Oncostatin M modulates the biology of cholangiocarcinoma cells and the tumor microenvironment

IF 4 3区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Digestive and Liver Disease Pub Date : 2025-02-01 DOI:10.1016/j.dld.2025.01.031

N. Porro , J. Nurcis , S. De Siervi , M. Cadamuro , C. Turato , S. Mantovani , B. Oliviero , L. Fabris , M. Mondelli , F. Marra , M. Parola , Al. Caligiuri , M. Pastore , S. Cannito , A. Gentilini

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引用次数: 0

Abstract

Background and Aims

Cholangiocarcinoma (CCA) is a highly aggressive tumor characterized by high resistance to chemotherapy and poor prognosis. Increasing evidence highlights that oncostatin M (OSM) regulates the tumor microenvironment (TME) and orchestrates the crosstalk between cancer and stromal cells. This project aims at elucidating the involvement of this factor and its receptor in iCCA progression, as well as in tumor-stroma interaction.

Method

Expression of OSM and its receptor was analysed in patients with iCCA by immunohistochemistry or RT-PCR. Two human iCCA cell lines (HuCCT-1 and CCLP-1) and two type of cultured stromal cells have been used in this study. Cell migration and invasiveness of iCCA cells has been evaluated by performing chemotaxis and invasion assays. Knockdown of OSMR and gp130 was carried out with specific siRNA in iCCA cells.

Results

iCCA cells expressed both OSM receptors and OSM at protein levels. In human CCA specimens, OSM was expressed at higher levels in cancer cells and in the tumor microenvironment with respect to peritumoral tissue. In addition, OSMR mRNA levels were higher in CCA. Exposure of iCCA to OSM induced a dose-dependent increase in cell migration and invasion. These effects were mediated by cytoskeletal rearrangement (increased expression of p-FAK, p-paxillin and p-MLC2), and inducing EMT. OSM also upregulated cancer-associated pathways including c-Myc, G6PD, p-Rb, and p-Akt The ability of OSM to induce iCCA cell migration and invasion was reduced after knockdown of the OSMR or of gp130, or treatment with ruxolitinib. Incubation of primary hepatic stellate cells, HSCs or cancer-associated fibroblasts, CAFs with conditioned medium collected from iCCA cells treated with OSM resulted in increased cell migration, suggesting a role in the formation of a dense fibrotic tumor microenvironment.

Conclusions

This study identifies the OSM/OSMR axis as a novel system potentially implicated in cholangiocarcinogenesis with modulation of the tumor microenvironment.

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来源期刊

Digestive and Liver Disease 医学-胃肠肝病学

CiteScore

6.10

自引率

2.20%

发文量

632

审稿时长

19 days

期刊介绍： Digestive and Liver Disease is an international journal of Gastroenterology and Hepatology. It is the official journal of Italian Association for the Study of the Liver (AISF); Italian Association for the Study of the Pancreas (AISP); Italian Association for Digestive Endoscopy (SIED); Italian Association for Hospital Gastroenterologists and Digestive Endoscopists (AIGO); Italian Society of Gastroenterology (SIGE); Italian Society of Pediatric Gastroenterology and Hepatology (SIGENP) and Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD). Digestive and Liver Disease publishes papers on basic and clinical research in the field of gastroenterology and hepatology. Contributions consist of: Original Papers Correspondence to the Editor Editorials, Reviews and Special Articles Progress Reports Image of the Month Congress Proceedings Symposia and Mini-symposia.