IL-18 receptor α chain (IL-18Rα) and SIGIRR expression in CD8+ T cells were measured by flow cytometry. Purified CD8+ T cells were stimulated with exogenous IL-37, and were co-cultured with breast cancer cell line MCF-7. The percentage of target cell death was calculated by measuring the level of lactate dehydrogenase. Perforin, granzyme B, interferon-γ（IFN-γ）, and the level of tumor necrosis factor-α (TNF-α) in the supernatants was detected by ELISA. Results: Plasma IL-37 level was significantly elevated in patients with breast cancer compared with that in patients with benign breast tumors ([554.17 ± 96.63] vs [499.52 ± 78.66] pg/mL, P = 0.020) and that in the controls ([483.97 ± 47.23] pg/mL, P = 0.003). The expression of IL-37 mRNA in the tumor tissues was higher than that in the para-cancerous tissues in patients with breast cancer ([1.88 ± 0.21] vs [1.00 ± 0.53] pg/mL, P < 0.001). There were no statistically significant differences of peripheral IL-18Rα+CD8+ cell percentage, SIGIRR+ CD8+ cell percentage, or the level of soluble SIGIRR among patients with breast cancer, patients with benign breast tumors, and the controls (P > 0.05). There were also no statistically significant differences of the percentages of IL-18Rα+ or SIGIRR+ expression in CD8+ TIL cells between the tumor tissues and the para-cancerous tissues (P > 0.05). The percentage of CD8+ T cell-induced target cell death, and the levels of IFN-γ and TNF-α in the supernatants in both direct contact and indirect contact co-culture systems were reduced with IL-37 stimulation compared with those without IL-37 stimulation(P < 0.05). In direct contact co-culture system, the levels of perforin and granzyme B in the supernatants were down-regulated in response to IL-37 stimulation compared with those without stimulation (P < 0.001). However, in indirect contact co-culture system there were no significant differences in the levels of perforin or granzyme B in the supernatants with or without IL-37 stimulation (P > 0.05). Conclusion: Elevated IL-37 level might take part in the induction of CD8+ T cell exhaustion in peripheral blood and tumor microenvironments in breast cancer patients.
[Abstract] Objective: To investigate the effects of changes in interleukin-37 (IL-37) expression on CD8+ T cell vitality in patients with breast cancers. Methods: Forty-six patients with breast cancers, twenty-four patients with benign breast tumors, and twenty controls enrolled at the First Affiliated Hospital of Xinxiang Medical University between July 2020 and September 2022 were included in the study. Peripheral blood was collected. Plasma and peripheral blood mononuclear cells (PBMC) were isolated. Tumor tissues and para-cancerous tissues were collected from breast cancer patients who received surgical treatment. Tumor infiltrating lymphocytes (TILs) were isolated and CD8+ T cells purified. IL-37 and the expressions of soluble single immunoglobin IL-1 receptor-related (SIGIRR) proteins were detected by enzyme-linked immunosorbent assay (ELISA). IL-37 mRNA in the tissue was measured by real time PCR. IL-18 receptor α chain (IL-18Rα) and SIGIRR expression in CD8+ T cells were measured by flow cytometry. Purified CD8+ T cells were stimulated with exogenous IL-37, and were co-cultured with breast cancer cell line MCF-7. The percentage of target cell death was calculated by measuring the level of lactate dehydrogenase. Perforin, granzyme B, interferon-γ（IFN-γ）, and the level of tumor necrosis factor-α (TNF-α) in the supernatants was detected by ELISA. Results: Plasma IL-37 level was significantly elevated in patients with breast cancer compared with that in patients with benign breast tumors ([554.17 ± 96.63] vs [499.52 ± 78.66] pg/mL, P = 0.020) and that in the controls ([483.97 ± 47.23] pg/mL, P = 0.003). The expression of IL-37 mRNA in the tumor tissues was higher than that in the para-cancerous tissues in patients with breast cancer ([1.88 ± 0.21] vs [1.00 ± 0.53] pg/mL, P < 0.001). There were no statistically significant differences of peripheral IL-18Rα+CD8+ cell percentage, SIGIRR+ CD8+ cell percentage, or the level of soluble SIGIRR among patients with breast cancer, patients with benign breast tumors, and the controls (P > 0.05). There were also no statistically significant differences of the percentages of IL-18Rα+ or SIGIRR+ expression in CD8+ TIL cells between the tumor tissues and the para-cancerous tissues (P > 0.05). The percentage of CD8+ T cell-induced target cell death, and the levels of IFN-γ and TNF-α in the supernatants in both direct contact and indirect contact co-culture systems were reduced with IL-37 stimulation compared with those without IL-37 stimulation(P < 0.05). In direct contact co-culture system, the levels of perforin and granzyme B in the supernatants were down-regulated in response to IL-37 stimulation compared with those without stimulation (P < 0.001). However, in indirect contact co-culture system there were no significant differences in the levels of perforin or granzyme B in the supernatants with or without IL-37 stimulation (P > 0.05). Conclusion: Elevated IL-37 level might take part in the induction of CD8+ T cell exhaustion in peripheral blood and tumor microenvironments in breast cancer patients.
