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Volume 29,Issue 4,2022 Table of Contents
2022, 29(4):267-275.
DOI: 10.3872/j.issn.1007-385X.2022.04.001
Abstract:
Tumor-associated macrophages (TAMs), key players in tumor development, metastasis and drug resistance, contain two polarizable phenotypes: inflammatory, tumor-inhibitory M1 type and anti-inflammatory, tumor-promoting M2 type. Epigenetic regulation plays a distinct role in functional programming of TAMs in the tumor microenvironment. It determines the polarization and function of TAMs mainly through mediating transcriptional or post-transcriptional regulation of polarization-related signal pathways, cytokines, metabolic enzymes, key transcription factors, MHC and its regulators. Therefore, epigenetic regulation-based inhibition of M2 polarization and promotion of M1 polarization to induce functional reprogramming of TAMs has gradually developed into a novel strategy in the field of antitumor immunotherapy. Identification of more specific and pivotal mechanisms in epigenetic regulation of TAMs and development of new TAM-targeting epigenetic drug delivery system, combined with other antitumor therapies, might improve targeting specificity of epigenetic regulation of TAMs, reduce adverse effects and achieve better antitumor effects.
Tumor-associated macrophages (TAMs), key players in tumor development, metastasis and drug resistance, contain two polarizable phenotypes: inflammatory, tumor-inhibitory M1 type and anti-inflammatory, tumor-promoting M2 type. Epigenetic regulation plays a distinct role in functional programming of TAMs in the tumor microenvironment. It determines the polarization and function of TAMs mainly through mediating transcriptional or post-transcriptional regulation of polarization-related signal pathways, cytokines, metabolic enzymes, key transcription factors, MHC and its regulators. Therefore, epigenetic regulation-based inhibition of M2 polarization and promotion of M1 polarization to induce functional reprogramming of TAMs has gradually developed into a novel strategy in the field of antitumor immunotherapy. Identification of more specific and pivotal mechanisms in epigenetic regulation of TAMs and development of new TAM-targeting epigenetic drug delivery system, combined with other antitumor therapies, might improve targeting specificity of epigenetic regulation of TAMs, reduce adverse effects and achieve better antitumor effects.
2022, 29(4):276-283.
DOI: 10.3872/j.issn.1007-385X.2022.04.002
Abstract:
The specific recognition and binding of tumor cells are crucial to targeted therapy. However, lacking effective targets is still the main challenge for targeted therapy. Glycan metabolic labeling provides a potential approach for tumor targeted therapy with advantages of in vivo labeling, high labeling efficiency, low toxicity and less interference. Through labeling tumor cells with hapten, antigen, chemotherapeutic drugs and cytotoxic drugs, labeling strategy based on glycan metabolism realizes the specific recognition of tumor cells or stimulates cellular and humoral immune responses in vivo. In addition, through labeling immune cells, this strategy also improves immune cells’specific recognition and binding of tumor cells. The strategy of glycan metabolic labeling provides broad application prospects in tumor targeted therapy.
The specific recognition and binding of tumor cells are crucial to targeted therapy. However, lacking effective targets is still the main challenge for targeted therapy. Glycan metabolic labeling provides a potential approach for tumor targeted therapy with advantages of in vivo labeling, high labeling efficiency, low toxicity and less interference. Through labeling tumor cells with hapten, antigen, chemotherapeutic drugs and cytotoxic drugs, labeling strategy based on glycan metabolism realizes the specific recognition of tumor cells or stimulates cellular and humoral immune responses in vivo. In addition, through labeling immune cells, this strategy also improves immune cells’specific recognition and binding of tumor cells. The strategy of glycan metabolic labeling provides broad application prospects in tumor targeted therapy.
2022, 29(4):284-293.
DOI: 10.3872/j.issn.1007-385X.2022.04.003
Abstract:
Objective: To explore the promotive effect of anti-HSP90 monoclonal antibody mAb 28C10 on Cisplatin (DDP) inhibiting malignant biological behavior of human gastric cancer PAMC82 cells by targeting tumor stem cells and the possible mechanisms of action. Methods: Human gastric cancer PAMC82 cells were treated with 28C10 alone or in combination with DDP. Then, the serum- free pellet-forming ability, clone-forming ability, migration and invasion ability of PAMC82 cells were detected by different experiments, and the effects of 28C10 on the malignant biological behaviors of PAMC82 cells and the synergistic anti-cancer effect of 28C10 and DDP were detected by CCK-8 method. The expression, localization, eHSP90 + subgroup ratio of HSP90 and eHSP90 (extracellular HSP90) in PAMC82 cells and the effects of 28C10 on ALDH + , CD44 + , eHSP90 + subgroups of PAMC82 cells were detected by cellular immunofluorescence and flow cytometry. The changes in HSP90, stemness-related proteins and PI3K/AKT/mTOR signaling pathway in PAMC82 cells treated with 28C10 were detected by WB. Results: eHSP90 was expressed on the membrane surface of gastric cancer PAMC82 cells, and there were about 2%-3% of eHSP90 + subgroup cells. eHSP90 + cells were mostly co-positive with ALDH + or CD44 + cells. 28C10 significantly inhibited the ability of pellet formation, clone formation, proliferation, drug resistance, migration and invasion of PAMC82 cells; moreover, the effect was more obvious when combined with DDP (all P<0.05 or P<0.01). Flow cytometry analysis showed that 28C10 treatment significantly inhibited the number of eHSP90 + , ALDH + and CD44 + subgroups of PAMC82 cells (all P<0.01). Immunofluorescence assay showed that endocytosis of eHSP90 occurred after 28C10 treatment. WB results showed that the expression levels of eHSP90, CD44, ALDH and the expression of stemness-related proteins OCT4 and SOX2 were decreased (P<0.05 or P<0.01). Conclusion: 28C10 can target ALDH + and CD44 + tumor stem cell-related subgroups of gastric cancer PAMC82 cells, internalize eHSP90, reduce the level of total HSP90, and inhibit PI3K/AKT/mTOR signaling pathway, thereby effectively inhibiting stemness, drug resistance and other malignant biological behaviors of PAMC82 cells and synergistically improving the anticancer effect of DDP.
