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FTO-mediated LINC01134 stabilization to promote chemoresistance through miR-140-3p/WNT5A/WNT pathway in PDAC

Jin Lu1, Yongsheng Yang2, Xiangliang Liu1

  • 1Cancer Center, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China.

Cell Death & Disease
|November 2, 2023
PubMed

Insights

Pancreatic cancer (PDAC) resistance to gemcitabine (GEM) chemotherapy is a major challenge. This study reveals LINC01134 promotes GEM resistance by enhancing stemness and cell cycle modulation, offering new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer often diagnosed at late stages, limiting treatment efficacy.
  • Gemcitabine (GEM) is the first-line chemotherapy for PDAC, but resistance significantly hinders clinical outcomes.
  • Lack of effective biomarkers for gemcitabine resistance necessitates the identification of novel prognostic markers and therapeutic targets.

Purpose of the Study:

  • To elucidate a novel regulatory mechanism driving gemcitabine resistance in pancreatic ductal adenocarcinoma.
  • To identify LINC01134 as a potential biomarker and therapeutic target for overcoming chemotherapy resistance in PDAC.

Main Methods:

  • Analysis of LINC01134 expression in PDAC patient tumors.
  • In vitro and in vivo functional studies to assess the role of LINC01134 in gemcitabine resistance.
  • Investigation of the molecular mechanisms involving microRNAs (miR-497-5p, miR-140-3p), WNT5A, and FTO.

Main Results:

  • LINC01134 was significantly upregulated in PDAC tumors.
  • LINC01134 promotes PDAC gemcitabine resistance by enhancing stem cell features and modulating the cell cycle.
  • LINC01134 downregulates miR-140-3p, leading to increased oncogenic WNT5A expression.
  • FTO-mediated stabilization of LINC01134 contributes to gemcitabine resistance via the miR-140-3p/WNT5A/WNT pathway.

Conclusions:

  • FTO-mediated stabilization of LINC01134 is a key mechanism promoting gemcitabine resistance in PDAC.
  • LINC01134, regulated by FTO, represents a promising prognostic marker and therapeutic target for PDAC patients.
  • Targeting the FTO-LINC01134-miR-140-3p-WNT5A axis could offer new strategies to overcome gemcitabine resistance in pancreatic cancer.

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