2025, 32(8):847-853.
DOI: 10.3872/j.issn.1007-385X.2025.08.008
Abstract:
[Abstract] Objective: To investigate the expression characteristics, biological functions, and regulatory mechanisms of dystrobrevin-ɑ (DTNA) in gastric cancer tissues. Methods: Bioinformatics analysis based on public databases was used to predict DTNA expression in gastric cancer and its correlation with prognosis. Bioinformatics analysis based on public databases was used to predict DTNA expression in gastric cancer and its correlation with prognosis. qPCR and immunohistochemistry (IHC) were employed to detect DTNA expression in gastric cancer tissues and cells. The chi-square test analyzed the correlations between DTNA and clinicopathological features of gastric cancer, while Kaplan Meier survival analysis assessed the relationship between DTNA expression and prognosis. CCK-8 and Transwell assays detected the effects of DTNA on the proliferation, migration, and invasion of gastric cancer MGC-803 cells. RNA interference, qPCR, and WB assay were used to examine the effects of far upstream element-binding protein 1 (FUBP1) on DTNA expression in MGC-803 cells. Results: Bioinformatics analysis revealed upregulated DTNA expression in gastric cancer tissues versus adjacent tissues, correlating with poor prognosis. DTNA was upregulated in gastric cancer tissues (P < 0.0001) and cells (P < 0.05), showing positive correlations with T stage (P < 0.001), TNM stage (P = 0.001), and poor prognosis (Log-Rank P = 0.0039). DTNA knockdown significantly inhibited the proliferation, migration, and invasion abilities of MGC-803 cells (all P < 0.01). FUBP1 downregulation reduced DTNA expression (P < 0.01). Conclusion: DTNA is upregulated in gastric cancer tissues and cells and is correlated with disease progression and poor prognosis. DTNA knockdown inhibits the proliferation, migration, and invasion of gastric cancer cells, and its expression is regulated by FUBP1.
[Abstract] Objective: To investigate the expression characteristics, biological functions, and regulatory mechanisms of dystrobrevin-ɑ (DTNA) in gastric cancer tissues. Methods: Bioinformatics analysis based on public databases was used to predict DTNA expression in gastric cancer and its correlation with prognosis. Bioinformatics analysis based on public databases was used to predict DTNA expression in gastric cancer and its correlation with prognosis. qPCR and immunohistochemistry (IHC) were employed to detect DTNA expression in gastric cancer tissues and cells. The chi-square test analyzed the correlations between DTNA and clinicopathological features of gastric cancer, while Kaplan Meier survival analysis assessed the relationship between DTNA expression and prognosis. CCK-8 and Transwell assays detected the effects of DTNA on the proliferation, migration, and invasion of gastric cancer MGC-803 cells. RNA interference, qPCR, and WB assay were used to examine the effects of far upstream element-binding protein 1 (FUBP1) on DTNA expression in MGC-803 cells. Results: Bioinformatics analysis revealed upregulated DTNA expression in gastric cancer tissues versus adjacent tissues, correlating with poor prognosis. DTNA was upregulated in gastric cancer tissues (P < 0.0001) and cells (P < 0.05), showing positive correlations with T stage (P < 0.001), TNM stage (P = 0.001), and poor prognosis (Log-Rank P = 0.0039). DTNA knockdown significantly inhibited the proliferation, migration, and invasion abilities of MGC-803 cells (all P < 0.01). FUBP1 downregulation reduced DTNA expression (P < 0.01). Conclusion: DTNA is upregulated in gastric cancer tissues and cells and is correlated with disease progression and poor prognosis. DTNA knockdown inhibits the proliferation, migration, and invasion of gastric cancer cells, and its expression is regulated by FUBP1.
