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SOX17 Antagonizes the WNT Signaling Pathway and is Epigenetically Inactivated in Clear-Cell Renal Cell Carcinoma

Lu Wang1, Zhe Wang2, Yuze Zhu1

  • 1Department of Urology, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China.

Oncotargets and Therapy
|June 3, 2021
PubMed
Abstract

Insights

SRY-box containing gene 17 (SOX17) is downregulated in clear-cell renal cell carcinoma (ccRCC) due to epigenetic silencing. SOX17 acts as a tumor suppressor by inhibiting ccRCC cell proliferation and migration, and negatively regulating the WNT pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • SRY-box containing gene 17 (SOX17) is a known tumor suppressor in various cancers.
  • Its role in clear-cell renal cell carcinoma (ccRCC) remains largely unexplored.
  • This study investigates the epigenetic regulation and tumor-suppressive functions of SOX17 in ccRCC.

Purpose of the Study:

  • To determine the expression levels of SOX17 in ccRCC tissues and cell lines.
  • To investigate the epigenetic mechanisms, specifically DNA promoter methylation, regulating SOX17 expression in ccRCC.
  • To elucidate the functional role of SOX17 as a tumor suppressor in ccRCC, including its impact on cell proliferation, migration, and the WNT signaling pathway.

Main Methods:

  • Analysis of SOX17 expression using immunohistochemistry (IHC) and real-time PCR in ccRCC tissues and cell lines.
  • Assessment of SOX17 promoter methylation via methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS).
  • Functional assays including CCK8, colony formation, wound healing, and Matrigel invasion assays to evaluate SOX17's effect on cell behavior. Luciferase assays were used to study SOX17's interaction with the WNT signaling pathway.

Main Results:

  • SOX17 expression was significantly lower in ccRCC tissues compared to adjacent non-malignant tissues.
  • DNA promoter methylation of SOX17 was observed in 60% of ccRCC tissues, indicating epigenetic silencing.
  • Overexpression of SOX17 suppressed ccRCC cell proliferation, migration, and invasion, and downregulated WNT pathway targets c-myc and cyclinD1.

Conclusions:

  • SOX17 is epigenetically silenced through promoter methylation in ccRCC, leading to its downregulation.
  • SOX17 functions as a tumor suppressor in ccRCC by inhibiting cell proliferation and migration.
  • SOX17 negatively regulates the WNT signaling pathway, contributing to its tumor-suppressive role in ccRCC.
Keywords:
DNA methylationSOX17WNT signaling pathwayccRCC

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