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Volume 30,Issue 3,2023 Table of Contents
2023, 30(3):187-195.
DOI: 10.3872/j.issn.1007-385X.2023.03.001
Abstract:
Immunotherapy is a major strategy of antitumor therapy, whereas it still faces many challenges in clinical application. Although a large number of studies have revealed numerous mechanisms for the occurrence of immunotherapy resistance, it is still the tip of the iceberg in the face of the complex immune microenvironment. How to determine the main mechanisms of immunotherapy resistance in different tumor types and developing efficient strategies for reversing immunotherapy resistance are key issues that need to be addressed in the field of current tumor immunotherapy. Systematically discuss the research progress of immunotherapy resistance mechanisms and response strategies, in order to provide new ideas for better clinical understanding of the process of immunotherapy resistance and discovering novel reversal strategies.
Immunotherapy is a major strategy of antitumor therapy, whereas it still faces many challenges in clinical application. Although a large number of studies have revealed numerous mechanisms for the occurrence of immunotherapy resistance, it is still the tip of the iceberg in the face of the complex immune microenvironment. How to determine the main mechanisms of immunotherapy resistance in different tumor types and developing efficient strategies for reversing immunotherapy resistance are key issues that need to be addressed in the field of current tumor immunotherapy. Systematically discuss the research progress of immunotherapy resistance mechanisms and response strategies, in order to provide new ideas for better clinical understanding of the process of immunotherapy resistance and discovering novel reversal strategies.
2023, 30(3):196-203.
DOI: 10.3872/j.issn.1007-385X.2023.03.002
Abstract:
Immune checkpoint inhibitors (ICIs) have attracted much attention in recent years due to their remarkable efficacy in tumor treatment. Immune mediated hepatotoxicity (IMH) caused by ICIs is a kind of common immune related adverse events (irAEs).However, a subtype of IMH, biliary type IMH (BIMH) is a rare irAE with insufficient cognition and lack of standardized diagnosis andtreatment, which has hidden clinical dangers. The patient with BIMH is characterized by significant increase of bile duct enzymes and hyperbilirubinemia. The histopathological manifestations of BIMH are bile duct inflammation, bile duct injury and disappearance. The patients with BIMH in cholestasis stage have poor response to immunosuppressive therapy and their prognoses are poor. Improving the understanding of BIMH, early diagnosis and early intervention are the keys to improve the prognosis of patients with BIMH. Constant understanding of the epidemiological characteristics, clinical characteristics, histopathological characteristics, pathogenesis and problems in the overall management of BIMH will help to put forward more effective diagnosis and treatment strategies for BIMH.
Immune checkpoint inhibitors (ICIs) have attracted much attention in recent years due to their remarkable efficacy in tumor treatment. Immune mediated hepatotoxicity (IMH) caused by ICIs is a kind of common immune related adverse events (irAEs).However, a subtype of IMH, biliary type IMH (BIMH) is a rare irAE with insufficient cognition and lack of standardized diagnosis andtreatment, which has hidden clinical dangers. The patient with BIMH is characterized by significant increase of bile duct enzymes and hyperbilirubinemia. The histopathological manifestations of BIMH are bile duct inflammation, bile duct injury and disappearance. The patients with BIMH in cholestasis stage have poor response to immunosuppressive therapy and their prognoses are poor. Improving the understanding of BIMH, early diagnosis and early intervention are the keys to improve the prognosis of patients with BIMH. Constant understanding of the epidemiological characteristics, clinical characteristics, histopathological characteristics, pathogenesis and problems in the overall management of BIMH will help to put forward more effective diagnosis and treatment strategies for BIMH.
2023, 30(3):204-210.
DOI: 10.3872/j.issn.1007-385X.2023.03.003
Abstract:
Objective: To investigate the molecular mechanism by which nerolidol inhibits the malignant biological behavior of melanoma A-375 and WM-115 cells through the Wnt-β-catenin pathway. Methods: Melanoma A-375 and WM-115 cells were cultured in vitro and then treated with different concentrations of nerolidol. The effects of nerolidol on the proliferation, cell cycle and apoptosis,and migration of A-375 and WM-115 cells were analyzed by SRB and clonogenic assays, FCM, Transwell, and cell scratch assays,respectively. The levels of reactive oxygen species (ROS) in the cells were examined with DCFH-DA staining. The Wnt- β -catenin pathway and the expression levels of its related downstream genes were determined by qPCR and WB. The relationship between patient prognosis and the activation of Wnt-β-catenin pathway in melanoma was analyzed using the ULCAN and GEPIA2 databases. Results:Compared with the control group, the proliferation, migration, and cell cycle of A-375 and WM-115 cells in the nerolidol-treated group were significantly inhibited (all P<0.01), while the apoptosis was significantly increased (all P<0.01); the ROS level was increased (P<0.01), and the Wnt-β-catenin pathway was inhibited, while its downstream gene expression was significantly up-regulated (P<0.01 or P<0.01). Analysis of database data showed that OS was lower in patients with high WNT1 gene expression than in patients with low expression (P<0.01). Conclusions: Nerolidol affects the Wnt-β-catenin pathway by upregulating ROS levels in A-375 andWM-115 cells, thereby inhibiting their malignant biological behaviors. The Wnt-β-catenin pathway may be a potential target for the treatment of melanoma.