Objective: To explore the promotive effect of anti-HSP90 monoclonal antibody mAb 28C10 on Cisplatin (DDP) inhibiting malignant biological behavior of human gastric cancer PAMC82 cells by targeting tumor stem cells and the possible mechanisms of action. Methods: Human gastric cancer PAMC82 cells were treated with 28C10 alone or in combination with DDP. Then, the serum- free pellet-forming ability, clone-forming ability, migration and invasion ability of PAMC82 cells were detected by different experiments, and the effects of 28C10 on the malignant biological behaviors of PAMC82 cells and the synergistic anti-cancer effect of 28C10 and DDP were detected by CCK-8 method. The expression, localization, eHSP90 + subgroup ratio of HSP90 and eHSP90 (extracellular HSP90) in PAMC82 cells and the effects of 28C10 on ALDH + , CD44 + , eHSP90 + subgroups of PAMC82 cells were detected by cellular immunofluorescence and flow cytometry. The changes in HSP90, stemness-related proteins and PI3K/AKT/mTOR signaling pathway in PAMC82 cells treated with 28C10 were detected by WB. Results: eHSP90 was expressed on the membrane surface of gastric cancer PAMC82 cells, and there were about 2%-3% of eHSP90 + subgroup cells. eHSP90 + cells were mostly co-positive with ALDH + or CD44 + cells. 28C10 significantly inhibited the ability of pellet formation, clone formation, proliferation, drug resistance, migration and invasion of PAMC82 cells; moreover, the effect was more obvious when combined with DDP (all P<0.05 or P<0.01). Flow cytometry analysis showed that 28C10 treatment significantly inhibited the number of eHSP90 + , ALDH + and CD44 + subgroups of PAMC82 cells (all P<0.01). Immunofluorescence assay showed that endocytosis of eHSP90 occurred after 28C10 treatment. WB results showed that the expression levels of eHSP90, CD44, ALDH and the expression of stemness-related proteins OCT4 and SOX2 were decreased (P<0.05 or P<0.01). Conclusion: 28C10 can target ALDH + and CD44 + tumor stem cell-related subgroups of gastric cancer PAMC82 cells, internalize eHSP90, reduce the level of total HSP90, and inhibit PI3K/AKT/mTOR signaling pathway, thereby effectively inhibiting stemness, drug resistance and other malignant biological behaviors of PAMC82 cells and synergistically improving the anticancer effect of DDP.
2022, 29(4):294-300.
DOI: 10.3872/j.issn.1007-385X.2022.04.004
Abstract:
Objective: To detect the expression of miR-452-5p in esophageal squamous cell cancer (ESCC) tissues, and to explore the effect of aberrant miR-452-5p expression on the proliferation, invasion and EMT process of esophageal cancer KYSE-150 cells as well as the possible molecular mechanism. Methods: Cancer tissue samples and corresponding paracancerous tissues were collected from 86 ESCC patients treated at the Fourth Hospital of Hebei Medical University from March 2012 to December 2015. The expression levels of miR-452-5p and other related genes were detected by qPCR method. KYSE-150 cells were transfected with miR-452-5p mimic or pcDNA3.1- SOX7 to construct over-expressed cell lines. Analysis of the relationship between miR-452-5p expression and ESCC pathological features and 5-year OS of patients. MTS and transwell assay were performed to assess the effect of miR-452-5p over-expression on proliferation, invasion and EMT progress of KYSE-150 cells. The interaction between miR-452-5p and SRY-box transcription factor 7 （SOX7）3'UTR and the activation of Wnt/β-catenin pathway were detected by Dual-luciferase reporter gene assay andTOP/FOPreporter gene system. Results: The expression of miR-452-5p was significantly up-regulated in ESCC tissues (P<0.01). High expression of miR-452-5p was correlated with the lymph node metastasis, TNM stage and the 5-year OS of ESCC patients (all P<0.01). Over-expression of miR-452-5p significantly promoted proliferation, invasion ability and the EMT process in KYSE-150 cells (P<0.05 or P<0.01). SOX7 was predicted to be the direct target gene of miR-452-5p. miR-452-5p affected the activation level of Wnt pathway through targeted regulation of SOX7 (P<0.05 or P<0.01).At the same time, the expression of miR-452-5p was also regulated by the activation level of Wnt pathway, and miR-452-5p might be a downstream target gene of Wnt pathway (P<0.05 or P<0.01). Conclusion: miR-452-5p promotes the activation level of Wnt pathway through miR-452-5p/SOX7/Wnt/miR-452-5p positive feedback loop, which further promoting the proliferation, invasion and the EMT process of esophageal cancer KYSE-150 cells. miR-452-5p is expected to be a potential target for molecular therapy and a novel molecular markerfortheprognosisevaluationofESCCpatients.
Objective: To detect the expression of miR-452-5p in esophageal squamous cell cancer (ESCC) tissues, and to explore the effect of aberrant miR-452-5p expression on the proliferation, invasion and EMT process of esophageal cancer KYSE-150 cells as well as the possible molecular mechanism. Methods: Cancer tissue samples and corresponding paracancerous tissues were collected from 86 ESCC patients treated at the Fourth Hospital of Hebei Medical University from March 2012 to December 2015. The expression levels of miR-452-5p and other related genes were detected by qPCR method. KYSE-150 cells were transfected with miR-452-5p mimic or pcDNA3.1- SOX7 to construct over-expressed cell lines. Analysis of the relationship between miR-452-5p expression and ESCC pathological features and 5-year OS of patients. MTS and transwell assay were performed to assess the effect of miR-452-5p over-expression on proliferation, invasion and EMT progress of KYSE-150 cells. The interaction between miR-452-5p and SRY-box transcription factor 7 （SOX7）3'UTR and the activation of Wnt/β-catenin pathway were detected by Dual-luciferase reporter gene assay andTOP/FOPreporter gene system. Results: The expression of miR-452-5p was significantly up-regulated in ESCC tissues (P<0.01). High expression of miR-452-5p was correlated with the lymph node metastasis, TNM stage and the 5-year OS of ESCC patients (all P<0.01). Over-expression of miR-452-5p significantly promoted proliferation, invasion ability and the EMT process in KYSE-150 cells (P<0.05 or P<0.01). SOX7 was predicted to be the direct target gene of miR-452-5p. miR-452-5p affected the activation level of Wnt pathway through targeted regulation of SOX7 (P<0.05 or P<0.01).At the same time, the expression of miR-452-5p was also regulated by the activation level of Wnt pathway, and miR-452-5p might be a downstream target gene of Wnt pathway (P<0.05 or P<0.01). Conclusion: miR-452-5p promotes the activation level of Wnt pathway through miR-452-5p/SOX7/Wnt/miR-452-5p positive feedback loop, which further promoting the proliferation, invasion and the EMT process of esophageal cancer KYSE-150 cells. miR-452-5p is expected to be a potential target for molecular therapy and a novel molecular markerfortheprognosisevaluationofESCCpatients.
