PIK3R3 is upregulated in liver cancer and activates Akt signaling to control cancer growth by regulation of CDKN1C and SMC1A

Cancer Med. 2023 Jul;12(13):14413-14425. doi: 10.1002/cam4.6068. Epub 2023 May 22.

Abstract

Background: Liver cancer is a highly malignant disease and the third leading cause of cancer death worldwide. Abnormal activation of PI3K/Akt signaling is common in cancer, but whether phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) plays a role in liver cancer is largely unexplored.

Methods: We determined the expression of PIK3R3 in liver cancer by using TCGA data and our clinical samples and knocked it down by siRNA or overexpressing it by the lentivirus vector system. We also investigated the function of PIK3R3 by colony formation, 5-Ethynyl-2-Deoxyuridine, flow cytometry assay, and subcutaneous xenograft model. The downstream of PIK3R3 was explored by RNA sequence and rescue assays.

Results: We found that PIK3R3 was significantly upregulated in liver cancer and correlated with prognosis. PIK3R3 promoted liver cancer growth in vitro and in vivo by controlling cell proliferation and cell cycle. RNA sequence revealed that hundreds of genes were dysregulated upon PIK3R3 knockdown in liver cancer cells. CDKN1C, a cyclin-dependent kinase inhibitor, was significantly upregulated by PIK3R3 knockdown, and CDKN1C siRNA rescued the impaired tumor cell growth. SMC1A was partially responsible for PIK3R3 regulated function, and SMC1A overexpression rescued the impaired tumor cell growth in liver cancer cells. Immunoprecipitation demonstrated there is indirect interaction between PIK3R3 and CNKN1C or SMC1A. Importantly, we verified that PIK3R3-activated Akt signaling determined the expression of CDKN1C and SMC1A, two downstream of PIK3R3 in liver cancer cells.

Conclusion: PIK3R3 is upregulated in liver cancer and activates Akt signaling to control cancer growth by regulation of CDNK1C and SMC1A. Targeting PIK3R3 could be a promising treatment strategy for liver cancer that deserves further investigation.

Keywords: CDKN1C; PIK3R3; SMC1A; cancer growth; liver cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p57 / genetics
  • Cyclin-Dependent Kinase Inhibitor p57 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver Neoplasms* / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt* / metabolism
  • RNA, Small Interfering

Substances

  • CDKN1C protein, human
  • Cyclin-Dependent Kinase Inhibitor p57
  • Phosphatidylinositol 3-Kinases
  • PIK3R3 protein, human
  • Proto-Oncogene Proteins c-akt
  • RNA, Small Interfering
  • structural maintenance of chromosome protein 1