CLCA1 Modulates Pancreatic Cancer Proliferation via SIRT1-HIF-1α Pathway.

Authors

Dingyuan Hu, Yilei Yang, Jinlin Ge, Wenyu Tong, Tianhao Xia, Yangyang Teng, Limiao Lin

Published in

Clinical laboratory. Volume 72. Issue 6. Jun 01, 2026.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a form of cancer known for its aggressive behavior, poor survival rates, and high resistance to chemotherapy. Our previous study has found that low calcium-activated chloride channel regulator 1 (CLCA1) expression is associated with worse survival of patients with PDAC, yet its underlying function in PDAC is not clear.
We constructed CLCA1-overexpressed Pancreatic Adenocarcinoma Cell Line 1 (PANC-1) cells and in-vestigated its effect on the cell growth and invasion by Cell Counting Kit-8 (CCK-8) Assay and Transwell Migration Assay. Sensitivity of PANC-1 cells to gemcitabine and hypoxia environment was also studied. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based-proteomics was employed to discover key molecular cause based on CLCA1-overexpression. Further mechanistic insights into the SIRT1/HIF-1α axis were obtained using Ribonucleic Acid (RNA) interference, qPCR, and western blotting.
CLCA1 expression was significantly reduced in PANC-1 cells. Overexpression of CLCA1 inhibited proliferation and invasion while enhancing sensitivity to gemcitabine. Proteomic study suggested that SIRT1 expression was dramatically downregulated in CLCA1-over expression PANC-1 cells compared with control PANC-1 cells. Mechanistic studies revealed that CLCA1 downregulates SIRT1 expression, leading to reduced stabilization of HIF-1α and subsequent suppression of its downstream hypoxia-responsive genes (GLUT1, LDHA). Hypoxia partially reversed this suppression. Synergistic effects were observed with CLCA1 overexpression and SIRT1 knockdown, significantly reducing tumor cell proliferation and HIF-1α expression.
We found that CLCA1 modulates the SIRT1/HIF-1α pathway, suppressing tumor proliferation, and might enhance gemcitabine sensitivity in pancreatic cancer cells. This investigation points to CLCA1 as a viable therapeutic target for tackling hypoxia-induced chemoresistance and enhancing treatment success in PDAC. Further exploration of CLCA1-based therapies could offer new opportunities for clinical translation.

PMID:
42295313
Bibliographic data and abstract were imported from PubMed on 15 Jun 2026.

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