2022, 29(4):301-307.
DOI: 10.3872/j.issn.1007-385X.2022.04.005
Abstract:
Objective: To evaluate the effect of oral administration of recombinant Bifidobacterium breve (B.breve) carrying HPV16 E7 shRNA and IL-12 gene in mice against cervical cancer xenografts. Methods: pMG36e-E7 shRNA and pMG36e-mIL-12D plasmids were used to modify the B.breve. After screening, verification and amplification, recombinant B.breve carrying HPV16 E7 shRNA and IL-12 gene were obtained. Tumor-bearing mouse model was established by subcutaneously injecting cervical cancer cells. On the 1st and 7th day after oral administration, the tumor-targeting property of recombinant B.breve were evaluated by counting the number of bacteria colonies formed in the homogenate of mouse major organs (heart, liver, spleen, lung and kidney) and tumor tissues or serum that cultured in PYG medium. The antitumor effect of recombinant B.breve was evaluated by in vivo tumor growth curve. The safety of oral administration of recombinant B.breve was evaluated by H-E staining of the tissue sections from major organs and determination of the levels of related cytokines in serum of tumor-bearing mice. Results: Recombinant B.breve and cervical TC-1 cell transplanted tumor bearing mice were successfully established. After 7 days, the number of colonies in the homogenate of tumor tissues and serum confirmed that recombinant B.breve had the property of targeting tumor tissues in vivo. Oral administration of recombinant B.breve significantly suppressed tumor growth in tumor-bearing mice (P<0.05 or P<0.01); however, there was no significant difference in tumor inhibition rate between the recombinant B.breve carrying both HPV16 E7 shRNA and IL-12 gene and those carrying single one. After the treatment, no major organ damage or significant changes in serum IL-12 and IFN-γ levels was observed in tumor-bearing mice. Conclusion: B. breve can be used as a safe and controllable therapeutic molecular delivery vehicle for targeting tumors, which exert significant treatment efficacy against cervical cancer xenografts.
Objective: To evaluate the effect of oral administration of recombinant Bifidobacterium breve (B.breve) carrying HPV16 E7 shRNA and IL-12 gene in mice against cervical cancer xenografts. Methods: pMG36e-E7 shRNA and pMG36e-mIL-12D plasmids were used to modify the B.breve. After screening, verification and amplification, recombinant B.breve carrying HPV16 E7 shRNA and IL-12 gene were obtained. Tumor-bearing mouse model was established by subcutaneously injecting cervical cancer cells. On the 1st and 7th day after oral administration, the tumor-targeting property of recombinant B.breve were evaluated by counting the number of bacteria colonies formed in the homogenate of mouse major organs (heart, liver, spleen, lung and kidney) and tumor tissues or serum that cultured in PYG medium. The antitumor effect of recombinant B.breve was evaluated by in vivo tumor growth curve. The safety of oral administration of recombinant B.breve was evaluated by H-E staining of the tissue sections from major organs and determination of the levels of related cytokines in serum of tumor-bearing mice. Results: Recombinant B.breve and cervical TC-1 cell transplanted tumor bearing mice were successfully established. After 7 days, the number of colonies in the homogenate of tumor tissues and serum confirmed that recombinant B.breve had the property of targeting tumor tissues in vivo. Oral administration of recombinant B.breve significantly suppressed tumor growth in tumor-bearing mice (P<0.05 or P<0.01); however, there was no significant difference in tumor inhibition rate between the recombinant B.breve carrying both HPV16 E7 shRNA and IL-12 gene and those carrying single one. After the treatment, no major organ damage or significant changes in serum IL-12 and IFN-γ levels was observed in tumor-bearing mice. Conclusion: B. breve can be used as a safe and controllable therapeutic molecular delivery vehicle for targeting tumors, which exert significant treatment efficacy against cervical cancer xenografts.
2022, 29(4):308-316.
DOI: 10.3872/j.issn.1007-385X.2022.04.006
Abstract:
Objective: To explore the value of inflammatory markers in predicting the efficacy and safety of anti-PD-1 therapy in patients with advanced NSCLC. Methods: Dynamically monitored the serum inflammatory markers of 222 patients with advanced NSCLC who accepted anti-PD-1 treatment at the First Affiliated Hospital of Navy Medical University between January 2018 and December 2020. The ROC curve was used to calculate the optimal cut-off value and the inflammatory indexes were divided into two groups: high and low levels. Log-Rank test and Kaplan-Meier method were used to analyze the relationship between patients’ clinicopathological characteristics , their levels of inflammatory markers and patients’prognosis. Univariate and multivariate Cox regression analysis were used to estimate hazard ratios for PFS and OS. Fisher's exact test was used to analyze the correlation between the baseline levels of inflammatory markers for the high and low level groups and irAE. The Wilcoxon rank test was used to compare the differences between the levels of inflammatory markers before treatment (baseline) and those at the time of the first PR or the first PD and those at the occurrence of irAE. Results: Elevated baseline levels of NLR, MLR, PLR, LDH, CRP and IL-6 were associated with significantly shorter PFS and OS (P<0.01). The results of multivariate analysis showed that elevated baseline levels of PLR, MLR and LDH were independent risk factors for PFS and OS (P<0.05 or P<0.01). The levels of NLR, LDH, CRP and IL-6 decreased significantly when the patients first obtained PR (P<0.05 or P<0.01), and the levels of LDH, CRP, IL-6 and TNF- αincreased significantly when PD occurred (P<0.05 or P<0.01). Compared with the baseline levels, the levels of LDH, CRP, IL-6, IL-10 and TNF-α at the occurrence of irAE increased significantly (P<0.05 or P<0.01). Conclusion: In NSCLC anti-PD-1 therapy, a decrease in the levels of inflammatory markers indicated an improvement of the patient's disease, while an increase indicated progression of the disease and was associated with the occurrence of irAE. Dynamic monitoring of inflammatory markers can predict the efficacy and safety of anti-PD-1 therapy and may contribute to selecting the most eligible advanced NSCLC patients for anti-PD-1 therapy.