Objective: To investigate the molecular mechanism by which nerolidol inhibits the malignant biological behavior of melanoma A-375 and WM-115 cells through the Wnt-β-catenin pathway. Methods: Melanoma A-375 and WM-115 cells were cultured in vitro and then treated with different concentrations of nerolidol. The effects of nerolidol on the proliferation, cell cycle and apoptosis,and migration of A-375 and WM-115 cells were analyzed by SRB and clonogenic assays, FCM, Transwell, and cell scratch assays,respectively. The levels of reactive oxygen species (ROS) in the cells were examined with DCFH-DA staining. The Wnt- β -catenin pathway and the expression levels of its related downstream genes were determined by qPCR and WB. The relationship between patient prognosis and the activation of Wnt-β-catenin pathway in melanoma was analyzed using the ULCAN and GEPIA2 databases. Results:Compared with the control group, the proliferation, migration, and cell cycle of A-375 and WM-115 cells in the nerolidol-treated group were significantly inhibited (all P<0.01), while the apoptosis was significantly increased (all P<0.01); the ROS level was increased (P<0.01), and the Wnt-β-catenin pathway was inhibited, while its downstream gene expression was significantly up-regulated (P<0.01 or P<0.01). Analysis of database data showed that OS was lower in patients with high WNT1 gene expression than in patients with low expression (P<0.01). Conclusions: Nerolidol affects the Wnt-β-catenin pathway by upregulating ROS levels in A-375 andWM-115 cells, thereby inhibiting their malignant biological behaviors. The Wnt-β-catenin pathway may be a potential target for the treatment of melanoma.
2023, 30(3):211-216.
DOI: 10.3872/j.issn.1007-385X.2023.03.004
Abstract:
Objective: To investigate the effects of Amentoflavone (AF) on the JAK2-STAT3 pathway activation, apoptosis，and proliferation of thyroid carcinoma SW579 cells. Methods: SW579 cells were treated with AF at different concentrations (0，50, 100, 150, and 200 μmol/L) for 24 h, 48 h, and 72 h, respectively. Then, the effects of AF on the proliferation and apoptosis of SW579 cells were detected by CCK-8 and Celigo cell count and FCM, respectively; and the effects of AF on the JAK2-STAT3 pathway activation and the mRNA and protein expression of its downstream genes c-Myc, Bcl2 and Survivin in SW579 cells were detected by qPCR and Western blotting. Results: After the treatment with AF, the proliferation of SW579 cells was suppressed significantly while the apoptosis was promoted significantly, which were all in a dose-dependent manner (both P<0.05). The activation of JAK2-STAT3 pathway was significantly inhibited (P<0.05), and the mRNA and protein expression of the downstream genes c-Myc, Bcl2, and survivin in SW579 cells was significantly decreased (all P<0.05) after the treatment with AF. Conclusion: AF may contribute to apoptosis induction and proliferation suppression of thyroid carcinoma SW579 cells via inhibiting the activation of JAK2-STAT3 pathway and its downstream gene expression. AF has the potential to serve as a novel therapeutic approach for the management of thyroid carcinoma.
Objective: To investigate the effects of Amentoflavone (AF) on the JAK2-STAT3 pathway activation, apoptosis，and proliferation of thyroid carcinoma SW579 cells. Methods: SW579 cells were treated with AF at different concentrations (0，50, 100, 150, and 200 μmol/L) for 24 h, 48 h, and 72 h, respectively. Then, the effects of AF on the proliferation and apoptosis of SW579 cells were detected by CCK-8 and Celigo cell count and FCM, respectively; and the effects of AF on the JAK2-STAT3 pathway activation and the mRNA and protein expression of its downstream genes c-Myc, Bcl2 and Survivin in SW579 cells were detected by qPCR and Western blotting. Results: After the treatment with AF, the proliferation of SW579 cells was suppressed significantly while the apoptosis was promoted significantly, which were all in a dose-dependent manner (both P<0.05). The activation of JAK2-STAT3 pathway was significantly inhibited (P<0.05), and the mRNA and protein expression of the downstream genes c-Myc, Bcl2, and survivin in SW579 cells was significantly decreased (all P<0.05) after the treatment with AF. Conclusion: AF may contribute to apoptosis induction and proliferation suppression of thyroid carcinoma SW579 cells via inhibiting the activation of JAK2-STAT3 pathway and its downstream gene expression. AF has the potential to serve as a novel therapeutic approach for the management of thyroid carcinoma.
