Acta Universitatis Medicinalis Anhui

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Anhui Provincial Education Department

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Anhui Medical University

Editor-in-chief

Weng Jianping

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Editorial Board of Acta Universitatis Medi-cinalis Anhui Meishan Road , Hefei 230032

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ISSN 1000 - 1492

CN 34 - 1065/R

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Challenges and opportunities in liver cancer immunotherapy

Sun Beicheng

DOI: 10.19405/j.cnki.issn1000-1492.2024.08.001

PDF(12) browse(601)

Knockout SQLE in melanoma cells potentiates anti-tumor immunity via improving CD8+T cell infiltration in tumor microenvironment

Ding Yao; Liu Wen; Liao Yiran; Lei Shun; Zhang Yan; Chen Yezi; Gong Yi; Huang Qizhao

DOI: 10.19405/j.cnki.issn1000-1492.2024.08.005

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Target gene analysis of PD-1 immunotherapy sensitivity in hepatocellular carcinoma

Shi Yuze; Ding Ke; Sun Beicheng

DOI: 10.19405/j.cnki.issn1000-1492.2024.08.006

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abstract:
Objective To investigate the characteristic genes of Programmed cell death protein 1(PD-1) immunotherapy sensitivity in Hepatocellular carcinoma(HCC). Methods The common differential genes in GSE202069 and ERP117672 data sets were investigated by Weighted Gene Co-expression Network Analysis(WGCNA) and Difference analysis, and the characteristic genes of PD-1 immunotherapy sensitivity were screened through Lassoregression. The expression levels of characteristic genes in HCC were predicted by GEPIA and Ualcan databases, and their expression was verified by real-time quantitative reverse transcription polymerase chain reaction(RT-qPCR), Western blot(WB) and Immunohistochemistry(IHC). 3-hydroxybutyrate dehydrogenase 1(BDH1) overexpressed cell line was constructed, followed by cell counting kit-8(CCK-8), EdU, cell scratches and Transwell experiment to investigate the effects ofBDH1on the proliferation, migration and invasion of HCC cells. Results Total of 118 common differentially expressed genes were identified in two datasets by WGCNA and differential analysis. The characteristic genes associated with PD-1 immunotherapy sensitivity screened through Lasso regression including Flavin containing dimethylaniline monoxygenase 3(FMO3), Peroxisomal trans-2-enoyl-CoA reductase(PECR),BDH1, Solute carrier family 7 member 1(SLC7A1), Cytochrome b5 type A(CYB5A) and Phosphoenolpyruvate carboxykinase 1(PCK1). Survival analysis showed thatBDH1was most associated with HCC(Overall survival:P<0.001, Recurrence:P=0.007). GEPIA and Ualcan databases showed low expression ofBDH1in HCC tissues, while RT-qPCR, WB, and IHC further confirmed this. CCK-8, plate cloning assay, EdU staining, cell scratch, and Transwell experiments showed that compared with the Hep3B pCDH group, overexpression ofBDH1resulted in a decrease in the absorbance of HCC cells(t=4.766,P<0.01), a decrease in the number of clone formation(t=16.02,P<0.000 1), a decrease in the proportion of proliferating cells(t=23.13,P<0.000 1), a decrease in cell migration rate(t=25.28,P<0.000 1), and a decrease in the number of small compartments(t=10.78,P=0.004). Conclusion BDH1is a characteristic gene for observing the sensitivity of PD-1 immunotherapy in HCC patients.BDH1could inhibit the proliferation, migration, and invasion ability of HCC cellsin vitro.

Expression of GPX2 in intrahepatic cholangiocarcinoma and its effect on progression