2025, 32(8):854-861.
DOI: 10.3872/j.issn.1007-385X.2025.08.009
Abstract:
[Abstract] Objective: To investigate the roles and regulatory mechanisms of versican (VCAN) and matrix metalloproteinase-9 (MMP9) in the invasion and metastasis of lung adenocarcinoma (LUAD). Methods: Thirty LUAD specimens and their matched adjacent non-tumor tissues were collected. Immunohistochemistry (IHC) was performed to detect VCAN and MMP9 expressions. Human LUAD cell lines NCI-H1975 and A549 were employed as models. siRNA interference and plasmid overexpression, combined with rescue assays, were applied. Cell proliferation, migration, and invasion abilities were evaluated by CCK-8, scratch-healing assay, and Transwell assay, respectively. Gene and protein expression were detected by RT-qPCR and WB assay. Results: VCAN and MMP9 were significantly up-regulated in LUAD tissues compared with those in adjacent non-tumor tissues (both P < 0.001), and their H-score increased progressively with advancing tumor stage (both P < 0.01). In vitro experiments revealed that si-VCAN markedly reduced VCAN and MMP9 mRNA and protein levels and suppressed cell viability, migration, and invasion (all P < 0.01), whereas MMP9 overexpression significantly promoted these malignant phenotypes (all P < 0.001); these effects were reversed by si-VCAN (all P < 0.01). MMP9 knockdown did not significantly affect VCAN protein levels (P > 0.05). Conclusion: VCAN enhances the proliferation, migration, and invasion of LUAD cells by up-regulating MMP9. The VCAN/MMP9 axis may represent a potential therapeutic target for LUAD.
[Abstract] Objective: To investigate the roles and regulatory mechanisms of versican (VCAN) and matrix metalloproteinase-9 (MMP9) in the invasion and metastasis of lung adenocarcinoma (LUAD). Methods: Thirty LUAD specimens and their matched adjacent non-tumor tissues were collected. Immunohistochemistry (IHC) was performed to detect VCAN and MMP9 expressions. Human LUAD cell lines NCI-H1975 and A549 were employed as models. siRNA interference and plasmid overexpression, combined with rescue assays, were applied. Cell proliferation, migration, and invasion abilities were evaluated by CCK-8, scratch-healing assay, and Transwell assay, respectively. Gene and protein expression were detected by RT-qPCR and WB assay. Results: VCAN and MMP9 were significantly up-regulated in LUAD tissues compared with those in adjacent non-tumor tissues (both P < 0.001), and their H-score increased progressively with advancing tumor stage (both P < 0.01). In vitro experiments revealed that si-VCAN markedly reduced VCAN and MMP9 mRNA and protein levels and suppressed cell viability, migration, and invasion (all P < 0.01), whereas MMP9 overexpression significantly promoted these malignant phenotypes (all P < 0.001); these effects were reversed by si-VCAN (all P < 0.01). MMP9 knockdown did not significantly affect VCAN protein levels (P > 0.05). Conclusion: VCAN enhances the proliferation, migration, and invasion of LUAD cells by up-regulating MMP9. The VCAN/MMP9 axis may represent a potential therapeutic target for LUAD.
ZHOU Qiao
,
LI Meiling
,
CHEN Zhigang
,
WANG Zhuang
,
SHANG Sunyulin
,
XU Qiuling
,
ZHU Yanping
,
ZHANG Yili
2025, 32(8):862-869.