2023, 30(3):217-222.
DOI: 10.3872/j.issn.1007-385X.2023.03.005
Abstract:
Objective: To investigate the effect of oridonin (Ori) in reversing cisplatin (DDP) resistance in human melanoma cells and its related mechanism. Methods: Melanoma cisplatin-resistant cell lines A375/DDP and M14/DDP were divided into control group,2 μmol/L Ori group, 4 mg/L DDP group and 2 μmol/L Ori+4 mg/L DDP group. Cell viability, invasion and migration, and apoptosis were detected by CCK-8, Annexin Ⅴ-FITC/PI staining flow cytometry and Transwell assay, respectively. The autophagosomes were observed by transmission electron microscopy, microtubule associated protein1 light chain 3 (LC3)-point structure was observed by immunofluorescence staining, and the expressions of autophagy related proteins Beclin-1, p62, LC3Ⅱ and LC3Ⅰ of A375/DDP cells were detected by WB.Results: Compared with 4 mg/LDDP group, cell proliferation viability, migration and invasion ability of 2 μmol/L Ori+4 mg/L DDP group were significantly decreased (all P<0.01), and apoptosis level was significantly increased (P<0.01). A large number of autophagosomes and LC3-point structures were observed in 4 mg/LDDPgroup; however, only a fewwere observed in 2 μmol/L Ori+4 mg/L DDP group. Compared with control group, the protein expression levels of Beclin-1 and LC3Ⅱ/LC3Ⅰ in 4 mg/L DDP group were significantly increased (all P<0.01), but the protein expression level of p62 was significantly decreased (P<0.05 or P<0.01); compared with 4 mg/L DDP group, the protein expression levels of Beclin-1 and LC3Ⅱ/LC3Ⅰin 2 μmol/L Ori+4 mg/L DDP group were significantly decreased (all P<0.01), but the protein expression level of p62 was significantly increased (P<0.05). Conclusion: Ori can increase the sensitivity of drug-resistant melanoma cells to DDP, which may be related to the inhibition of DDP-induced autophagy.
Objective: To investigate the effect of oridonin (Ori) in reversing cisplatin (DDP) resistance in human melanoma cells and its related mechanism. Methods: Melanoma cisplatin-resistant cell lines A375/DDP and M14/DDP were divided into control group,2 μmol/L Ori group, 4 mg/L DDP group and 2 μmol/L Ori+4 mg/L DDP group. Cell viability, invasion and migration, and apoptosis were detected by CCK-8, Annexin Ⅴ-FITC/PI staining flow cytometry and Transwell assay, respectively. The autophagosomes were observed by transmission electron microscopy, microtubule associated protein1 light chain 3 (LC3)-point structure was observed by immunofluorescence staining, and the expressions of autophagy related proteins Beclin-1, p62, LC3Ⅱ and LC3Ⅰ of A375/DDP cells were detected by WB.Results: Compared with 4 mg/LDDP group, cell proliferation viability, migration and invasion ability of 2 μmol/L Ori+4 mg/L DDP group were significantly decreased (all P<0.01), and apoptosis level was significantly increased (P<0.01). A large number of autophagosomes and LC3-point structures were observed in 4 mg/LDDPgroup; however, only a fewwere observed in 2 μmol/L Ori+4 mg/L DDP group. Compared with control group, the protein expression levels of Beclin-1 and LC3Ⅱ/LC3Ⅰ in 4 mg/L DDP group were significantly increased (all P<0.01), but the protein expression level of p62 was significantly decreased (P<0.05 or P<0.01); compared with 4 mg/L DDP group, the protein expression levels of Beclin-1 and LC3Ⅱ/LC3Ⅰin 2 μmol/L Ori+4 mg/L DDP group were significantly decreased (all P<0.01), but the protein expression level of p62 was significantly increased (P<0.05). Conclusion: Ori can increase the sensitivity of drug-resistant melanoma cells to DDP, which may be related to the inhibition of DDP-induced autophagy.
2023, 30(3):223-229.
