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Miz1 promotes KRAS-driven lung tumorigenesis by repressing the protocadherin Pcdh10

Jing Yang1, Changchun Hou1, Huashan Wang1

  • 1Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA.

Cancer Letters
|December 20, 2022
PubMed

Insights

Loss of Miz1 function inhibits KRAS-driven lung cancer by downregulating Protocadherin-10 (Pcdh10). This Miz1/Pcdh10 axis is crucial for tumor growth and patient survival in non-small cell lung cancer (NSCLC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Targeting KRAS-mutated non-small cell lung cancer (NSCLC) is a significant clinical challenge.
  • Miz1's role in oncogenic KRAS-driven lung tumorigenesis is not well understood.
  • Understanding novel molecular pathways is critical for developing effective NSCLC therapies.

Purpose of the Study:

  • To investigate the role of Miz1 in KRAS-mutated NSCLC.
  • To identify downstream targets of Miz1 in this context.
  • To explore the therapeutic potential of targeting the Miz1/Pcdh10 axis.

Main Methods:

  • Utilized mouse models of KRAS-driven lung cancer.
  • Performed in vitro studies including gene knockout/silencing and cell proliferation assays.
  • Conducted RNA-sequencing, chromatin immunoprecipitation, and in vivo allograft tumor studies.
  • Analyzed human lung adenocarcinoma (LUAD) patient data for Miz1 and Pcdh10 expression and survival correlations.

Main Results:

  • Loss of Miz1 function significantly inhibited proliferation, migration, and invasion in mutant KRAS NSCLC cells.
  • Protocadherin-10 (Pcdh10) was identified as a top upregulated gene upon Miz1 knockout and is directly regulated by Miz1.
  • Silencing Pcdh10 rescued the oncogenic phenotypes of Miz1-deficient cells and reduced tumor growth in vivo.
  • Miz1 was upregulated and Pcdh10 downregulated in human LUAD, particularly in KRAS-mutated tumors, correlating with poor patient survival.

Conclusions:

  • The Miz1/Pcdh10 axis plays a critical role in promoting oncogenic KRAS-driven lung tumorigenesis.
  • Miz1 acts as an oncogene in MT KRAS NSCLC by upregulating Pcdh10.
  • Targeting the Miz1/Pcdh10 pathway represents a potential therapeutic strategy for KRAS-mutated NSCLC.
Keywords:
Gene regulationKRASMiz1Non-small cell lung cancerPcdh10

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