Objective: To explore the value of inflammatory markers in predicting the efficacy and safety of anti-PD-1 therapy in patients with advanced NSCLC. Methods: Dynamically monitored the serum inflammatory markers of 222 patients with advanced NSCLC who accepted anti-PD-1 treatment at the First Affiliated Hospital of Navy Medical University between January 2018 and December 2020. The ROC curve was used to calculate the optimal cut-off value and the inflammatory indexes were divided into two groups: high and low levels. Log-Rank test and Kaplan-Meier method were used to analyze the relationship between patients’ clinicopathological characteristics , their levels of inflammatory markers and patients’prognosis. Univariate and multivariate Cox regression analysis were used to estimate hazard ratios for PFS and OS. Fisher's exact test was used to analyze the correlation between the baseline levels of inflammatory markers for the high and low level groups and irAE. The Wilcoxon rank test was used to compare the differences between the levels of inflammatory markers before treatment (baseline) and those at the time of the first PR or the first PD and those at the occurrence of irAE. Results: Elevated baseline levels of NLR, MLR, PLR, LDH, CRP and IL-6 were associated with significantly shorter PFS and OS (P<0.01). The results of multivariate analysis showed that elevated baseline levels of PLR, MLR and LDH were independent risk factors for PFS and OS (P<0.05 or P<0.01). The levels of NLR, LDH, CRP and IL-6 decreased significantly when the patients first obtained PR (P<0.05 or P<0.01), and the levels of LDH, CRP, IL-6 and TNF- αincreased significantly when PD occurred (P<0.05 or P<0.01). Compared with the baseline levels, the levels of LDH, CRP, IL-6, IL-10 and TNF-α at the occurrence of irAE increased significantly (P<0.05 or P<0.01). Conclusion: In NSCLC anti-PD-1 therapy, a decrease in the levels of inflammatory markers indicated an improvement of the patient's disease, while an increase indicated progression of the disease and was associated with the occurrence of irAE. Dynamic monitoring of inflammatory markers can predict the efficacy and safety of anti-PD-1 therapy and may contribute to selecting the most eligible advanced NSCLC patients for anti-PD-1 therapy.
2022, 29(4):317-326.
DOI: 10.3872/j.issn.1007-385X.2022.04.007
Abstract:
Objective: To investigate the expression of hypoxia inducible factor 1 subunit alpha (HIF1A) in breast cancer (BC) and its relationship with prognosis and tumor immune cell infiltration in BC based on various cancer bioinformatics databases. Methods: The expression of HIF1A gene in BC tissues and its correlation with the prognosis and clinicopathological characteristics of patients were analyzed using the Oncomine, the Human Protein Atlas and TCGA databases, which were then verified in human breast cancer tissue specimens (93 cases of breast cancer tissues and 14 cases of benign breast disease tissues surgically resected from January 2011 to December 2015 in Renmin Hospital of Wuhan University). Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted to analyze the differentially expressed genes between HIF1A-high and HIF1A- low expression groups. The differences in the abundance of immune cell infiltration in samples with high and low HIF1A expression were assessed by CIBERSORT. Results: As indicated by bioinformatics data, HIF1A was highly expressed in BC tissues and predicted a better prognosis (P<0.05). The expression of HIF1A was associated with estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) levels in BC (all P<0.05). The GO biological function analysis and KEGG pathway enrichment analysis suggested that HIF1A might be involved in tumor immunoregulation. CIBERSORT analysis suggested the correlation between HIF1A and tumor immune cell infiltration, and found that activated memory CD4 + T cells, M0 and M1 macrophages were positively correlated with HIF1A expression, while Treg cells, activated NK cells, and M2 macrophages were negatively correlated with HIF1A expression (all P<0.05). Conclusion: HIF1A is involved in regulating the immunological activity of the tumor microenvironment and is related to the disease-free survival (DFS) of breast cancer patients. It can be served as a biomarker for graded diagnosis, immunotherapy and prognosis judgment of BC.
Objective: To investigate the expression of hypoxia inducible factor 1 subunit alpha (HIF1A) in breast cancer (BC) and its relationship with prognosis and tumor immune cell infiltration in BC based on various cancer bioinformatics databases. Methods: The expression of HIF1A gene in BC tissues and its correlation with the prognosis and clinicopathological characteristics of patients were analyzed using the Oncomine, the Human Protein Atlas and TCGA databases, which were then verified in human breast cancer tissue specimens (93 cases of breast cancer tissues and 14 cases of benign breast disease tissues surgically resected from January 2011 to December 2015 in Renmin Hospital of Wuhan University). Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted to analyze the differentially expressed genes between HIF1A-high and HIF1A- low expression groups. The differences in the abundance of immune cell infiltration in samples with high and low HIF1A expression were assessed by CIBERSORT. Results: As indicated by bioinformatics data, HIF1A was highly expressed in BC tissues and predicted a better prognosis (P<0.05). The expression of HIF1A was associated with estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) levels in BC (all P<0.05). The GO biological function analysis and KEGG pathway enrichment analysis suggested that HIF1A might be involved in tumor immunoregulation. CIBERSORT analysis suggested the correlation between HIF1A and tumor immune cell infiltration, and found that activated memory CD4 + T cells, M0 and M1 macrophages were positively correlated with HIF1A expression, while Treg cells, activated NK cells, and M2 macrophages were negatively correlated with HIF1A expression (all P<0.05). Conclusion: HIF1A is involved in regulating the immunological activity of the tumor microenvironment and is related to the disease-free survival (DFS) of breast cancer patients. It can be served as a biomarker for graded diagnosis, immunotherapy and prognosis judgment of BC.
2022, 29(4):327-331.