He Jianbo; Sun Beicheng

DOI: 10.19405/j.cnki.issn1000-1492.2024.08.007

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abstract:
Objective To investigate the role of Glutathione peroxidase 2(GPX2) in the occurrence and progression of intrahepatic cholangiocarcinoma(ICC). Methods The Omicshare website was used to analyzeGPX2expression levels in ICC. The expression levels in ICC were validated using quantitative real-time reverse transcription PCR(RT-qPCR), Western blot, and immunohistochemistry. Stable GPX2 knockdown and overexpression HuCCT1 cell lines were constructed. The effects of GPX2 on ICC cell proliferation, migration, apoptosis, and epithelial-mesenchymal transition(EMT) were investigated using colony formation assays, cell counting kit-8(CCK-8) assays, wound healing assays, Transwell assays, and flow cytometry. A mouse model of cholangiocarcinoma was constructed to assess GPX2 expression in mouse cholangiocarcinoma tissues. Results Based on the analysis results from the Omicshare website,GPX2was generally upregulated in intrahepatic cholangiocarcinoma(ICC)(P<0.001). Western blot(P<0.000 1), RT-qPCR(P<0.001), and immunohistochemistry experiments showed that, compared to adjacent non-cancerous tissues, the expression of GPX2 was significantly elevated in ICC. When GPX2 was knocked down, the colony formation rate of cells decreased significantly(P<0.01), and the proliferation capacity was reduced(P<0.001). Conversely, overexpression of GPX2 led to a significant increase in colony formation rate(P<0.01) and enhanced proliferation capacity(P<0.01). Results from wound healing and Transwell assays demonstrated that GPX2 knockdown slowed down cell wound healing(P<0.01) and reduced migration ability(P<0.01). Additionally, GPX2 knockdown resulted in an increase in E-cadherin(P<0.01) and a decrease in N-cadherin(P<0.01) and Vimentin(P<0.05). On the other hand, overexpression of GPX2 accelerated wound healing(P<0.05) and enhanced migration ability(P<0.05), while E-cadherin expression decreased(P<0.05) and N-cadherin(P<0.01) and Vimentin(P<0.001) expression increased. Flow cytometry for apoptosis and Western blot experiments indicated that GPX2 knockdown increased the apoptosis rate(P<0.001), decreased the expression of Bcl-2(P<0.001), and increased the expression of BAX(P<0.01). But overexpression of GPX2 reduced the apoptosis rate(P<0.01), increased Bcl-2 expression(P<0.000 1), and decreased BAX expression(P<0.001). Finally, elevated levels of GPX2 were observed in a mouse model of cholangiocarcinoma. Conclusion GPX2 is highly expressed in human and mouse cholangiocarcinoma tissues, and it may enhance cholangiocarcinoma cell proliferation and migration, promote tumor cell EMT, and inhibit tumor cell apoptosis.

Expression of UROC1 in hepatocellular carcinoma and its effect on tumor development

Yan Hongyao; Lao Yuanxiang; Sun Beicheng

DOI: 10.19405/j.cnki.issn1000-1492.2024.08.008

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NDRG1 enhances Sorafenib resistance in hepatocellular carcinoma through ERK pathway

Song Bojiao; Sun Beicheng

DOI: 10.19405/j.cnki.issn1000-1492.2024.08.009

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abstract:
Objective To investigate the effect of N-myc downstream regulatory gene 1(NDRG1) on Hepatocellular carcinoma(HCC) and whether NDRG1 affects the sensitivity of HCC to Sorafenib. Methods The expression level of NDRG1 in HCC was predicted by TCGA database, and verified by Western blot(WB) and Immunohistochemistry(IHC). NDRG1 knockout cell lines were constructed, followed by cell counting kit-8(CCK-8), EdU, cell scratches and Transwell experiment to investigate the effects of NDRG1 and its combination with Sorafenib on the proliferation, migration and invasion of HCC cells. In addition, flow cytometry was used to detect the apoptosis of HCC cells. The effect of NDRG1 and Sorafenib on HCC tumor formation was studiedin vivoby subcutaneous tumor bearing in nude mice. WB and IHC were used to determine the pathway regulating the sensitivity of HCC to Sorafenib. Results WB and IHC confirmed that NDRG1 is highly expressed in HCC, consistent with the results of TCGA data. Tumor functional experiments showed that NDRG1 knockout or Sorafenib stimulation weakened the proliferation, migration, and invasion ability of HCC cells, and increased tumor cell apoptosis. However, NDRG1 knockout combined with Sorafenib further weakened the proliferation, migration and invasion ability of HCC cells, and further increased tumor cell apoptosis(P<0.000 1). Mouse subcutaneous tumor model showed that NDRG1 knockout or Sorafenib stimulation reduced the tumor volume and quality, while NDRG1 knockout combined with Sorafenib further reduced the tumor volume and quality(P<0.000 1). The WB and IHC results indicated that NDRG1 knockout combined with Sorafenib could reduce the phosphorylation level of Erk1/2. Conclusion NDRG1 is highly expressed in HCC, which promotes the proliferation, migration and invasion of HCC cells, and restricts apoptosis. NDRG1 knockout enhances HCC sensitivity to Sorafenib by reducing ERK signaling pathway phosphorylation.

