title: PIK3R1 negatively regulates the epithelial-mesenchymal transition and stem-like phenotype of renal cancer cells through the AKT/GSK3β/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-GSK3β 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/GSK3β/CTNNB1 pathway, and may contribute to progression and metastasis of RCC.
authors.affiliation: Department of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou 510280, China.
authors.forename: Youcheng
authors.initials: Y
authors.lastname: Lin
authors.affiliation: 1] CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou 510280, China.
authors.forename: Abai
authors.initials: A
authors.lastname: Xu
authors.affiliation: Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Dong
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Clinical Application of Cancer Genomics, Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Feida
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Urology, the Second Affiliated Hospital of Kunming Medical College, Kunming 650101, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Clinical Application of Cancer Genomics, Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Da
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou 510280, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zou
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Clinical Application of Cancer Genomics, Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Zou
authors.affiliation: Department of Pathology, Zhujiang Hospital of Southern Medical University, Guangzhou 510280, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Duo
authors.initials: D
authors.lastname: Zhang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou 510280, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Wu
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Clinical Application of Cancer Genomics, Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Clinical Application of Cancer Genomics, Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Clinical Application of Cancer Genomics, Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Department of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou 510280, China.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Liu
authors.affiliation: 1] National-Regional Key Technology Engineering Laboratory for Clinical Application of Cancer Genomics, Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China [2] Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China [3] The Genome Institute, Washington University in St. Louis, 4444 Forest Park Ave, St. Louis, Missouri 63108, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Wu
mesh_terms: D001483:Base Sequence; D064113:CRISPR-Cas Systems; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D058543:Class Ia Phosphatidylinositol 3-Kinase; D018450:Disease Progression; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D055786:Gene Knockout Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006239:Haplotypes; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051176:beta Catenin; C495270:CTNNB1 protein, human; C588001:PIK3R1 protein, human; C000605506:GSK3B protein, human