COL4A1 promotes the growth and metastasis of hepatocellular carcinoma cells by activating FAK-Src signaling

Abstract Background: Collagens are the most abundant proteins in extra cellular matrix and important components of tumor microenvironment. Recent studies have showed that aberrant expression of collagens can influence tumor cell behaviors. However, their roles in hepatocellular carcinoma (HCC) are poorly understood. Methods: In this study, we screened all 44 collagen members in HCC using whole transcriptome sequencing data from the public datasets, and collagen type IV alpha1 chain (COL4A1) was identified as its most significantly differential expression. Expression of COL4A1 was detected in HCC samples by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Relationship between COL4A1 expression and clinicopathological parameters was also analyzed. Finally, functions and potential mechanisms of COL4A1 were explored in HCC progression. Results: COL4A1 is the most significantly overexpressed collagen gene in HCC and it closely correlates with clinical stage. Upregulation of COL4A1 facilitates the proliferation, migration and invasion of HCC cells through FAK-Src signaling. Expression of COL4A1 is upregulated by RUNX1 in HCC. HCC cells with high COL4A1 expression are sensitive to the treatment with FAK or Src inhibitor. Conclusion: COL4A1 facilitates growth and metastasis in HCC via activation of FAK-Src signaling. High level of COL4A1 may be a potential biomarker for diagnosis and treatment with FAK or Src inhibitor for HCC.

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COL4A1 promotes the growth and metastasis of hepatocellular carcinoma cells by activating FAK-Src signaling

10.21203/rs.3.rs-20811/v2 ◽

2020 ◽

Author(s):

Ting Wang ◽

Haojie Jin ◽

Jingying Hu ◽

Xi Li ◽

Haoyu Ruan ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Migration And Invasion ◽

Collagen Type Iv ◽

Sequencing Data ◽

Aberrant Expression ◽

Src Signaling ◽

Src Inhibitor ◽

Potential Biomarker ◽

Public Datasets ◽

Hcc Cells

Abstract Background: Collagens are the most abundant proteins in extra cellular matrix and important components of tumor microenvironment. Recent studies have showed that aberrant expression of collagens can influence tumor cell behaviors. However, their roles in hepatocellular carcinoma (HCC) are poorly understood. Methods: In this study, we screened all 44 collagen members in HCC using whole transcriptome sequencing data from the public datasets, and collagen type IV alpha1 chain (COL4A1) was identified as most significantly differential expressed gene. Expression of COL4A1 was detected in HCC samples by quantitative real-time polymerase chain reaction (qRT-PCR), western blot and immunohistochemistry (IHC). Finally, functions and potential mechanisms of COL4A1 were explored in HCC progression.Results: COL4A1 is the most significantly overexpressed collagen gene in HCC. Upregulation of COL4A1 facilitates the proliferation, migration and invasion of HCC cells through FAK-Src signaling. Expression of COL4A1 is upregulated by RUNX1 in HCC. HCC cells with high COL4A1 expression are sensitive to the treatment with FAK or Src inhibitor. Conclusion: COL4A1 facilitates growth and metastasis in HCC via activation of FAK-Src signaling. High level of COL4A1 may be a potential biomarker for diagnosis and treatment with FAK or Src inhibitor for HCC.

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CircRNA profiling identifies circRNF180 as a tumor suppressor in hepatocellular carcinoma

Epigenomics ◽

10.2217/epi-2020-0385 ◽

2021 ◽

Vol 13 (7) ◽

pp. 513-530

Author(s):

Xi Zeng ◽

Chao Tan ◽

Meile Mo ◽

Xiaoling Qin ◽

Xiaoyun Ma ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Suppressor ◽

Real Time ◽

Real Time Pcr ◽

Expression Profiles ◽

Cell Counting ◽

Migration And Invasion ◽

Quantitative Real Time Pcr ◽

Potential Biomarker ◽

Hcc Cells

Aim: To explore the expression profiles and functions of circRNAs in hepatocellular carcinoma (HCC). Materials & methods: We obtained circRNA expression profiles through RNA sequencing. Expression levels of circRNAs were confirmed by quantitative real-time PCR. The effects on HCC progression were determined using Cell Counting Kit 8, clone formation and transwell assays. Results: We identified 114 upregulated and 144 downregulated circRNAs in HCC tissues. The results of quantitative real-time PCR showed that circGNAO1, circRNF180 and circMERTK were significantly downregulated in HCC tissues, whereas circSNX6 was significantly upregulated. CircRNF180 was associated with microvascular invasion. Overexpression of circRNF180 inhibits the proliferation, colony formation, migration and invasion of HCC cells. Conclusion: CircRNF180 may function as a tumor suppressor and could serve as a potential biomarker and therapeutic target in HCC.