DOI: 10.3872/j.issn.1007-385X.2023.03.006
Abstract:
Objective: To investigate the potential mechanism of Atractylodes macrocephala aqueous extract inhibiting gastric cancer SGC7901 cells. Methods: Gastric perfusion was performed on SD rats using distilled water and Atractylodes macrocephala aqueous extract respectively. Venous blood was collected and insolated to get serum, which was then filtered and named as control group serum (CON-S) and Atractylodes macrocephala group serum (AM-S), respectively. SGC7901 cells were divided into control group, 10% AM-S group and 20% AM-S group. The two AM-S group cells were cultured in AM-S serum of corresponding density for 24 h while the control group cells were cultured with normal medium for the same time. The SGC7901 cells and supernatant were collected for further analysis. MTT assay was used to detect cell viability. Lactate dehydrogenase (LDH), malondialdehyde (MDA) and superoxide dismutase (SOD) were determined by commercial kits. Enzyme-linked immuno sorbent assay (ELISA) kits were applied to detect thecontents of interleukin IL-6 and tumor necrosis factor TNF- α in the cells of all the groups. The expressions of phosphatidylinositol 3-kinase PI3K-Akt-NF- κB signaling pathway-related proteins were evaluated by western blot. Results: The proliferative activity of SGC7901 gastric cancer cells in 10% AM-S group and 20% AM-S group decreased by 48.9% and 53.25% respectively compared with the control group (P<0.05 or P<0.01). In the supernatant of gastric cancer cells, compared with the control group, the LDH level of 10% AM-S group and 20% AM-S group increased by 29.25% and 123%; the SOD activity increased by 18% and 54.60%; the MDA leveldecreased by 27.8% and 40.0%; the IL-6 level decreased by 15% and 17.5%, and the TNF-α αlevel decreased by 29.71% and 40.16% respectively (P<0.05 or P<0.01). Compared with the control group, the levels of PI3K-Akt-NF-κB signaling pathway-related protein in AM-S group were significantly reduced (P<0.05 or P<0.01). Conclusion: Atractylodes macrocephala aqueous extract can inhibit gastric cancer by inhibiting the proliferation activity of cancer cells, promoting apoptosis, inhibiting the production of pro-inflammatory factors in tumor microenvironment and changing the level of intracellular oxidative stress, the mechanism of which might be that these anti-cancerous effects are achieved by inhibiting PI3K-Akt-NF-κB signaling pathway.
Objective: To investigate the potential mechanism of Atractylodes macrocephala aqueous extract inhibiting gastric cancer SGC7901 cells. Methods: Gastric perfusion was performed on SD rats using distilled water and Atractylodes macrocephala aqueous extract respectively. Venous blood was collected and insolated to get serum, which was then filtered and named as control group serum (CON-S) and Atractylodes macrocephala group serum (AM-S), respectively. SGC7901 cells were divided into control group, 10% AM-S group and 20% AM-S group. The two AM-S group cells were cultured in AM-S serum of corresponding density for 24 h while the control group cells were cultured with normal medium for the same time. The SGC7901 cells and supernatant were collected for further analysis. MTT assay was used to detect cell viability. Lactate dehydrogenase (LDH), malondialdehyde (MDA) and superoxide dismutase (SOD) were determined by commercial kits. Enzyme-linked immuno sorbent assay (ELISA) kits were applied to detect thecontents of interleukin IL-6 and tumor necrosis factor TNF- α in the cells of all the groups. The expressions of phosphatidylinositol 3-kinase PI3K-Akt-NF- κB signaling pathway-related proteins were evaluated by western blot. Results: The proliferative activity of SGC7901 gastric cancer cells in 10% AM-S group and 20% AM-S group decreased by 48.9% and 53.25% respectively compared with the control group (P<0.05 or P<0.01). In the supernatant of gastric cancer cells, compared with the control group, the LDH level of 10% AM-S group and 20% AM-S group increased by 29.25% and 123%; the SOD activity increased by 18% and 54.60%; the MDA leveldecreased by 27.8% and 40.0%; the IL-6 level decreased by 15% and 17.5%, and the TNF-α αlevel decreased by 29.71% and 40.16% respectively (P<0.05 or P<0.01). Compared with the control group, the levels of PI3K-Akt-NF-κB signaling pathway-related protein in AM-S group were significantly reduced (P<0.05 or P<0.01). Conclusion: Atractylodes macrocephala aqueous extract can inhibit gastric cancer by inhibiting the proliferation activity of cancer cells, promoting apoptosis, inhibiting the production of pro-inflammatory factors in tumor microenvironment and changing the level of intracellular oxidative stress, the mechanism of which might be that these anti-cancerous effects are achieved by inhibiting PI3K-Akt-NF-κB signaling pathway.
2023, 30(3):230-236.