DOI: 10.3872/j.issn.1007-385X.2022.04.008
Abstract:
Objective: To investigate the expression of hsa_circ_0087378 in esophageal squamous cell carcinoma (ESCC) tissues, and its effect on the clinicopathological characteristics and prognosis of ESCC patients. Methods: The differentially expressed circRNAs between ESCC tissues and corresponding para-cancerous tissues were screened by GEO database, which were then validated in 10 pairs of ESCC tissues and corresponding para-cancerous tissues by qPCR method. 90 pairs of cancer tissues and corresponding para-cancerous tissues resected from ESCC patients who admitted to the Fourth Hospital of Hebei Medical University from October 2015 to April 2016 were collected to detect the expression of hsa_circ_0087378 by FISH method, and the relationship between the expression of hsa_circ_0087378 and the clinicopathological indicators and prognosis of ESCC patients were also analyzed. Results: GEO database and qPCR analysis results showed that hsa_circ_0087378 was significantly up-regulated in ESCC tissues. FISH results showed that hsa_circ_0087378 were highly expressed in 21 (23.3%) of 90 cases of para-cancerous tissues, but in 65 (72.2%) of 90 cases of ESCC tissues. The hsa_circ_0087378 over-expression rate in ESCC tissues was significantly higher than that in para-cancerous tissues (P<0.05). The high expression of hsa_circ_0087378 in ESCC tissues was related to the clinical stage and lymph node metastasis of ESCC patients (P<0.05). The 5-year overall survival rate of patients with high hsa_circ_0087378 expression was significantly lower than that in patients with low circ_0087378 expression (P<0.05). Conclusion: hsa_circ_0087378 is highly expressed in ESCC tissues and positively correlated with the clinical stage, lymph node metastasis, and poor prognosis of patients, suggesting that hsa_circ_0087378 can be used as a potential therapeutic target for ESCC.
Objective: To investigate the expression of hsa_circ_0087378 in esophageal squamous cell carcinoma (ESCC) tissues, and its effect on the clinicopathological characteristics and prognosis of ESCC patients. Methods: The differentially expressed circRNAs between ESCC tissues and corresponding para-cancerous tissues were screened by GEO database, which were then validated in 10 pairs of ESCC tissues and corresponding para-cancerous tissues by qPCR method. 90 pairs of cancer tissues and corresponding para-cancerous tissues resected from ESCC patients who admitted to the Fourth Hospital of Hebei Medical University from October 2015 to April 2016 were collected to detect the expression of hsa_circ_0087378 by FISH method, and the relationship between the expression of hsa_circ_0087378 and the clinicopathological indicators and prognosis of ESCC patients were also analyzed. Results: GEO database and qPCR analysis results showed that hsa_circ_0087378 was significantly up-regulated in ESCC tissues. FISH results showed that hsa_circ_0087378 were highly expressed in 21 (23.3%) of 90 cases of para-cancerous tissues, but in 65 (72.2%) of 90 cases of ESCC tissues. The hsa_circ_0087378 over-expression rate in ESCC tissues was significantly higher than that in para-cancerous tissues (P<0.05). The high expression of hsa_circ_0087378 in ESCC tissues was related to the clinical stage and lymph node metastasis of ESCC patients (P<0.05). The 5-year overall survival rate of patients with high hsa_circ_0087378 expression was significantly lower than that in patients with low circ_0087378 expression (P<0.05). Conclusion: hsa_circ_0087378 is highly expressed in ESCC tissues and positively correlated with the clinical stage, lymph node metastasis, and poor prognosis of patients, suggesting that hsa_circ_0087378 can be used as a potential therapeutic target for ESCC.
2022, 29(4):332-337.
DOI: 10.3872/j.issn.1007-385X.2022.04.009
Abstract:
Objective: To investigate the changes in PD-1/PD-L1 pathway and related immune cells in the occurrence and development of cervical squamous cell cancer (CSCC) and their clinical significance. Methods: Cervical tissue/cancerous tissue and peripheral blood samples were collected from CSCC patients who underwent surgery and healthy controls who had physical examination at the First Hospital of Fuzhou City from December 2018 to September 2020 and were divided into healthy control group, cervical intraepithelial neoplasia (CIN) grade Ⅱ group, CIN grade Ⅲ group, and CSCC group to represent the occurrence and development of CSCC (n=50 in each group). The expression levels of PD-1, PD-L1 and forkhead box transcription factor P3 (FOXP3) in the peripheral blood of each group were detected by ELISA, the numbers of PD-1 + CD4 + CD25 + CD127 -/low cells in the peripheral blood of each group were detected by FCM, and the distribution of tumor-invasive lymphocytes (TIL) in CSCC tissues was detected by multicolor fluorescent immunohistochemistry. Results: The expression of PD-1, PD-L1 and FOXP3 in peripheral blood tended to increase with the onset and progression of mock CSCC and to decrease after surgery. The proportion of CD4 + , CD4 + CD25 + CD127 -/low and PD-1 + CD4 + CD25 + CD127 -/low cells in lymphocytes increased in the anticoagulated whole blood of CSCC patients. Massive infiltration of CD4 + , CD8 + and FOXP3 + cells was observed in CSCC tissues, with CD4 + and FOXP3 + cells mainly distributed around tumor cells and CD8 + and PD-L1 + cells widely and diffusely distributed. Conclusion: PD-1, PD-L1, FOXP3 and adaptive regulatory T cells are important factors contributing to the development of CSCC, which can be used as potential immunotherapeutic targets and potential prognostic markers for CSCC.
Objective: To investigate the changes in PD-1/PD-L1 pathway and related immune cells in the occurrence and development of cervical squamous cell cancer (CSCC) and their clinical significance. Methods: Cervical tissue/cancerous tissue and peripheral blood samples were collected from CSCC patients who underwent surgery and healthy controls who had physical examination at the First Hospital of Fuzhou City from December 2018 to September 2020 and were divided into healthy control group, cervical intraepithelial neoplasia (CIN) grade Ⅱ group, CIN grade Ⅲ group, and CSCC group to represent the occurrence and development of CSCC (n=50 in each group). The expression levels of PD-1, PD-L1 and forkhead box transcription factor P3 (FOXP3) in the peripheral blood of each group were detected by ELISA, the numbers of PD-1 + CD4 + CD25 + CD127 -/low cells in the peripheral blood of each group were detected by FCM, and the distribution of tumor-invasive lymphocytes (TIL) in CSCC tissues was detected by multicolor fluorescent immunohistochemistry. Results: The expression of PD-1, PD-L1 and FOXP3 in peripheral blood tended to increase with the onset and progression of mock CSCC and to decrease after surgery. The proportion of CD4 + , CD4 + CD25 + CD127 -/low and PD-1 + CD4 + CD25 + CD127 -/low cells in lymphocytes increased in the anticoagulated whole blood of CSCC patients. Massive infiltration of CD4 + , CD8 + and FOXP3 + cells was observed in CSCC tissues, with CD4 + and FOXP3 + cells mainly distributed around tumor cells and CD8 + and PD-L1 + cells widely and diffusely distributed. Conclusion: PD-1, PD-L1, FOXP3 and adaptive regulatory T cells are important factors contributing to the development of CSCC, which can be used as potential immunotherapeutic targets and potential prognostic markers for CSCC.