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DEAH-box polypeptide 32 promotes hepatocellular carcinoma progression via activating the β-catenin pathway

10.21203/rs.3.rs-27420/v1 ◽

2020 ◽

Author(s):

Xiaoyun Hu ◽

Guosheng Yuan ◽

Qi Li ◽

Jing Huang ◽

Xiao Cheng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Tumor Growth ◽

Ectopic Expression ◽

Migration And Invasion ◽

High Morbidity ◽

Rt Pcr ◽

Mesenchymal Transition ◽

Potential Biomarker ◽

Hcc Cells

Abstract Background Hepatocellular carcinoma (HCC) is a refractory cancer with high morbidity and high mortality. It has been reported that DEAH-box polypeptide 32 (DHX32) was upregulated in several types of malignancies and predicted poor prognosis, which was associated with tumor growth and metastasis. However, the expression of DHX32 in HCC and its role in HCC progression remain largely unknown. Methods Western blot and RT-PCR assays were used to detect the expression of DHX32 and epithelial mesenchymal transition (EMT)-related genes in HCC cells. Wound-healing and Transwell invasion assays were performed to determine the effect of DHX32 and β-catenin on the migration and invasion of HCC cells. Cell proliferation was examined by EdU cell proliferation assay. Results In our study, we found that high level of DHX32 expression was associated with reduced overall survival in HCC patients. DHX32 expression was upregulated in human HCC cells and ectopic expression of DHX32 induced EMT, promoted the migration, invasion, and proliferation of HCC cells, and enhanced tumor growth. Silencing DHX32 reversed EMT, inhibited the migration, invasion, and proliferation of HCC cells, and suppressed tumor growth. RT-PCR assay revealed that DHX32 regulated the expression of CTNNB1, CCND1, COX2, MMP7, and WIF1 in HCC cells. Mechanistic investigations showed that silencing DHX32 decreased the expression of β-catenin in nucleus and β-catenin siRNA abrogated DHX32-mediated EMT, migration, invasion, and proliferation in HCC cells. Conclusions Our data suggested that DHX32 was an attractive regulator of HCC progression and indicated DHX32 can serve as a potential biomarker and therapeutic target for HCC patients.

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MicroRNA-625-3p improved proliferation and involved chemotherapy resistance via targeting PTEN in high grade ovarian serous carcinoma

Journal of Ovarian Research ◽

10.1186/s13048-021-00939-1 ◽

2022 ◽

Vol 15 (1) ◽

Author(s):

Lili Zhong ◽

Xiumin Liu ◽

Lixing Wang ◽

Yu Liu ◽

Duohan Zhang ◽

...

Keyword(s):

Clinical Stage ◽

Chemotherapy Resistance ◽

Luciferase Reporter ◽

Serous Carcinoma ◽

Migration And Invasion ◽

Chemotherapy Response ◽

High Grade ◽

Aberrant Expression ◽

Potential Biomarker ◽

Induced Apoptosis

Abstract Objective High-grade serous ovarian cancer (HGSOC) is an aggressive gynaecological malignancy and associated with poor prognosis. Here we examined the effects of miR-625-3p on proliferation, treatment, migration and invasion in HGSOC. Methods The proliferation of HGSOC cells was evaluated by MTT assay. Transwell assay was performed to examine migration and matrigel assay were used to assess invasion. The effect of miR-625-3p on cisplatin-induced apoptosis was investigated by Caspase-Glo3/7 assay. The dual-luciferase reporter assay was carried out to confirm the potential binding site. Results Overexpression of miR-625-3p promoted proliferation, and increased migration and invasion in HGSOC cells. MiR-625-3p significantly inhibited cisplatin sensitivity in HGSOC cells. Meanwhile, miR-625-3p decreased cisplatin-induced apoptosis by regulation of BAX and Bcl-2 expression. Furthermore, aberrant expression of miR-625-3p changed PTEN expression by directly binding to 3’UTR of PTEN. Further study showed miR-625-3p expression was higher in human HGSOC tissue than normal ovarian tissues and associated with higher clinical stage. Conclusions miR-625-3p promotes HGSOC growth, involves chemotherapy resistance and might serve as a potential biomarker to predict chemotherapy response and prognosis in HGSOC.