DOI: 10.3872/j.issn.1007-385X.2023.03.007
Abstract:
Objective: To explore the molecular mechanism of COUP-TFⅡ regulating lymphatic metastasis-related factor VEGFR3-NRP2 axis in gastric cancer. Methods: Sixty cases of gastric cancer tissues and paracancerous tissues surgically resected at the Binzhou Medical University Hospital between March 2015 and August 2015 were collected, and the expression of COUP-TFⅡ, VEGFR3 and NRP2 in the tissues was detected by immunohistochemistry and qPCR. Gastric cancer SGC7901 and BGC823 cells were cultured, and COUP-TF Ⅱ overexpression and siRNA-COUP-TF Ⅱ plasmids were constructed and further transfected into SGC7901 cells. The expression of COUP-TFⅡ, VEGFR3 and NRP2 in SGC7901 cells after transfection was detected by WB and qPCR, and the targeting relationship between COUP-TFⅡ and VEGFR3-NRP2 axis was verified by immunoprecipitation (CHIP) and dual-luciferase reporter assay. Results: Immunohistochemistry showed that VEGFR3, NRP2, and COUP-TFⅡ were highly expressed in gastric cancer tissues (all P<0.01). qPCR results showed that the mRNA levels of VEGFR3, NRP2 and COUP-TFⅡ were also highly expressed in gastric cancer tissues compared with paraneoplastic and normal tissues (P<0.05 or P<0.001). WB and qPCR methods showed that compared with the control group, both the mRNA and protein levels of COUP-TFⅡ were significantly higher in the COUP-TFⅡ overexpression group (both P<0.01); while the mRNA and protein levels of COUP-TFⅡ were significantly decreased in the SGC7901 cells of COUP-TFⅡ knockdown group (P<0.05 or P<0.01), and the VEGFR3 and NRP2 mRNA levels were also significantly decreased (both P<0.01). CHIP results showed that the immunoprecipitates of COUP-TFⅡ antibodies in SGC7901 and BGC823 cell lines contained VEGFR3 and NRP2 promoter DNA sequences. The results of dual-luciferase reporter assay showed that COUP-TFⅡ expression level was positively correlated with VEGFR3 and NRP2 levels. Conclusion: COUP-TF Ⅱ has a direct positive regulatory effect on the VEGFR3-NRP2 axis and is highly expressed in gastric cancer. COUP-TFⅡ may serve as a new target for the treatment of gastric cancer.
Objective: To explore the molecular mechanism of COUP-TFⅡ regulating lymphatic metastasis-related factor VEGFR3-NRP2 axis in gastric cancer. Methods: Sixty cases of gastric cancer tissues and paracancerous tissues surgically resected at the Binzhou Medical University Hospital between March 2015 and August 2015 were collected, and the expression of COUP-TFⅡ, VEGFR3 and NRP2 in the tissues was detected by immunohistochemistry and qPCR. Gastric cancer SGC7901 and BGC823 cells were cultured, and COUP-TF Ⅱ overexpression and siRNA-COUP-TF Ⅱ plasmids were constructed and further transfected into SGC7901 cells. The expression of COUP-TFⅡ, VEGFR3 and NRP2 in SGC7901 cells after transfection was detected by WB and qPCR, and the targeting relationship between COUP-TFⅡ and VEGFR3-NRP2 axis was verified by immunoprecipitation (CHIP) and dual-luciferase reporter assay. Results: Immunohistochemistry showed that VEGFR3, NRP2, and COUP-TFⅡ were highly expressed in gastric cancer tissues (all P<0.01). qPCR results showed that the mRNA levels of VEGFR3, NRP2 and COUP-TFⅡ were also highly expressed in gastric cancer tissues compared with paraneoplastic and normal tissues (P<0.05 or P<0.001). WB and qPCR methods showed that compared with the control group, both the mRNA and protein levels of COUP-TFⅡ were significantly higher in the COUP-TFⅡ overexpression group (both P<0.01); while the mRNA and protein levels of COUP-TFⅡ were significantly decreased in the SGC7901 cells of COUP-TFⅡ knockdown group (P<0.05 or P<0.01), and the VEGFR3 and NRP2 mRNA levels were also significantly decreased (both P<0.01). CHIP results showed that the immunoprecipitates of COUP-TFⅡ antibodies in SGC7901 and BGC823 cell lines contained VEGFR3 and NRP2 promoter DNA sequences. The results of dual-luciferase reporter assay showed that COUP-TFⅡ expression level was positively correlated with VEGFR3 and NRP2 levels. Conclusion: COUP-TF Ⅱ has a direct positive regulatory effect on the VEGFR3-NRP2 axis and is highly expressed in gastric cancer. COUP-TFⅡ may serve as a new target for the treatment of gastric cancer.