DOI: 10.3872/j.issn.1007-385X.2025.08.010
Abstract:
[Abstract] Objective: To create a luciferase (Luc) / green fluorescent protein (GFP) dual-fluorescent labeled tumor cell line and establish a detection method for the cytotoxic activity of human cascade-primed immune cell injection against non-small cell lung cancer (NSCLC), and to conduct preliminary verification. Methods: NSCLC lines, which possessed homozygous HLA-A, HLA-B, and HLA-C genotypes and an allelic distribution frequency higher than 2.500% were screened through high-resolution HLA typing for use as cell models. The cell line stably expressing the green fluorescent protein (GFP) and luciferase (Luc) was obtained through infecting the original cell line with a recombinant lentivirus that carries the GFP gene and Luc gene. This cell line was then used as the target cell. Through co-culturing effector cells and target cells as well as optimizing parameters including the pretreatment steps of target cells, co-culture duration, and effector-to-target proportion, a detection method for the cytotoxic activity of human cascade-primed immune cell injection against NSCLC was established, Subsequently, both the specificity and precision of this method were thoroughly verified. Results: Through high-resolution HLA typing, the non-small cell lung cancer cell line HCC827 harboring high-frequency alleles HLA-A11:01:01 (20.893%), HLA-B52:01:01 (2.991%), and HLA-C*12:02:02 (3.139%) was successfully selected as the cellular model. The HCC827 cell line with GFP and Luc dual fluorescence labeling was successfully constructed using a lentiviral vector, with a 96% GFP-positive rate. The titer of the recombinant lentivirus was 1.83 × 10? TU/mL. Significant differences in the cytotoxic activity were observed among groups with effector-to-target (E∶T) ratios of 5∶1, 10∶1, 15∶1, and 20∶1 (P < 0.05), and the cytotoxic activity increased significantly with prolonged co-culture duration (P < 0.000 1). After comprehensive evaluation, the optimal parameters were determined as an effector-to-target (E∶T) ratio of 10:1 and a co-culture duration of 72 h. Methodological verification demonstrated that the established method exhibited strong specificity, with a coefficient of variation of 0.80% - 1.86% for repeatability and 1.00% - 1.58% for precision. Furthermore, no significant differences were observed via variance analysis (P > 0.05), confirming good repeatability of the method. Conclusion: A detection method for the cytotoxic activity of human cascade-primed immune cell injection against NSCLC has been successfully established and verified. This method might help human cascade-primed immune cell injection play an important role in the effectiveness evaluation of cellular immunotherapy.
[Abstract] Objective: To create a luciferase (Luc) / green fluorescent protein (GFP) dual-fluorescent labeled tumor cell line and establish a detection method for the cytotoxic activity of human cascade-primed immune cell injection against non-small cell lung cancer (NSCLC), and to conduct preliminary verification. Methods: NSCLC lines, which possessed homozygous HLA-A, HLA-B, and HLA-C genotypes and an allelic distribution frequency higher than 2.500% were screened through high-resolution HLA typing for use as cell models. The cell line stably expressing the green fluorescent protein (GFP) and luciferase (Luc) was obtained through infecting the original cell line with a recombinant lentivirus that carries the GFP gene and Luc gene. This cell line was then used as the target cell. Through co-culturing effector cells and target cells as well as optimizing parameters including the pretreatment steps of target cells, co-culture duration, and effector-to-target proportion, a detection method for the cytotoxic activity of human cascade-primed immune cell injection against NSCLC was established, Subsequently, both the specificity and precision of this method were thoroughly verified. Results: Through high-resolution HLA typing, the non-small cell lung cancer cell line HCC827 harboring high-frequency alleles HLA-A11:01:01 (20.893%), HLA-B52:01:01 (2.991%), and HLA-C*12:02:02 (3.139%) was successfully selected as the cellular model. The HCC827 cell line with GFP and Luc dual fluorescence labeling was successfully constructed using a lentiviral vector, with a 96% GFP-positive rate. The titer of the recombinant lentivirus was 1.83 × 10? TU/mL. Significant differences in the cytotoxic activity were observed among groups with effector-to-target (E∶T) ratios of 5∶1, 10∶1, 15∶1, and 20∶1 (P < 0.05), and the cytotoxic activity increased significantly with prolonged co-culture duration (P < 0.000 1). After comprehensive evaluation, the optimal parameters were determined as an effector-to-target (E∶T) ratio of 10:1 and a co-culture duration of 72 h. Methodological verification demonstrated that the established method exhibited strong specificity, with a coefficient of variation of 0.80% - 1.86% for repeatability and 1.00% - 1.58% for precision. Furthermore, no significant differences were observed via variance analysis (P > 0.05), confirming good repeatability of the method. Conclusion: A detection method for the cytotoxic activity of human cascade-primed immune cell injection against NSCLC has been successfully established and verified. This method might help human cascade-primed immune cell injection play an important role in the effectiveness evaluation of cellular immunotherapy.
2025, 32(8):881-887.