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Identification of Circ_001569 as a Potential Biomarker in the Diagnosis and Prognosis of Pancreatic Cancer

Technology in Cancer Research & Treatment ◽

10.1177/1533033820983302 ◽

2021 ◽

Vol 20 ◽

pp. 153303382098330

Author(s):

Xianbo Shen ◽

Yun Chen ◽

Jibin Li ◽

Huaiyin Huang ◽

Chuping Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cox Regression ◽

Clinical Stage ◽

Flow Cytometric Analysis ◽

Clinicopathological Parameters ◽

Migration And Invasion ◽

Circular Rnas ◽

Cox Regression Analysis ◽

Diagnosis And Prognosis ◽

Potential Biomarker

Emerging evidence has shown that circular RNAs (circRNAs) serve as a promising biomarker in different malignancies. Specifically, circ_001569 has been found to be upregulated in some types of human gastrointestinal cancer. In this study, we aimed to investigate clinical significances, diagnostic and prognostic values of circ_001569 in pancreatic cancer (PC), and identify its effects on the malignant behaviors of PC cells. The expression of circ_001569 was determined in 26 tissues samples and 97 plasma samples from PC patients by qRT-PCR. Relationship between circ_001569 expression and clinicopathological parameters was analyzed by Chi-square test. Diagnostic and prognostic values of circ_001569 were evaluated by ROC curves, Kaplan-Meier curves, and Cox regression analysis. The effects of circ_001569 on the proliferation, migration, invasion, and apoptosis of PC cells were assessed by MTT, wound healing, Transwell invasion assays, and flow cytometric analysis, respectively. Results showed that the expression of circ_001569 was upregulated in tissues and plasma of PC patients. High circ_001569 level was positively correlated with lymphatic metastasis, clinical stage, and venous invasion. Circ_001569 level was an independent prognostic indicator for overall survival rates of PC patients, and patients with high circ_001569 level had a poor prognosis. The AUC of circ_001569 was 0.716 (95% CI: 0.642-0.790) with a sensitivity and specificity of 62.76% and 74.29%, respectively. In vitro, circ_001569 silencing decreased cell proliferation, migration, and invasion, but promoted cell apoptosis of PC cells. Our data demonstrate that high circ_001569 level associates with tumor malignant behaviors, and may serve as a potential biomarker in the diagnosis and prognosis of PC.

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Overexpression of p62 Induces Autophagy and Promotes Proliferation, Migration and Invasion of Nasopharyngeal Carcinoma Cells through Promoting ERK Signaling Pathway

Current Cancer Drug Targets ◽

10.2174/1568009620666200424145122 ◽

2020 ◽

Vol 20 (8) ◽

pp. 624-637 ◽

Cited By ~ 3

Author(s):

Qiong Wu ◽

Manlin Xiang ◽

Kun Wang ◽

Zhen Chen ◽

Lu Long ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Clinical Analysis ◽

Carcinoma Cells ◽

Immunofluorescent Staining ◽

Clinicopathological Parameters ◽

Migration And Invasion ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Potential Biomarker

Background: Increasing evidence has shown that p62 plays an important role in tumorigenesis. However, relatively little is known about the association between p62 and tumor invasion and metastasis; in addition, its role in NPC (nasopharyngeal carcinoma, NPC) has been rarely investigated. Objective: To investigate the effect of p62 on tumorigenesis and metastasis in nasopharyngeal carcinoma. Methods: Western blotting, immunofluorescent staining and immunohistochemistry were used to evaluate p62 protein expression. Subsequently, cell viability, colony formation, migration, invasion and autophagy assays were performed. anti-p62 autoantibodies in sera were detected by ELISA. These data were correlated with clinicopathological parameters. Results: We confirmed that p62 was significantly up-regulated in NPC tissues. Furthermore, high expression of p62 was observed in NPC cell lines, and especially in the highly metastatic 5-8F cells. In vitro, down-regulation of p62 inhibited proliferation, clone forming ability, autophagy, migration, and invasion in 5-8F cells, whereas p62 overexpression resulted in the opposite effects in 6-10B cells. Moreover, we confirmed that p62 promotes NPC cell proliferation, migration, and invasion by activating ERK (extracellular signal-regulated kinase, ERK). Clinical analysis indicated that high p62 expression correlates with lymph node and distant metastasis (P<0.05). Serum anti-p62 autoantibodies were increased in NPC patients and levels were associated with metastasis. Conclusion : Our data establish p62 targeting ERK as potential determinant in the NPC, which supplies a new pathway to treat NPC. Furthermore, p62 is a potential biomarker which might be closely related to the tumorigenesis and metastasis in NPC.

