HIF‐1α‐regulated stanniocalcin‐1 mediates gemcitabine resistance in pancreatic ductal adenocarcinoma via PI3K/AKT signaling pathway

• Published in: Molecular carcinogenesis 2022-09, Vol.61 (9), p.839-850
• Main Authors: Zhao, Fangyu, Yang, Gang, Qiu, Jiangdong, Liu, Yueze, Tao, Jinxin, Chen, Guangyu, Su, Dan, You, Lei, Zheng, Lianfang, Zhang, Taiping, Zhao, Yupei
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenocarcinoma; AKT protein; Animals; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Cell Line, Tumor; Chemoresistance; Chemotherapy; Deoxycytidine - analogs & derivatives; Drug Resistance, Neoplasm - genetics; Gemcitabine; gemcitabine resistance; Glycoproteins; HIF‐1α; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Nude; mRNA; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; PI3K/AKT pathway; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Stanniocalcin; STC1; Therapeutic targets; Tumorigenesis
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.23420

Pancreatic ductal adenocarcinoma (PDAC) has a poor response to the first‐line chemotherapy drug gemcitabine. We previously identified stanniocalcin‐1 as a gemcitabine‐resistant‐related gene, but its specific role and function in pancreatic cancer remain unclear. RT‐qPCR and Western blot were used to evaluate differential protein and mRNA expressions. The biological functions of genes were determined using proliferation and drug‐resistance experiments. Subcutaneous tumorigenesis experiment was performed on nude mice. Prognostic analysis was performed using public databases and our clinical data. We found HIF‐1α‐regulated STC1 expression mediated chemoresistance in pancreatic cancer. Deeper, we explored the action mechanism of STC1 and identified PI3K/AKT as the downstream signaling pathway of STC1. Furthermore, we analyzed clinical data and found that STC1 expression was related to the prognosis of gemcitabine‐treated patients after surgery. In general, we proved the HIF‐1α/STC1/PI3K‐AKT axis participated in PDAC progression and chemoresistance, and STC1 may serve as a potential prognostic factor and therapeutic target for PDAC treatment.