Pseudogene KRT17P3 Promotes NSCLC Progression Through Mir-338-3p/USP7/C-Myc

Anticancer Res. 2024 Dec;44(12):5405-5423. doi: 10.21873/anticanres.17367.

Abstract

Background/aim: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, yet its underlying molecular mechanisms remain poorly understood. Previous research has identified the pseudogene KRT17P3 as a key player in NSCLC chemoresistance, but its functional role in tumor development has not been thoroughly investigated.

Materials and methods: In this study, we utilized in vitro assays to evaluate the impact of KRT17P3 on NSCLC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Additionally, we conducted in vivo experiments to assess tumor metastasis. The mechanisms underlying the action of KRT17P3 were explored through bioinformatics analyses, as well as RNA immunoprecipitation (RIP), luciferase, and chromatin immunoprecipitation (ChIP) assays.

Results: Our findings revealed that KRT17P3 significantly enhances NSCLC cell proliferation, migration, invasion, and EMT, while also promoting tumor metastasis. We discovered that KRT17P3 stabilizes the oncogenic protein c-Myc by competitively binding to miR-338-3p, which leads to upregulation of deubiquitinase USP7. This stabilization of c-Myc serves as a critical driver of NSCLC tumorigenesis, with KRT17P3 expression being upregulated through FOXA1-mediated activation of its promoter.

Conclusion: KRT17P3 plays a pivotal role in NSCLC progression by regulating the USP7/c-Myc axis via miR-338-3p, suggesting its potential as both a prognostic biomarker and a therapeutic target for NSCLC treatment.

Keywords: FOXA1; KRT17P3; NSCLC; USP7; c-Myc.

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation* / genetics
  • Disease Progression*
  • Epithelial-Mesenchymal Transition* / genetics
  • Gene Expression Regulation, Neoplastic*
  • Hepatocyte Nuclear Factor 3-alpha / genetics
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • Humans
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Mice
  • Mice, Nude
  • MicroRNAs* / genetics
  • Proto-Oncogene Proteins c-myc* / genetics
  • Proto-Oncogene Proteins c-myc* / metabolism
  • Pseudogenes* / genetics
  • Ubiquitin-Specific Peptidase 7* / genetics
  • Ubiquitin-Specific Peptidase 7* / metabolism

Substances

  • MicroRNAs
  • MIRN338 microRNA, human
  • Ubiquitin-Specific Peptidase 7
  • Proto-Oncogene Proteins c-myc
  • USP7 protein, human
  • MYC protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • FOXA1 protein, human