2022, 29(4):338-344.
DOI: 10.3872/j.issn.1007-385X.2022.04.010
Abstract:
Objective: To systematically review the effectiveness and safety of single-agent programmed cell death-1 (PD-1) inhibitors versus the second-line chemotherapy in advanced esophageal squamous cell carcinoma (ESCC) patients in order to provide optimal evidence-based medical proof for clinical decision-making. Methods: Relevant literatures about randomized controlled trails (RCTs) of single-agent PD-1 inhibitors versus traditional second-line chemotherapy in treating advanced ESCC patients were retrieved through The Cochrane Library, Web of science, PubMed, EMbase, CNKI and Wanfang data, J Clin Oncol, N England Oncol and Lancet Oncol, etc. as well as ASCO and ESMO meeting abstract. The data were extracted for Meta-analysis which was conducted using RevMan5.3 software. Results: Totally 5 RCT with 1732 patients were included in this study. The Meta-analysis showed that compared with chemotherapy, single-agent PD-1 inhibitors significantly prolonged the OS (overall survival) (HR＝0.75, 95% CI: 0.67-0.83, P<0.000 01) of advanced ESCC patients. In the sub-group analysis based on different PD-L1 expression, results showed that while the TPS<1%, second-line single-agent PD-1 inhibitors showed no obvious advantage in extending the OS of advanced ESCC patients; but when TPS≥1%, TPS<5%, TPS≥5%, TPS<10% or TPS≥10%, single- agent PD-1 inhibitors significantly prolonged the OS of advanced ESCC patients, with more significant effect in patients with higher PD-L1 level. However, there was no statistical significance in prolonging PFS (progression-free survival) (HR＝0.93, 95% CI: 0.79-1.10, P=0.41) or increasing ORR (objective response rate) (RR=1.62, 95% CI: 0.95-2.74, P=0.07) between single-agent PD-1 inhibitors and chemotherapy. Compared with chemotherapy group, the incidence of grade 3-5 treatment-related adverse effect was lower in the single drug PD-1 inhibitor group (RR=0.37, 95% CI: 0.28-0.50, P<0.000 01). Conclusion: Second-line single-agent PD-1 inhibitors can significantly prolong the OS of advanced ESCC patients with good safety. Single-agent PD-1 inhibitors should be used as the preferential second-line treatment in advanced ESCC patient with high PD-L1 expression.
Objective: To systematically review the effectiveness and safety of single-agent programmed cell death-1 (PD-1) inhibitors versus the second-line chemotherapy in advanced esophageal squamous cell carcinoma (ESCC) patients in order to provide optimal evidence-based medical proof for clinical decision-making. Methods: Relevant literatures about randomized controlled trails (RCTs) of single-agent PD-1 inhibitors versus traditional second-line chemotherapy in treating advanced ESCC patients were retrieved through The Cochrane Library, Web of science, PubMed, EMbase, CNKI and Wanfang data, J Clin Oncol, N England Oncol and Lancet Oncol, etc. as well as ASCO and ESMO meeting abstract. The data were extracted for Meta-analysis which was conducted using RevMan5.3 software. Results: Totally 5 RCT with 1732 patients were included in this study. The Meta-analysis showed that compared with chemotherapy, single-agent PD-1 inhibitors significantly prolonged the OS (overall survival) (HR＝0.75, 95% CI: 0.67-0.83, P<0.000 01) of advanced ESCC patients. In the sub-group analysis based on different PD-L1 expression, results showed that while the TPS<1%, second-line single-agent PD-1 inhibitors showed no obvious advantage in extending the OS of advanced ESCC patients; but when TPS≥1%, TPS<5%, TPS≥5%, TPS<10% or TPS≥10%, single- agent PD-1 inhibitors significantly prolonged the OS of advanced ESCC patients, with more significant effect in patients with higher PD-L1 level. However, there was no statistical significance in prolonging PFS (progression-free survival) (HR＝0.93, 95% CI: 0.79-1.10, P=0.41) or increasing ORR (objective response rate) (RR=1.62, 95% CI: 0.95-2.74, P=0.07) between single-agent PD-1 inhibitors and chemotherapy. Compared with chemotherapy group, the incidence of grade 3-5 treatment-related adverse effect was lower in the single drug PD-1 inhibitor group (RR=0.37, 95% CI: 0.28-0.50, P<0.000 01). Conclusion: Second-line single-agent PD-1 inhibitors can significantly prolong the OS of advanced ESCC patients with good safety. Single-agent PD-1 inhibitors should be used as the preferential second-line treatment in advanced ESCC patient with high PD-L1 expression.
2022, 29(4):345-348.