2023, 30(3):237-248.
DOI: 10.3872/j.issn.1007-385X.2023.03.008
Abstract:
Objective: To screen lncRNAs related to ferroptosis in renal clear cell carcinoma (ccRCC) by bioinformatics methods, and to explore their correlation with clinical prognosis and immune cell infiltration, in order to provide new targets for the treatment of ccRCC patients. Methods: Transcript data and clinical data of ccRCC were downloaded from The Cancer Genome Atlas (TCGA) database, and ferroptosis-related lncRNAs were obtained using single-sample gene set enrichment analysis (ssGSEA) and correlation analysis. Through univariate and multivariate regression analyses, the characteristics of lncRNAs related to ferroptosis were constructed, and their prognostic value was further analyzed. R software was used to analyze the relationship between the characteristics of ferroptosis-related lncRNAs and tumor immune infiltration and drug sensitivity. A ferroptosis-related ceRNA network was constructed, and the expression of key lncRNAs in Chinese ccRCC tissues and paraneoplastic tissues (samples from 8 cases surgically resected at the Affiliated Hospital of Southwest Medical University between Dec 2019 and Mar 2021) was verified by qPCR. Results: Kaplan-Meier analysis showed that patients with high ferroptosis scores had lower overall survival (OS) than patients with low ferroptosis scores. Univariate and multivariate regression analyses identified 11 ccRCC ferroptosis-related prognostic lncRNAs, and the nomograms for predicting the prognosis of ccRCC patients at 1, 3, and 5 years were constructed. Immune infiltration analysis showed that the characteristics of ferroptosis-related lncRNAs were closely related to ccRCC immune infiltration, among which LINC01871, PRKAR1B-AS1 and CYTOR were the key lncRNAs regulating tumor immune infiltration. Chemotherapy drug sensitivity analysis showed that high-risk patients were more sensitive to methotrexate, paclitaxel, cisplatin, and doxorubicin. Finally, A ceRNA network containing 3 lncRNAs, 15 miRNAs and 15 mRNAs was constructed. qPCR indicated that LINC01871, LINC00472 and CYTOR were significantly up-regulated in ccRCC tissues. Conclusion: Eleven ferroptosis-related lncRNAs were obtained by bioinformatics methods, and they were proved to be related to ccRCC prognosis, immune infiltration and chemotherapeutic drug sensitivity, providing an important reference for exploring ferroptosis-related lncRNA markers in ccRCC.
Objective: To screen lncRNAs related to ferroptosis in renal clear cell carcinoma (ccRCC) by bioinformatics methods, and to explore their correlation with clinical prognosis and immune cell infiltration, in order to provide new targets for the treatment of ccRCC patients. Methods: Transcript data and clinical data of ccRCC were downloaded from The Cancer Genome Atlas (TCGA) database, and ferroptosis-related lncRNAs were obtained using single-sample gene set enrichment analysis (ssGSEA) and correlation analysis. Through univariate and multivariate regression analyses, the characteristics of lncRNAs related to ferroptosis were constructed, and their prognostic value was further analyzed. R software was used to analyze the relationship between the characteristics of ferroptosis-related lncRNAs and tumor immune infiltration and drug sensitivity. A ferroptosis-related ceRNA network was constructed, and the expression of key lncRNAs in Chinese ccRCC tissues and paraneoplastic tissues (samples from 8 cases surgically resected at the Affiliated Hospital of Southwest Medical University between Dec 2019 and Mar 2021) was verified by qPCR. Results: Kaplan-Meier analysis showed that patients with high ferroptosis scores had lower overall survival (OS) than patients with low ferroptosis scores. Univariate and multivariate regression analyses identified 11 ccRCC ferroptosis-related prognostic lncRNAs, and the nomograms for predicting the prognosis of ccRCC patients at 1, 3, and 5 years were constructed. Immune infiltration analysis showed that the characteristics of ferroptosis-related lncRNAs were closely related to ccRCC immune infiltration, among which LINC01871, PRKAR1B-AS1 and CYTOR were the key lncRNAs regulating tumor immune infiltration. Chemotherapy drug sensitivity analysis showed that high-risk patients were more sensitive to methotrexate, paclitaxel, cisplatin, and doxorubicin. Finally, A ceRNA network containing 3 lncRNAs, 15 miRNAs and 15 mRNAs was constructed. qPCR indicated that LINC01871, LINC00472 and CYTOR were significantly up-regulated in ccRCC tissues. Conclusion: Eleven ferroptosis-related lncRNAs were obtained by bioinformatics methods, and they were proved to be related to ccRCC prognosis, immune infiltration and chemotherapeutic drug sensitivity, providing an important reference for exploring ferroptosis-related lncRNA markers in ccRCC.
