Cyclin G1 Expands Liver Tumor-Initiating Cells by Sox2 Induction via Akt/mTOR Signaling

Wen, Wen; Han, Tao; Chen, Cheng; Huang, Lei; Sun, Wen; Wang, Xue; Chen, Shuzhen; Xiang, Di; Tang, Liang; Cao, Dan; Feng, Gen‐Sheng; Wu, Mengchao; Ding, Jin; Wang, Hongyang

doi:10.1158/1535-7163.mct-13-0099

Cited by 42 publications

(28 citation statements)

References 39 publications

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“…The activation of mTOR signaling pathway emerges in 40%-50% of HCC patients and indicates their poor prognosis, revealing its pivotal role in HCC progression [39]. Sporadic literatures support the possibility of a linkage between mTOR activity and tumor-initiating cell maintenance or expansion [40–42], and the blockage of Akt/mTOR signaling could diminish cyclin G1-mediated sex determining region Y box 2 (SOX2) induction, and suppress self-renewal, chemoresistance, and tumorigenicity of hepatoma cells [43]. Our previous data also showed that higher phosphorylation levels of AKT and mTOR occur in HCC cells in response to higher matrix stiffness stimulation (data not shown).…”

Section: Introductionmentioning

confidence: 99%

Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells

et al. 2016

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Matrix stiffness as an important physical attribute of extracellular matrix exerts significant impacts on biological behaviors of cancer cells such as growth, proliferation, motility, metabolism and invasion. However, its influence on cancer stemness still remains elusive. Here, we explore whether matrix stiffness-mediated effects on stemness characteristics occur in HCC cells. As the substrate stiffness increased, HCC cells exhibited high proportion of cells with CD133(+)/EpCAM(+), high expression levels of CD133, EpCAM, Nanog and SOX2, greater self-renewing ability and oxaliplatin resistance. Simultaneously, their phosphorylation levels of Akt and mTOR, as well as p-4E-BP and SOX2 expressions were also obviously upregulated. Conversely, knockdown of integrin β1 partially attenuated higher stiffness-mediated stemness characteristics in HCC cells, and reversed the phosphorylation levels of Akt and mTOR, and expressions of p-4E-BP and SOX2, suggesting that integrin β1 may deliver higher stiffness signal into HCC cells and activate mTOR signaling pathway. Additionally, mTOR inhibitor suppressed the mTOR phosphorylation level and expression levels of p-4E-BP and SOX2 in HCC cells grown on higher stiffness substrate, as well as depressed their stemness properties significantly, favoring a regulating role of mTOR signaling pathway in matrix stiffness-mediated effects on stemness. In summary, matrix stiffness may be involved in the process of stemness regulation via activating integrin β1/Akt/mTOR/SOX2 signaling pathway. To the best of our knowledge, this study first reveals a novel regulating pathway to direct the stemness characteristics in HCC cells.

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Section: Introductionmentioning

confidence: 99%

Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells

et al. 2016

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“…CCNG1, a member of G-type cyclins, acted as cell cycle regulator and was overexpressed in human tumor cells especially in lung carcinoma. CCNG1 was up-expressed in lung carcinoma and could increase cell sensitivity to radiotherapy to promote cell death (24,34). Luciferase reporter assay was performed to verify miR-23b binding to the 3′UTR of CCNG1, which was consistent with the findings in ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

“…CCNG1 acts as a cell cycle regulator in human tumor cells such as cervical carcinoma, hepatocellular carcinoma, breast cancer and lung carcinoma (21,23–26). In hepatocellular carcinoma, Wen et al revealed that CCNG1 may act as a promising biomarker and contribute to the recurrence and chemoresistance (24). Morever, some miRNAs could interact with CCNG1 to affect tumor progression.…”