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Apoptotic Effects of Xanthium strumarium via PI3K/AKT/mTOR Pathway in Hepatocellular Carcinoma

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/2176701 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13

Author(s):

Juyoung Kim ◽

Kyung Hee Jung ◽

Hyung Won Ryu ◽

Doo-Young Kim ◽

Sei-Ryang Oh ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Growth ◽

Caspase 3 ◽

Mtor Pathway ◽

Terminal Deoxynucleotidyl Transferase ◽

Mechanistic Study ◽

Migration And Invasion ◽

Xanthium Strumarium ◽

Apoptotic Effects ◽

Hcc Cells

Xanthium strumarium (XS) has been traditionally used as a medicinal herb for treating inflammatory diseases, such as appendicitis, chronic bronchitis, rheumatism, and rhinitis. In this study, we yielded ethanol extracts from XS and investigated whether they could inhibit the progression of hepatocellular carcinoma (HCC) and its underlying mechanism. The XS-5 and XS-6 extracts dose-dependently inhibited the growth and proliferation in HCC cell lines. The apoptotic effects of them were observed via increased levels of cleaved caspase-3 and cleaved PARP, as well as elevated numbers of terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling- (TUNEL-) positive apoptotic cells. They also decreased XIAP and Mcl-1 expression via loss of mitochondrial membrane potential. Additionally, they inhibited the invasion and migration of HCC cells. In an ex vivo model, the extracts significantly inhibited tumor cell growth and induced apoptosis by increasing the expression of the cleaved caspase-3. A mechanistic study revealed that they effectively suppressed PI3K/AKT/mTOR signaling pathways in HCC cells. Taken together, our findings demonstrate that they could efficiently not only induce apoptosis but also inhibit cell growth, migration, and invasion of human HCC cells by blocking the PI3K/AKT/mTOR pathway. We suggest XS-5 and XS-6 as novel natural anti-HCC agents.

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KLF7/VPS35 axis contributes to hepatocellular carcinoma progression through CCDC85C-activated β-catenin pathway

Cell & Bioscience ◽

10.1186/s13578-021-00585-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yarong Guo ◽

Bao Chai ◽

Junmei Jia ◽

Mudan Yang ◽

Yanjun Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Tumor Growth ◽

Luciferase Reporter ◽

Aberrant Expression ◽

Proliferation And Invasion ◽

Hcc Cells

Abstract Objective Dysregulation of KLF7 participates in the development of various cancers, but it is unclear whether there is a link between HCC and aberrant expression of KLF7. The aim of this study was to investigate the role of KLF7 in proliferation and migration of hepatocellular carcinoma (HCC) cells. Methods CCK8, colony growth, transwell, cell cycle analysis and apoptosis detection were performed to explore the effect of KLF7, VPS35 and Ccdc85c on cell function in vitro. Xenografted tumor growth was used to assess in vivo role of KLF7. Chip-qPCR and luciferase reporter assays were applied to check whether KLF7 regulated VPS35 at transcriptional manner. Co-IP assay was performed to detect the interaction between VPS35 and Ccdc85c. Immunohistochemical staining and qRT-PCR analysis were performed in human HCC sampels to study the clinical significance of KLF7, VPS35 and β-catenin. Results Firstly, KLF7 was highly expressed in human HCC samples and correlated with patients’ differentiation and metastasis status. KLF7 overexpression contributed to cell proliferation and invasion of HCC cells in vitro and in vivo. KLF7 transcriptional activation of VPS35 was necessary for HCC tumor growth and metastasis. Further, co-IP studies revealed that VPS35 could interact with Ccdc85c in HCC cells. Rescue assay confirmed that overexpression of VPS35 and knockdown of Ccdc85c abolished the VPS35-medicated promotion effect on cell proliferation and invasion. Finally, KLF7/VPS35 axis regulated Ccdc85c, which involved in activation of β-catenin signaling pathway, confirmed using β-catenin inhibitor, GK974. Functional studies suggested that downregulation of Ccdc85c partly reversed the capacity of cell proliferation and invasion in HCC cells, which was regulated by VPS35 upregulation. Lastly, there was a positive correlation among KLF7, VPS35 and active-β-catenin in human HCC patients. Conclusion We demonstrated that KLF7/VPS35 axis promoted HCC cell progression by activating Ccdc85c-medicated β-catenin pathway. Targeting this signal axis might be a potential treatment strategy for HCC.

