Sec62 promotes early recurrence of hepatocellular carcinoma through activating integrinα/CAV1 signalling

Du, Juan; Zhao, Zhihao; Zhao, Hetong; Liu, Dong; Liu, Hui; Cheng, Baohua; Zhai, Xiaofeng; Yin, Zifei; Zhang, Yani; Ling, Changquan

doi:10.1038/s41389-019-0183-6

Cited by 16 publications

(43 citation statements)

References 35 publications

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“…Sec62 was initially found as a translocation-related protein in the membrane of endoplasmic reticulum [ 38 , 39 ]. Recent studies have reported that Sec62 is correlated with metastasis in breast cancer and promotes recurrence of hepatocellular carcinoma, suggesting that Sec62 is associated with cancer progression [ 40 , 41 ]. However, the mechanism by which Sec62 acts in the tumorigenesis remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway

Liu

Sun

et al. 2021

J Exp Clin Cancer Res

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Background Cancer stem cell (CSC)-related chemoresistance leads to poor outcome of the patients with colorectal cancer (CRC). In this study, we identified the chemoresistance-relevant molecules and decipher the involved mechanisms to provide potential therapeutic target for CRC. We focused on Sec62, a novel target with significantly increased expression in chemoresistant CRC tissues, and further investigated its role in the progression of CRC. Methods Through analyzing the differentially-expressed genes between chemoresistant and chemosensitive CRCs, we selected Sec62 as a novel chemoresistance-related target in CRC. The expression and clinical significance of Sec62 were determined by immunoblotting and immunohistochemistry in tissues and cell lines of CRC. The roles of Sec62 in drug resistance, stemness and tumorigenesis were evaluated in vitro and in vivo using functional experiments. GST pull-down, western blot, coimmunoprecipitation and Me-RIP assays were performed to further explore the downstream molecular mechanisms. Results Sec62 upregulation was associated with the chemoresistance of CRC and poor outcome of CRC patients. Depletion of Sec62 sensitized CRC cells to chemotherapeutic drugs. Sec62 promoted the stemness of CRC cells through activating Wnt/β-catenin signaling. Mechanistically, Sec62 bound to β-catenin and inhibited the degradation of β-catenin. Sec62 competitively disrupted the interaction between β-catenin and APC to inhibit the β-catenin destruction complex assembly. Moreover, Sec62 expression was upregulated by the m6A-mediated stabilization of Sec62 mRNA. Conclusions Sec62 upregulated by the METTL3-mediated m6A modification promotes the stemness and chemoresistance of CRC by binding to β-catenin and enhancing Wnt signalling. Thus, m6A modification-Sec62-β-catenin molecular axis might act as therapeutic targets in improving treatment of CRC.

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Section: Discussionmentioning

confidence: 99%

Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway

Liu

Sun

et al. 2021

J Exp Clin Cancer Res

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“…With the developments in gene chips and highthroughput sequencing, gene signature based on mRNA expression levels have shown great potential in predicting HCC prognosis. The abnormal expression levels of single gene such as SEC62 [6], SHP-1 [7], RING1 [8], AGBL2 [9] have been reported to be independent prognostic factors for HCC patients. Moreover, a risk-coefficient model based on a multigene mRNA expression signature has been identified to be an independent prognostic factor for overall survival (OS) and could stratify patients into high-and low-risk group with significantly different OS [10][11][12].…”

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confidence: 99%

A robust twelve-gene signature for prognosis prediction of hepatocellular carcinoma