DOI: 10.3872/j.issn.1007-385X.2025.08.012
Abstract:
[摘 要] 靶向蛋白质降解技术作为一种突破性治疗方法，在肿瘤治疗领域展现出替代传统抑制剂的巨大潜力。其中溶酶体靶 向嵌合体（LYTAC）是一种新兴技术，通过标记特定蛋白并将其引导至溶酶体降解，可有效降解癌细胞膜上的蛋白和细胞外靶蛋 白，突破了传统蛋白酶体依赖型降解技术的空间局限性。相较于蛋白水解靶向嵌合体等泛素-蛋白酶体依赖技术，LYTAC展现出 三大显著优势：（1）降解靶标范围扩展至传统“不可成药”靶点；（2）通过配体工程实现组织特异性递送；（3）克服获得性耐药机制。 重点评述LYTAC在肿瘤治疗中的突破性应用，尤其是同类首创的有效药物，强调了其在靶向难治性蛋白质方面的广泛应用潜 力，以期为研究人员提供全面参考，推动LYTAC技术的深入研究与临床转化。
[摘 要] 靶向蛋白质降解技术作为一种突破性治疗方法，在肿瘤治疗领域展现出替代传统抑制剂的巨大潜力。其中溶酶体靶 向嵌合体（LYTAC）是一种新兴技术，通过标记特定蛋白并将其引导至溶酶体降解，可有效降解癌细胞膜上的蛋白和细胞外靶蛋 白，突破了传统蛋白酶体依赖型降解技术的空间局限性。相较于蛋白水解靶向嵌合体等泛素-蛋白酶体依赖技术，LYTAC展现出 三大显著优势：（1）降解靶标范围扩展至传统“不可成药”靶点；（2）通过配体工程实现组织特异性递送；（3）克服获得性耐药机制。 重点评述LYTAC在肿瘤治疗中的突破性应用，尤其是同类首创的有效药物，强调了其在靶向难治性蛋白质方面的广泛应用潜 力，以期为研究人员提供全面参考，推动LYTAC技术的深入研究与临床转化。
2025, 32(8):888-895.
DOI: 10.3872/j.issn.1007-385X.2025.08.013
Abstract:
[摘 要] 基因突变、信号传导通路异常、表观遗传及代谢重编程会导致肿瘤获得性耐药，对治疗和预后造成了巨大挑战。驱动 蛋白家族成员14（KIF14）在多种肿瘤中高表达，调节肿瘤的增殖、侵袭、迁移和耐药。宫颈癌中高表达的KIF14促进PI3K/AKT通 路磷酸化激活，促进p21-S146位点磷酸化、p21活化激酶（PAK）和丝裂原活化蛋白激酶（MAPK）级联信号传导、BAX凋亡途径抑 制、DNA损伤修复，从而参与宫颈癌紫杉醇获得性耐药。PI3K/AKT通路中磷脂酰肌醇4,5-二磷酸3-激酶催化亚基α（PIK3CA）是 宫颈癌中最常发生的突变基因之一，介导紫杉醇和铂化合物获得性耐药。放化疗等DNA损伤疗法通过PI3K相关蛋白激酶 （PIKK）家族成员ATM和ATR促进p-KIFC1-S26稳定HeLa细胞中KIF14家族成员KIFC1蛋白表达，触发中心体扩增和聚集，介 导获得性耐药/耐放疗。表观遗传重编程调控基因表达，KIF14表达水平受启动子区CpG位点甲基化、组蛋白去甲基化酶赖氨酸 去甲基化酶3A（KDM3A）、circRNA/lncRNA-miRNA-mRNA网络和m6A修饰的调控。综述KIF14遗传及表观遗传在泛癌中的作 用，重点讨论KIF14对宫颈癌增殖、侵袭、迁移、耐药等恶性生物表型的作用和机制，为逆转宫颈癌化疗耐药提供新的可能性。
[摘 要] 基因突变、信号传导通路异常、表观遗传及代谢重编程会导致肿瘤获得性耐药，对治疗和预后造成了巨大挑战。驱动 蛋白家族成员14（KIF14）在多种肿瘤中高表达，调节肿瘤的增殖、侵袭、迁移和耐药。宫颈癌中高表达的KIF14促进PI3K/AKT通 路磷酸化激活，促进p21-S146位点磷酸化、p21活化激酶（PAK）和丝裂原活化蛋白激酶（MAPK）级联信号传导、BAX凋亡途径抑 制、DNA损伤修复，从而参与宫颈癌紫杉醇获得性耐药。PI3K/AKT通路中磷脂酰肌醇4,5-二磷酸3-激酶催化亚基α（PIK3CA）是 宫颈癌中最常发生的突变基因之一，介导紫杉醇和铂化合物获得性耐药。放化疗等DNA损伤疗法通过PI3K相关蛋白激酶 （PIKK）家族成员ATM和ATR促进p-KIFC1-S26稳定HeLa细胞中KIF14家族成员KIFC1蛋白表达，触发中心体扩增和聚集，介 导获得性耐药/耐放疗。表观遗传重编程调控基因表达，KIF14表达水平受启动子区CpG位点甲基化、组蛋白去甲基化酶赖氨酸 去甲基化酶3A（KDM3A）、circRNA/lncRNA-miRNA-mRNA网络和m6A修饰的调控。综述KIF14遗传及表观遗传在泛癌中的作 用，重点讨论KIF14对宫颈癌增殖、侵袭、迁移、耐药等恶性生物表型的作用和机制，为逆转宫颈癌化疗耐药提供新的可能性。
2025, 32(8):8670-880.
