Dataset Information

PIK3R1 negatively regulates the epithelial-mesenchymal transition and stem-like phenotype of renal cancer cells through the AKT/GSK3?/CTNNB1 signaling pathway.

ABSTRACT: The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway has been identified as an important pathway in renal cell carcinoma (RCC). We have reported a nonsense mutation in PIK3R1, which encodes the regulatory subunit of PI3K, in a metastatic RCC (mRCC), while the mutation was absent in the corresponding primary RCC (pRCC). To identify the function of PIK3R1 in RCC, we examined its expression in normal kidney, pRCC and mRCC by immunohistochemistry and real-time polymerase chain reaction. The expression of PIK3R1 significantly decreased in pRCC and was further reduced in mRCC compared with normal tissue. Besides, its expression levels were negatively correlated with T-category of tumor stage. Additionally, 786-O and A-704 cells with PIK3R1 depletion introduced by CRISPR/Cas9 system displayed enhanced proliferation, migration and epithelial-mesenchymal transition (EMT), and acquired a stem-like phenotype. Moreover, the PIK3R1 depletion promoted the phosphorylation of AKT in the cells. The knockdown of AKT by shRNA reduced p-GSK3? and CTNNB1 expression in the cells, while the depletion of CTNNB1 impaired stem-like phenotype of the cells. Overall, PIK3R1 down-regulation in RCC promotes propagation, migration, EMT and stem-like phenotype in renal cancer cells through the AKT/GSK3?/CTNNB1 pathway, and may contribute to progression and metastasis of RCC.

SUBMITTER: Lin Y

PROVIDER: S-EPMC4355729 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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PIK3R1 negatively regulates the epithelial-mesenchymal transition and stem-like phenotype of renal cancer cells through the AKT/GSK3β/CTNNB1 signaling pathway.

Lin Youcheng Y Yang Zhao Z Xu Abai A Dong Pei P Huang Yi Y Liu Huan H Li Feida F Wang Haifeng H Xu Qian Q Wang Yongqiang Y Sun Da D Zou Yong Y Zou Xiaowen X Wang Yu Y Zhang Duo D Liu Hongjie H Wu Xun X Zhang Meng M Fu Yu Y Cai Zhiming Z Liu Chunxiao C Wu Song S

Scientific reports 20150311

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway has been identified as an important pathway in renal cell carcinoma (RCC). We have reported a nonsense mutation in PIK3R1, which encodes the regulatory subunit of PI3K, in a metastatic RCC (mRCC), while the mutation was absent in the corresponding primary RCC (pRCC). To identify the function of PIK3R1 in RCC, we examined its expression in normal kidney, pRCC and mRCC by immunohistochemistry and real-time polymerase chain reactio ...[more]

PMID: 25757764

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Project description:Metastatic dissemination of solid tumors is often initiated by reactivation of an embryonic development program, epithelial-to-mesenchymal-transition (EMT). EMT has been associated with acquiring invasiveness and resistance to conventional therapies. However, the precise role of EMT during renal cell carcinoma is still debatable and is under investigation. In this context, our study is designed to evaluate the role of cyclosporine (CsA) and transforming growth factor-? (TGF?) administration in inducing EMT-like state in renal carcinoma cells. We also studied the associated phenotypic changes which may lead to tumor metastasis.The morphological changes in renal cell carcinoma cells (A498) treated with TGF-?/CsA were observed by microscopy. Atomic force microscope was used to evaluate the changes in elasticity of cells treated with TGF-?/CsA. The expression of mesenchymal and chemoresistance genes were checked by RT-PCR. Assays for migration, invasion, sphere formation ability and expression of cancer stem cell-like phenotypes were done to evaluate the metastatic potential of these cells. Lineage specific differentiations were also done to determine the acquisition of stem-cell like phenotype.Our results showed that treatment with TGF-?/CsA led to loss of epithelial characteristics and gain of mesenchymal phenotype in vitro. Changes in shape and elastic properties of the cancer cells favoured metastatic progression, increased tumorisphere formation and invasiveness post treatment. We also observed higher expression of chemoresistance and stemness markers in EMT-induced cells. These cells also differentiated to various lineages like osteoblasts, adipocytes, neural and hepatic cells when induced with the respective differentiation media.We concluded that TGF-?/CsA treatment led to acquisition of EMT-like cancer stem cells phenotype that enhanced local invasion and dissemination of renal carcinoma cells. This subpopulation of cells with EMT-like phenotype a can provide a better perception of the metastatic process. This can provide an in vitro system for testing pharmaceuticals for modulating EMT as a viable strategy within the therapeutic armamentarium for RCC patients. The results of our findings also suggest that CsA directly induced EMT like changes in epithelial cell which may be responsible for the potential risk of malignancy in transplant patients.

Project description:Perturbations in the adipocytokine profile, especially higher levels of leptin, are a major cause of breast tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether leptin is involved in epithelial-mesenchymal transition (EMT). Here, we provide molecular evidence that leptin induces breast cancer cells to undergo a transition from epithelial to spindle-like mesenchymal morphology. Investigating the downstream mediator(s) that may direct leptin-induced EMT, we found functional interactions between leptin, metastasis-associated protein 1 (MTA1), and Wnt1 signaling components. Leptin increases accumulation and nuclear translocation of ?-catenin leading to increased promoter recruitment. Silencing of ?-catenin or treatment with the small molecule inhibitor, ICG-001, inhibits leptin-induced EMT, invasion, and tumorsphere formation. Mechanistically, leptin stimulates phosphorylation of glycogen synthase kinase 3? (GSK3?) via Akt activation resulting in a substantial decrease in the formation of the GSK3?-LKB1-Axin complex that leads to increased accumulation of ?-catenin. Leptin treatment also increases Wnt1 expression that contributes to GSK3? phosphorylation. Inhibition of Wnt1 abrogates leptin-stimulated GSK3? phosphorylation. We also discovered that leptin increases the expression of an important modifier of Wnt1 signaling, MTA1, which is integral to leptin-mediated regulation of the Wnt/?-catenin pathway as silencing of MTA1 inhibits leptin-induced Wnt1 expression, GSK3? phosphorylation, and ?-catenin activation. Furthermore, analysis of leptin-treated breast tumors shows increased expression of Wnt1, pGSK3?, and vimentin along with higher nuclear accumulation of ?-catenin and reduced E-cadherin expression providing in vivo evidence for a previously unrecognized cross-talk between leptin and MTA1/Wnt signaling in epithelial-mesenchymal transition of breast cancer cells.

Dataset Information

PIK3R1 negatively regulates the epithelial-mesenchymal transition and stem-like phenotype of renal cancer cells through the AKT/GSK3?/CTNNB1 signaling pathway.

Publications

PIK3R1 negatively regulates the epithelial-mesenchymal transition and stem-like phenotype of renal cancer cells through the AKT/GSK3β/CTNNB1 signaling pathway.

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