Ouyang

Pan

et al. 2020

Cancer Cell Int

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Background: The prognosis of hepatocellular carcinoma (HCC) patients remains poor. Identifying prognostic markers to stratify HCC patients might help to improve their outcomes. Methods: Six gene expression profiles (GSE121248, GSE84402, GSE65372, GSE51401, GSE45267 and GSE14520) were obtained for differentially expressed genes (DEGs) analysis between HCC tissues and non-tumor tissues. To identify the prognostic genes and establish risk score model, univariable Cox regression survival analysis and Lasso-penalized Cox regression analysis were performed based on the integrated DEGs by robust rank aggregation method. Then Kaplan-Meier and time-dependent receiver operating characteristic (ROC) curves were generated to validate the prognostic performance of risk score in training datasets and validation datasets. Multivariable Cox regression analysis was used to identify independent prognostic factors in liver cancer. A prognostic nomogram was constructed based on The Cancer Genome Atlas (TCGA) dataset. Finally, the correlation between DNA methylation and prognosis-related genes was analyzed. Results: A twelve-gene signature including SPP1, KIF20A, HMMR, TPX2, LAPTM4B, TTK, MAGEA6, ANX10, LECT2, CYP2C9, RDH16 and LCAT was identified, and risk score was calculated by corresponding coefficients. The risk score model showed a strong diagnosis performance to distinguish HCC from normal samples. The HCC patients were stratified into high-risk and low-risk group based on the cutoff value of risk score. The Kaplan-Meier survival curves revealed significantly favorable overall survival in groups with lower risk score (P < 0.0001). Time-dependent ROC analysis showed well prognostic performance of the twelve-gene signature, which was comparable or superior to AJCC stage at predicting 1-, 3-, and 5-year overall survival. In addition, the twelve-gene signature was independent with other clinical factors and performed better in predicting overall survival after combining with age and AJCC stage by nomogram. Moreover, most of the prognostic twelve genes were negatively correlated with DNA methylation in HCC tissues, which SPP1 and LCAT were identified as the DNA methylation-driven genes. Conclusions: We identified a twelve-gene signature as a robust marker with great potential for clinical application in risk stratification and overall survival prediction in HCC patients.

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“…In line with these observations, Sec62 was shown to be a prognostic biomarker in prostate cancer, head and neck-cancer, and lung cancer, as well as breast cancer [12, 13, 15, 16, 26]. Several studies indicate a role of Sec62 in cell migration and invasion processes [13, 14, 18], which may explain its role as a prognostic factor. In our study, we also found stronger SEC62 expression confirmed by immunohistochemistry in patients with recurrent HCC.…”

Section: Discussionmentioning

confidence: 73%

“…It has been shown that high expression of Sec62 in HCC tissue and peripheral blood mononuclear cells is an independent risk factor for HCC recurrence after liver resection [17, 18]. In line with these observations, Sec62 was shown to be a prognostic biomarker in prostate cancer, head and neck-cancer, and lung cancer, as well as breast cancer [12, 13, 15, 16, 26].…”

Section: Discussionmentioning

confidence: 84%

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SEC62 and SEC63 Expression in Hepatocellular Carcinoma and Tumor-Surrounding Liver Tissue

Casper

Linxweiler

et al. 2021

Visc Med

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Introduction: The endoplasmic reticulum transmembrane proteins Sec61, Sec62, and Sec63 are responsible for the intracellular trafficking of precursor proteins and affect intracellular signaling. SEC62 overexpression has been linked to various human cancers. Our aim was to investigate SEC62 and SEC63 expression in hepatocellular carcinoma (HCC) and surrounding liver tissue. Patients and Methods: Primary liver tissue was collected from 11 consecutive patients (70 ± 9 years; 10 men) who underwent HCC resection. In the HCC and the tumor-surrounding liver tissue we investigated SEC62 und SEC63 mRNA expression using quantitative real-time PCR. For Sec62, immunohistochemistry was performed. Results: SEC62and SEC63 total mRNA contents were significantly (p = 0.001) higher in HCCs (CT 22.5 ± 0.4 and 22.6 ± 0.3) when compared to the surrounding tissue (CT 24.6 ± 0.6 and 25.1 ± 0.9). Using the comparative CTmethod, SEC62 and SEC63 expression in HCC was increased 5- and 8.1-fold, respectively, in comparison to surrounding tissue. For Sec62 immunohistochemistry, the mean immunoreactive scores (IRS) were 7.9 ± 2.9 for HCC and 4.8 ± 1.2 for non-tumorous liver (p = 0.027). The mean IRS in HCC were 5.7 ± 3.5 and 8.9 ± 2.3 for patients without (n = 3) and with tumor recurrence (n = 8), respectively. Conclusions: Overexpression of SEC62 and SEC63 is a common feature of HCC. The role of Sec62 as a prognostic marker for tumor recurrence after surgery and its potential role in treatment stratification must be addressed in future studies.

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Sec62 promotes early recurrence of hepatocellular carcinoma through activating integrinα/CAV1 signalling

Cited by 16 publications

References 35 publications

Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway

Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway

A robust twelve-gene signature for prognosis prediction of hepatocellular carcinoma

<b><i>SEC62</i></b> and <b><i>SEC63</i></b> Expression in Hepatocellular Carcinoma and Tumor-Surrounding Liver Tissue

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