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A Bioinformatics Analysis Identifies the Telomerase Inhibitor MST-312 for Treating High-STMN1-Expressing Hepatocellular Carcinoma

Journal of Personalized Medicine ◽

10.3390/jpm11050332 ◽

2021 ◽

Vol 11 (5) ◽

pp. 332

Author(s):

Szu-Jen Wang ◽

Pei-Ming Yang

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitors ◽

Cancer Genomics ◽

Gene Signature ◽

Migration And Invasion ◽

Advanced Hcc ◽

Telomerase Inhibitor ◽

Cell Cycle Related Gene ◽

Hcc Cells

Hepatocellular carcinoma (HCC) is a relatively chemo-resistant tumor. Several multi-kinase inhibitors have been approved for treating advanced HCC. However, most HCC patients are highly refractory to these drugs. Therefore, the development of more effective therapies for advanced HCC patients is urgently needed. Stathmin 1 (STMN1) is an oncoprotein that destabilizes microtubules and promotes cancer cell migration and invasion. In this study, cancer genomics data mining identified STMN1 as a prognosis biomarker and a therapeutic target for HCC. Co-expressed gene analysis indicated that STMN1 expression was positively associated with cell-cycle-related gene expression. Chemical sensitivity profiling of HCC cell lines suggested that High-STMN1-expressing HCC cells were the most sensitive to MST-312 (a telomerase inhibitor). Drug–gene connectivity mapping supported that MST-312 reversed the STMN1-co-expressed gene signature (especially BUB1B, MCM2/5/6, and TTK genes). In vitro experiments validated that MST-312 inhibited HCC cell viability and related protein expression (STMN1, BUB1B, and MCM5). In addition, overexpression of STMN1 enhanced the anticancer activity of MST-312 in HCC cells. Therefore, MST-312 can be used for treating STMN1-high expression HCC.

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Regulation of TREM1-Mediated Inflammation in Hepatocellular Carcinoma Cells

Reports ◽

10.3390/reports4020017 ◽

2021 ◽

Vol 4 (2) ◽

pp. 17

Author(s):

Vikrant Rai ◽

Devendra K. Agrawal

Keyword(s):

Hepatocellular Carcinoma ◽

Vitamin D ◽

Chronic Inflammation ◽

Therapeutic Target ◽

Primary Liver Cancer ◽

Migration And Invasion ◽

Potential Therapeutic Target ◽

Mediators Of Inflammation ◽

Tnf Α ◽

Hcc Cells

Hepatocellular carcinoma (HCC), accounting for more than 90% of cases of primary liver cancer, is the third most common cause of cancer-related death worldwide. Chronic inflammation precedes the development of cirrhosis and HCC. TREM (triggering receptor expressed on myeloid cell)-1 is an inflammatory marker and amplifier of inflammation that signals through PI3K and ERK1/2 to activate transcription factors, resulting in increased secretion of pro-inflammatory cytokines, causing chronic inflammation and predisposing the liver to carcinogenesis. Thus, targeting TREM-1 in HCC might be a potential therapeutic target. A low level of vitamin D has been associated with chronic inflammation and poor prognosis in HCC. Thus, we evaluated the effect of vitamin D on TREM-1 expression in the HCC cell line. Additionally, the effects of high mobility group box-1, lipopolysaccharide, and transcription factor PU.1 on the expression of TREM-1 in normal liver cells and HCC cells have been investigated in the presence and absence of vitamin D. The results showed increased expression of TREM-1 in HCC cells and with IL-6, TNF-α, LPS, and rHMGB-1 and decreased expression with calcitriol. Calcitriol also attenuated the effect of IL-6, TNF-α, LPS, and rHMGB-1 on TREM-1. Calcitriol treatment attenuated the proliferation, migration, and invasion of HCC cells. These results (in vitro) provide molecular and biochemical evidence that calcitriol significantly attenuates the expression of mediators of inflammation, and thus might be used therapeutically together with conventional treatment to delay the progression of HCC. Additionally, the negative regulation of TREM-1 by PU.1 suggests PU.1 as a potential therapeutic target.

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