2023, 30(3):249-254.
DOI: 10.3872/j.issn.1007-385X.2023.03.009
Abstract:
溶瘤病毒能够选择性地感染、破坏和裂解肿瘤细胞，并诱发和增强机体的抗肿瘤免疫反应。天然溶瘤病毒由于存在感染风险、低效率、容易引起免疫应答而被清除等问题，严重限制其在临床中的运用。近十年来，随着肿瘤免疫治疗的兴起，以及基因工程和生物工程技术的飞速发展，经相关基因修饰的新型溶瘤病毒展现出令人惊喜的溶瘤效应，其安全性、有效性、特异性均得到极大改善。目前全球已有超过百种相关产品处于研发或临床试验期，其中已有产品获得批准上市，并已取得良好的临床效果，展现出极具临床运用的前景。本文主要从溶瘤病毒基因修饰的新策略及其与肿瘤免疫治疗联合运用两个方面进行综述。
溶瘤病毒能够选择性地感染、破坏和裂解肿瘤细胞，并诱发和增强机体的抗肿瘤免疫反应。天然溶瘤病毒由于存在感染风险、低效率、容易引起免疫应答而被清除等问题，严重限制其在临床中的运用。近十年来，随着肿瘤免疫治疗的兴起，以及基因工程和生物工程技术的飞速发展，经相关基因修饰的新型溶瘤病毒展现出令人惊喜的溶瘤效应，其安全性、有效性、特异性均得到极大改善。目前全球已有超过百种相关产品处于研发或临床试验期，其中已有产品获得批准上市，并已取得良好的临床效果，展现出极具临床运用的前景。本文主要从溶瘤病毒基因修饰的新策略及其与肿瘤免疫治疗联合运用两个方面进行综述。
2023, 30(3):255-260.
DOI: 10.3872/j.issn.1007-385X.2023.03.010
Abstract:
嵌合抗原受体T（CAR-T）细胞疗法是目前治疗癌症最有效的一种免疫治疗方法，但CAR-T 细胞功能障碍很大程度限制其自身对癌症治疗的效果。T细胞功能的差异以及记忆和效应T细胞的作用被证明在CAR-T 细胞治疗中极为重要。CD8+ T细胞作为发挥抗癌作用的主要效应细胞一直是研究焦点，而对CD4+ T细胞的关注较少。CD4+ T细胞不仅可以通过激活CD8+ T细胞使其杀伤肿瘤细胞，还可以独立发挥抗肿瘤作用。现有研究发现，细胞因子、共刺激域和细胞代谢等因素均可影响CD4+ CAR-T 细胞亚群的增殖和分化。本文主要综述了CD4+ CAR-T 细胞亚群在治疗肿瘤中的重要性以及影响其增殖分化因素的研究进展，为进一步研发高效的CAR-T细胞提供新思路。
嵌合抗原受体T（CAR-T）细胞疗法是目前治疗癌症最有效的一种免疫治疗方法，但CAR-T 细胞功能障碍很大程度限制其自身对癌症治疗的效果。T细胞功能的差异以及记忆和效应T细胞的作用被证明在CAR-T 细胞治疗中极为重要。CD8+ T细胞作为发挥抗癌作用的主要效应细胞一直是研究焦点，而对CD4+ T细胞的关注较少。CD4+ T细胞不仅可以通过激活CD8+ T细胞使其杀伤肿瘤细胞，还可以独立发挥抗肿瘤作用。现有研究发现，细胞因子、共刺激域和细胞代谢等因素均可影响CD4+ CAR-T 细胞亚群的增殖和分化。本文主要综述了CD4+ CAR-T 细胞亚群在治疗肿瘤中的重要性以及影响其增殖分化因素的研究进展，为进一步研发高效的CAR-T细胞提供新思路。
2023, 30(3):261-266.