DOI: 10.3872/j.issn.1007-385X.2022.04.011
Abstract:
回顾1例难治性胰腺癌患者的临床资料。该患者在胰腺癌根治术后辅助化疗结束2个月后出现腹腔转移，后行白蛋白结合型紫杉醇+奥沙利铂化疗联合腹膜后淋巴结区域局部放疗，治疗期间病情再次进展，腹腔一病灶再次增大，遂予该腹腔转移病灶原位疫苗模式治疗。局部大剂量分割免疫增敏放疗+OK432瘤内注射+抗PD-1单抗静脉治疗后，血清CA125持续下降至正常范围。治疗1周期后，转移病灶穿刺病理显示大面积坏死；治疗3周期后，复查CT显示腹腔转移病灶消失，客观疗效评价达CR；无进展生存时间已达16个月。该治疗模式为晚期难治性胰腺癌及其他难治性恶性肿瘤患者的治疗提供了新思路和新方法。
回顾1例难治性胰腺癌患者的临床资料。该患者在胰腺癌根治术后辅助化疗结束2个月后出现腹腔转移，后行白蛋白结合型紫杉醇+奥沙利铂化疗联合腹膜后淋巴结区域局部放疗，治疗期间病情再次进展，腹腔一病灶再次增大，遂予该腹腔转移病灶原位疫苗模式治疗。局部大剂量分割免疫增敏放疗+OK432瘤内注射+抗PD-1单抗静脉治疗后，血清CA125持续下降至正常范围。治疗1周期后，转移病灶穿刺病理显示大面积坏死；治疗3周期后，复查CT显示腹腔转移病灶消失，客观疗效评价达CR；无进展生存时间已达16个月。该治疗模式为晚期难治性胰腺癌及其他难治性恶性肿瘤患者的治疗提供了新思路和新方法。
2022, 29(4):349-353.
DOI: 10.3872/j.issn.1007-385X.2022.04.012
Abstract:
免疫检查点分子是一组表达于免疫细胞表面，主要调控免疫细胞稳态的分子。嵌合抗原受体修饰的T细胞（CAR-T）免疫疗法是通过生物技术构建表达特异性抗原的人工合成T细胞，实现肿瘤靶向杀伤的免疫治疗技术。CAR-T治疗策略已在血液肿瘤临床治疗中取得了较好的疗效，但针对实体肿瘤的CAR-T免疫治疗技术有待进一步研究完善。本文就免疫检查点分子联用CAR-T免疫疗法在实体肿瘤治疗中面临的问题及新进展进行综述。
免疫检查点分子是一组表达于免疫细胞表面，主要调控免疫细胞稳态的分子。嵌合抗原受体修饰的T细胞（CAR-T）免疫疗法是通过生物技术构建表达特异性抗原的人工合成T细胞，实现肿瘤靶向杀伤的免疫治疗技术。CAR-T治疗策略已在血液肿瘤临床治疗中取得了较好的疗效，但针对实体肿瘤的CAR-T免疫治疗技术有待进一步研究完善。本文就免疫检查点分子联用CAR-T免疫疗法在实体肿瘤治疗中面临的问题及新进展进行综述。
2022, 29(4):354-359.
DOI: 10.3872/j.issn.1007-385X.2022.04.013
Abstract:
成纤维细胞激活蛋白（FAP）为Ⅱ型丝氨酸蛋白酶，在多种肿瘤间质中高表达，是肿瘤相关成纤维细胞（CAF）表面标志物之一，与肿瘤进展和总生存期缩短显著相关。近年研究发现，FAP具有介导肿瘤免疫逃逸的重要作用，通过影响天然免疫和适应性免疫反应中细胞种类、数量及功能的变化，调控多种趋化因子和细胞因子的分泌，重塑肿瘤免疫微环境并诱导肿瘤免疫治疗抵抗。通过综述FAP与肿瘤免疫逃逸的关系、作用机制以及在免疫治疗、特别是转化研究进展，可为优化肿瘤免疫治疗提供新思路。
成纤维细胞激活蛋白（FAP）为Ⅱ型丝氨酸蛋白酶，在多种肿瘤间质中高表达，是肿瘤相关成纤维细胞（CAF）表面标志物之一，与肿瘤进展和总生存期缩短显著相关。近年研究发现，FAP具有介导肿瘤免疫逃逸的重要作用，通过影响天然免疫和适应性免疫反应中细胞种类、数量及功能的变化，调控多种趋化因子和细胞因子的分泌，重塑肿瘤免疫微环境并诱导肿瘤免疫治疗抵抗。通过综述FAP与肿瘤免疫逃逸的关系、作用机制以及在免疫治疗、特别是转化研究进展，可为优化肿瘤免疫治疗提供新思路。
2022, 29(4):360-366.
DOI: 10.3872/j.issn.1007-385X.2020.04.014
Abstract:
Objective: To screen candidate epitopes of breast cancer HLA-A2 restrictive neoantigen and to identify high frequency mutation sites in breast cancer neoantigen by using bioinformatics method. Methods: NCBI and GDC databases were used to search missense mutation sites formed by single nucleotide mutation in breast cancer among reported literatures and sequencing data. The new antigen epitopes were predicted by HLA-A2 antigen epitope prediction website BIMAS, SYFPEITHI and artificial neural networkbased NetMHC4.0, and the epitopes with TAP binding power less than Intermediate were eliminated. The candidate epitopes were prioritized by mutation frequency and prediction results. Results: A total of 17 high-frequency mutation genes, including BTLA,ERBB2 and NBPF12 etc, were screened by the above-mentioned methods, and a total of 26 neoantigen epitopes were identified. The binding power of epitopes predicted using BIMAS and SYFPEITHI showed great difference (P<0.05), epitopes in high priority as GSTP1 (A114V, mutation frequency of 5.94%) and BRCA2 (N991H, mutation frequency of 5.40%) etc, were expected to be candidate neo-antigen epitopes; however, their mutation frequency was relatively too low to achieve“universal use”. The possibility of these epitopes used as general breast cancer neo-antigen epitopes is less likely. Conclusion: The common mutation frequency of breast cancer is lower than that of other tumors; it ’s difficult to find“universal”new antigen epitopes of breast cancer;the individualized neoantigen vaccine may be of more promise, which needs further research.
Objective: To screen candidate epitopes of breast cancer HLA-A2 restrictive neoantigen and to identify high frequency mutation sites in breast cancer neoantigen by using bioinformatics method. Methods: NCBI and GDC databases were used to search missense mutation sites formed by single nucleotide mutation in breast cancer among reported literatures and sequencing data. The new antigen epitopes were predicted by HLA-A2 antigen epitope prediction website BIMAS, SYFPEITHI and artificial neural networkbased NetMHC4.0, and the epitopes with TAP binding power less than Intermediate were eliminated. The candidate epitopes were prioritized by mutation frequency and prediction results. Results: A total of 17 high-frequency mutation genes, including BTLA,ERBB2 and NBPF12 etc, were screened by the above-mentioned methods, and a total of 26 neoantigen epitopes were identified. The binding power of epitopes predicted using BIMAS and SYFPEITHI showed great difference (P<0.05), epitopes in high priority as GSTP1 (A114V, mutation frequency of 5.94%) and BRCA2 (N991H, mutation frequency of 5.40%) etc, were expected to be candidate neo-antigen epitopes; however, their mutation frequency was relatively too low to achieve“universal use”. The possibility of these epitopes used as general breast cancer neo-antigen epitopes is less likely. Conclusion: The common mutation frequency of breast cancer is lower than that of other tumors; it ’s difficult to find“universal”new antigen epitopes of breast cancer;the individualized neoantigen vaccine may be of more promise, which needs further research.