Section: Introductionmentioning

confidence: 99%

miR‑23b suppresses lung carcinoma cell proliferation through CCNG1

et al. 2018

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Lung carcinoma with high incidence rate could be divided into four subtypes, including small cell carcinoma, squamous cell carcinoma, adenocarcinoma and large cell carcinoma. miR-23b has been reported to have a low expression and play major roles in abundant tumors, however there is little research in lung carcinoma and hence the purpose of this study was to explore the impact of miR-23b in lung carcinoma. The RNA level of miR-23b and cyclin G1 (CCNG1) was measured by reverse transcription quantitative PCR. Luciferase activity reporter assay was used to verify that CCNG1 is a target of miR-23b. MTT and Transwell assays were utilized to test the functional studies of miR-23b in lung cancer cells. In lung carcinoma and lung cancer cells miR-23b expression is low compared with that in paracancerous tissues and normal lung cells. Low miR-23b expression inhibited lung cancer cell proliferation measured by MTT assay. We applied luciferase reporter to determine whether CCNG1 is a target of miR-23b and there was a negative correlation between them. Moreover, interference with CCNG1 reduced the cell proliferation ability, which partially reversed function of miR-23b. miR-23b inhibited cell proliferation of lung cancer by directly targeting CCNG1. It is suggested that miR-23b/CCNG1 axis may present a new target for the treatment of lung cancer.

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“…It is a subtype of Cyclin G of the cyclin family that has a positive and negative regulator of cell growth for different kinds of cells. Although the precise function of Cyclin G1 remains unclear, accumulating evidence has showed that Cyclin G1 abnormally expressed in many types of malignant cancers such as cervical carcinoma (Liang et al 2006), hepatocellular carcinoma (Wen et al 2013), lung carcinoma (Zhao et al 2015) and breast cancer (Reimer et al 1999). Unlike other cyclins, Cyclin G1 has neither a destruction box nor PEST sequences that are responsible for cyclin degradation (Tamura et al 1993).…”

Section: Introductionmentioning

confidence: 99%

The role of Cyclin G1 in cellular proliferation and apoptosis of human epithelial ovarian cancer

et al. 2015

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Cyclin G1 plays an essential role in the development of human carcinoma. Here, we characterized the clinical significance of Cyclin G1 and investigated its role in cellular proliferation and apoptosis of epithelial ovarian cancer (EOC). Western blot was used to evaluate the expression of Cyclin G1 in nine fresh EOC tissues and three fresh normal ovarian tissues. Immunohistochemistry analysis was performed on formalin-fixed paraffin-embedded section of 119 cases of EOCs. Using cell counting kit (CCK)-8 and colony formation assays, we analyzed the effect of Cyclin G1 in cellular proliferation of EOC. Besides, the immunofluorescence and flow cytometry analysis was performed to study the role of Cyclin G1 in cellular apoptosis of EOC. We found Cyclin G1 was up-regulated in EOC tissues compared with the normal ovary tissues. Cyclin G1 expression in EOC was closely correlated with differentiation grade (P = 0.009) and malignant tumor cells in ascites (P = 0.009). The Kaplan-Meier curve showed that higher expression of Cyclin G1 was associated with significantly shorter survival in EOC patients. Multivariate analysis suggested Cyclin G1 expression was an independent prognostic factor for overall survival. CCK-8 and colony formation assays revealed that depletion of Cyclin G1 inhibited the proliferation and clone formation. Combined immunofluorescence and flow cytometry analysis showed that silencing of Cyclin G1 with shRNA could promote apoptosis of ovarian cancer cells. Additionally, the result of immunoprecipitation test showed Cyclin G1 interacted with CDK2 in EOC cells. In summary, our findings suggest that Cyclin G1 may be involved in the prognosis of EOC patients and be a useful therapeutic target for EOC.

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Cyclin G1 Expands Liver Tumor-Initiating Cells by Sox2 Induction via Akt/mTOR Signaling

Cited by 42 publications

References 39 publications

Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells

Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells

miR‑23b suppresses lung carcinoma cell proliferation through CCNG1

The role of Cyclin G1 in cellular proliferation and apoptosis of human epithelial ovarian cancer

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