The role and regulation mechanism of HYOU1 in the pathogenesis and development of pancreatic cancer

Ding Jialu; Sun Beicheng

DOI: 10.19405/j.cnki.issn1000-1492.2024.08.010

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abstract:
Objective To investigate the mechanism by which human hypoxia up-regulation 1(HYOU1) regulates pancreatic cancer development. Methods Bioinformatic and immunohistochemical staining analyses of HYOU1 expression level in pancreatic tumor tissues, normal and paracancerous tissues and its correlation with patients′ survival. Quantitative real-time PCR(qPCR) and Western blot were used to clarify the expression level of HYOU1 in a number of human pancreatic ductal adenocarcinoma cell lines and a normal human pancreatic ductal cell line. Two cell lines with the highest expression levels of HYOU1, BXPC-3 and Panc-1, were selected to knock out HYOU1 by CRISPR-Cas9,and then cell survival, proliferation and migration of these cells were examined by cell counting kit-8(CCK-8),colony formation assay and wound healing experiment separately,as well as apoptosis was detected by flow cytometry. Subsequently,the protein levels of the PI3K/Akt signaling including PI3K,p-PI3K,Akt,and pAkt were detected by Western blot in parental and HYOU1-ablated BXPC-3 and Panc-1 cells. Cell proliferation was also examined in HYOU1-ablated cells after treatment of recilisib,an activator of the PI3K/Akt pathway. Results The expression of HYOU1 in pancreatic tumor tissues was significantly higher than that in normal tissues,and the patients with high expression of HYOU1 had a much shorter survival compared to the patients with low HYOU1(P<0.01). Immunohistochemical staining of pancreatic cancer specimens showed that the expression of HYOU1 was higher in tumor tissues than in paracancerous tissues(P<0.01). The mRNA and protein levels of HYOU1 were higher in all pancreatic cancer cell lines compared to the human normal pancreatic ductal cell(P<0.001,P<0.01). HYOU1 ablation inhibited BXPC-3 and Panc-1 cells survival,proliferation and migration,and promoted early cell apoptosis. In addition,loss of HYOU1 decreased PI3K/Akt signaling activity,whereas the PI3K/Akt activator Recilisib reversed the effects of HYOU1 ablation on cell survival and proliferation. Conclusion HYOU1promotes pancreatic cancer progression by activating the PI3K/Akt signaling pathway.

Effect of TBC1D5 on hepatocellular carcinoma progression via JAK/STAT pathway

Wei Haowei; Tao Xuewen; Yu Decai

DOI: 10.19405/j.cnki.issn1000-1492.2024.08.011

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abstract:
Objective To investigate the role of Tre2-Bub2-Cdc16 1 domain family member5(TBC1D5) in the development of hepatocellular carcinoma(HCC). Methods Western blot(WB), Immunohistochemistry(IHC) and quantitative real-time PCR(qPCR) were used to verify the difference inTBC1D5expression in clinical samples. The HCC cell lines MHCC97H and Hep3B were chosen to construct the knockdown model. The effects on cell proliferation were detected by cell proliferation assay, colony formation assay and EdU assay. Wound assay and Transwell assay were used to detect cell migration and invasion. Flow cytometry was used to detect the changes of cell cycle and H2O2-induced apoptosis of HCC cells. Finally, the effects of knockdown and overexpression ofTBC1D5on JAK/STAT pathway were detected by WB. Results The results of WB, IHC and qPCR showed that the expression ofTBC1D5in HCC tissues was higher at the protein level(P<0.000 1) and mRNA level(P<0.01) than that in corresponding adjacent tissues. Compared with the control group, the proliferation level of HCC cells withTBC1D5knockdown was decreased(P<0.05), the formation of plate colony number decreased(P<0.001), and the proportion of EdU-positive cells decreased(P<0.001). The results of scratch assay and Transwell assay showed that the migration(P<0.01) and invasion ability(P<0.01) of HCC cells afterTBC1D5knockdown were significantly lower than those in the control group. AfterTBC1D5knockdown, the cell cycle of HCC cells was slowed down(P<0.05) and the ability to resist apoptosis was reduced(P<0.01)than those in the control group. Compare with the control group, knockdown ofTBC1D5decreased the phosphorylation level of JAK and STAT proteins and inhibit the JAK/STAT pathway. Conclusion TBC1D5is highly expressed in HCC. After knocking downTBC1D5, the proliferation, migration and invasion ability, cell cycle rate and anti-apoptosis ability of HCC cells decreased and may affect HCC progression through the JAK/STAT pathway.