DOI: 10.3872/j.issn.1007-385X.2025.08.011
Abstract:
[摘 要] 乳腺癌（BC）是全球最常见的恶性肿瘤之一，其细胞代谢具有高度的可塑性，可以根据环境变化适应不同的代谢需 求，这种现象被称为代谢重编程。BC细胞通过调控多种代谢通路，包括糖代谢、脂质代谢、谷氨酰胺代谢等，改变细胞表型，促进 细胞增殖、侵袭、转移及耐药性。糖代谢的关键蛋白GLUT1、HK2、PHGDH等的表达紊乱促进了糖酵解过程，增强肿瘤细胞的生 长与转移能力。脂肪酸合成和氧化代谢的平衡为BC细胞提供了生存和增殖的优势。谷氨酰胺作为细胞的重要碳源和氮源，一 方面通过补充作用增强三羧酸循环的通量，进一步支持BC细胞的代谢需求，另一方面通过维持氧化还原平衡促进BC细胞的免 疫逃避及治疗耐药。本文旨在全面总结BC中能量物质代谢的重编程现象及其已知的关键调控机制，为发现新的治疗靶点、优化 治疗策略、阐明耐药机制以及克服耐药性提供宝贵参考。
[摘 要] 乳腺癌（BC）是全球最常见的恶性肿瘤之一，其细胞代谢具有高度的可塑性，可以根据环境变化适应不同的代谢需 求，这种现象被称为代谢重编程。BC细胞通过调控多种代谢通路，包括糖代谢、脂质代谢、谷氨酰胺代谢等，改变细胞表型，促进 细胞增殖、侵袭、转移及耐药性。糖代谢的关键蛋白GLUT1、HK2、PHGDH等的表达紊乱促进了糖酵解过程，增强肿瘤细胞的生 长与转移能力。脂肪酸合成和氧化代谢的平衡为BC细胞提供了生存和增殖的优势。谷氨酰胺作为细胞的重要碳源和氮源，一 方面通过补充作用增强三羧酸循环的通量，进一步支持BC细胞的代谢需求，另一方面通过维持氧化还原平衡促进BC细胞的免 疫逃避及治疗耐药。本文旨在全面总结BC中能量物质代谢的重编程现象及其已知的关键调控机制，为发现新的治疗靶点、优化 治疗策略、阐明耐药机制以及克服耐药性提供宝贵参考。
联系方式
- 《中国肿瘤生物治疗杂志》
- 1994年创刊
- 主办单位：Chinese Society of Immunology, Chinese Anti-cancer Association
- 邮编：200433
- 电话：021-81871002-22
- 电子邮箱：cjcb@biother.cn
- 网址:http://www.biother.cn
- 刊号：ISSN 1007-385X
- CN 31-1725/R
- 国内定价： ￥20元/册
您是第位访问者
Chinese Journal Of Cancer Biotheray ® 2025 All Rights Reserved
Supported by:Beijing E-Tiller Technology Development Co., Ltd.
Chinese Journal Of Cancer Biotheray ® 2025 All Rights Reserved
Supported by:Beijing E-Tiller Technology Development Co., Ltd.