2022, 29(4):367-373.
DOI: 10.3872/j.issn.1007-385X.2020.04.015
Abstract:
Objective: To investigate the expression of one cut homeobox 2, OC-2 (ONECUT2) gene in human gastric cancer and its clinical significance. Methods: Based on bioinformatics technology, Oncomine, GEPIA, CCLE and EBI databases were searched to analyze the expression level of OC-2 in gastric cancer (GC) and other tumors. Kmplot database was used to verify the correlation between OC-2 expression and the prognosis of gastric cancer patients. STRING database was used to construct proteinprotein interaction network (PPI network), and the co-expressed genes of OC-2 related with gastric cancer were also analyzed.Results: The expression of OC-2 was generally up-regulated in different kinds of tumors with differential OC-2 expression. The expression level of OC-2 increased significantly in gastric cancer tissues and cells (all P<0.05) and might be irrelevant with tissue type and tumor stage (all P>0.05). The expression level of OC-2 was correlated with prognosis of gastric cancer patients. The median overall survival (40.0 vs 26.5 months) and median disease-free survival (26.2 vs 16.1 months) of gastric cancer patients with low OC-2 expression was significantly longer than those patients with high expression (both P<0.01). Fifteen co-expressed genes of OC-2 were obtained; the PPI network predicted 30 functional proteins interacting with OC-2, among which 11 proteins were also related to the occurrence and development of gastric cancer. After Pearson correlation analysis, 4 proteins that closely and positively related to OC-2 were identified: PDX1 (R=0.49), CREB1 (R=0.31), MAPK1 (R=0.26) and CTSS (R=0.25). Conclusion: OC-2 may play an important role in the occurrence and development, as well as invasion and metastasis of gastric cancer, which is expected to become a new target for the diagnosis and treatment of gastric cancer, and also an important indicator for the prognosis prediction of gastric cancer patients.
Objective: To investigate the expression of one cut homeobox 2, OC-2 (ONECUT2) gene in human gastric cancer and its clinical significance. Methods: Based on bioinformatics technology, Oncomine, GEPIA, CCLE and EBI databases were searched to analyze the expression level of OC-2 in gastric cancer (GC) and other tumors. Kmplot database was used to verify the correlation between OC-2 expression and the prognosis of gastric cancer patients. STRING database was used to construct proteinprotein interaction network (PPI network), and the co-expressed genes of OC-2 related with gastric cancer were also analyzed.Results: The expression of OC-2 was generally up-regulated in different kinds of tumors with differential OC-2 expression. The expression level of OC-2 increased significantly in gastric cancer tissues and cells (all P<0.05) and might be irrelevant with tissue type and tumor stage (all P>0.05). The expression level of OC-2 was correlated with prognosis of gastric cancer patients. The median overall survival (40.0 vs 26.5 months) and median disease-free survival (26.2 vs 16.1 months) of gastric cancer patients with low OC-2 expression was significantly longer than those patients with high expression (both P<0.01). Fifteen co-expressed genes of OC-2 were obtained; the PPI network predicted 30 functional proteins interacting with OC-2, among which 11 proteins were also related to the occurrence and development of gastric cancer. After Pearson correlation analysis, 4 proteins that closely and positively related to OC-2 were identified: PDX1 (R=0.49), CREB1 (R=0.31), MAPK1 (R=0.26) and CTSS (R=0.25). Conclusion: OC-2 may play an important role in the occurrence and development, as well as invasion and metastasis of gastric cancer, which is expected to become a new target for the diagnosis and treatment of gastric cancer, and also an important indicator for the prognosis prediction of gastric cancer patients.
2022, 29(4):374-379.
DOI: 10.3872/j.issn.1007-385X.2020.04.016
Abstract:
二甲双胍是目前Ⅱ型糖尿病的一线用药，主要通过抑制肝脏糖异生和胰岛素抵抗发挥降血糖作用。近年来随着对二甲双胍研究的深入，二甲双胍用于抗肿瘤治疗展现出了巨大的潜力。研究发现二甲双胍不仅能单独抑制肿瘤生长，能显著提升肿瘤放化疗和生物治疗等疗效。但目前关于二甲双胍发挥抗肿瘤作用的具体机制尚未达成共识。本文就近几年来二甲双胍在抗肿瘤领域的研究进展进行综述，主要从二甲双胍对肿瘤细胞的凋亡、自噬、上皮间质转化、肿瘤细胞代谢、联合用药等方面展开讨论，以期未来能够更深入和全面地理解二甲双胍的抗癌机制与临床应用范围，为临床肿瘤治疗提供新的思路。
二甲双胍是目前Ⅱ型糖尿病的一线用药，主要通过抑制肝脏糖异生和胰岛素抵抗发挥降血糖作用。近年来随着对二甲双胍研究的深入，二甲双胍用于抗肿瘤治疗展现出了巨大的潜力。研究发现二甲双胍不仅能单独抑制肿瘤生长，能显著提升肿瘤放化疗和生物治疗等疗效。但目前关于二甲双胍发挥抗肿瘤作用的具体机制尚未达成共识。本文就近几年来二甲双胍在抗肿瘤领域的研究进展进行综述，主要从二甲双胍对肿瘤细胞的凋亡、自噬、上皮间质转化、肿瘤细胞代谢、联合用药等方面展开讨论，以期未来能够更深入和全面地理解二甲双胍的抗癌机制与临床应用范围，为临床肿瘤治疗提供新的思路。
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Chinese Journal Of Cancer Biotheray ® 2025 All Rights Reserved
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Chinese Journal Of Cancer Biotheray ® 2025 All Rights Reserved
Supported by:Beijing E-Tiller Technology Development Co., Ltd.