DOI: 10.3872/j.issn.1007-385X.2023.03.011
Abstract:
合成生物学借助工程化技术在人工生物系统的设计与构建方面已经取得了长足进展，尤其在CAR-T细胞的开发和应用中为实体肿瘤治疗带来了深刻变革。在合成生物学技术的支持下，新一代的CAR-T细胞可以在靶向肿瘤后激活细胞因子释放通路，实现CAR-T 细胞在肿瘤部位的自我调节；工程化的T细胞在CAR的基础上也可以表达其他受体元件（如正交型IL-2、IL-9受体等），通过人工给药干预可在体内实现多功效、特异性刺激，这对于实现CAR-T 细胞在体内的精准刺激和克服抑制性肿瘤微环境等意义非凡。此外，智能化CAR回路系统如synNotch 基因回路系统和CAR开关系统等研究结果表明，CAR-T 细胞可以通过自身基因回路的反馈或人工给药干预来发挥或终止杀伤功能，可有效保证CAR-T细胞在治疗过程中的安全性。虽然针对实体肿瘤靶点难题的CAR-T细胞开发目前尚未有突破性进展，但对于有明确靶点的肿瘤，Ⅰ期临床试验结果已经显示CAR-T细胞治疗实体肿瘤具有巨大潜力。因此，明确当下 CAR-T 细胞治疗实体肿瘤的作用机制和应用现状，可以对后续开发高效低毒CAR-T细胞提供新思路。
合成生物学借助工程化技术在人工生物系统的设计与构建方面已经取得了长足进展，尤其在CAR-T细胞的开发和应用中为实体肿瘤治疗带来了深刻变革。在合成生物学技术的支持下，新一代的CAR-T细胞可以在靶向肿瘤后激活细胞因子释放通路，实现CAR-T 细胞在肿瘤部位的自我调节；工程化的T细胞在CAR的基础上也可以表达其他受体元件（如正交型IL-2、IL-9受体等），通过人工给药干预可在体内实现多功效、特异性刺激，这对于实现CAR-T 细胞在体内的精准刺激和克服抑制性肿瘤微环境等意义非凡。此外，智能化CAR回路系统如synNotch 基因回路系统和CAR开关系统等研究结果表明，CAR-T 细胞可以通过自身基因回路的反馈或人工给药干预来发挥或终止杀伤功能，可有效保证CAR-T细胞在治疗过程中的安全性。虽然针对实体肿瘤靶点难题的CAR-T细胞开发目前尚未有突破性进展，但对于有明确靶点的肿瘤，Ⅰ期临床试验结果已经显示CAR-T细胞治疗实体肿瘤具有巨大潜力。因此，明确当下 CAR-T 细胞治疗实体肿瘤的作用机制和应用现状，可以对后续开发高效低毒CAR-T细胞提供新思路。
2023, 30(3):267-270.
DOI: 10.3872/j.issn.1007-385X.2023.03.012
Abstract:
肝细胞癌（HCC）的发病率和病死率正在逐年增长，严重威胁人类的健康和生命。近年来，以PD-1/PD-L1抑制剂为代表的免疫治疗迅速发展，但对晚期HCC疗效有限。治疗中实时监测循环肿瘤细胞（CTC）PD-L1表达，是评估免疫治疗有效性的重要指标之一。本案例通过TumorFisher 检测技术实时监测1例HCC患者免疫治疗前后总CTC数及PD-L1+ CTC个数，结合影像学和血清学检查结果进一步评估患者免疫治疗疗效。患者治疗前总CTC数为5个/2 mL，PD-L1+ CTC为5个/2 mL，PD-L1+ CTC/总CTC为100%。用PD-1/PD-L1抑制剂行3周期免疫治疗后，PD-L1+ CTC/总CTC逐渐降低，肿瘤缩小，血清AFP及PIVKA-Ⅱ逐渐下降，PD-L1+ CTC/总CTC变化与肿瘤标志物、MRI检查结果一致。PD-L1+ CTC/总CTC可作为HCC免疫治疗疗效评估的辅助指标。
肝细胞癌（HCC）的发病率和病死率正在逐年增长，严重威胁人类的健康和生命。近年来，以PD-1/PD-L1抑制剂为代表的免疫治疗迅速发展，但对晚期HCC疗效有限。治疗中实时监测循环肿瘤细胞（CTC）PD-L1表达，是评估免疫治疗有效性的重要指标之一。本案例通过TumorFisher 检测技术实时监测1例HCC患者免疫治疗前后总CTC数及PD-L1+ CTC个数，结合影像学和血清学检查结果进一步评估患者免疫治疗疗效。患者治疗前总CTC数为5个/2 mL，PD-L1+ CTC为5个/2 mL，PD-L1+ CTC/总CTC为100%。用PD-1/PD-L1抑制剂行3周期免疫治疗后，PD-L1+ CTC/总CTC逐渐降低，肿瘤缩小，血清AFP及PIVKA-Ⅱ逐渐下降，PD-L1+ CTC/总CTC变化与肿瘤标志物、MRI检查结果一致。PD-L1+ CTC/总CTC可作为HCC免疫治疗疗效评估的辅助指标。
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Supported by:Beijing E-Tiller Technology Development Co., Ltd.