HMGA2 promotes epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma via transforming growth factor-β/small mothers against decapentaplegic 2

doi:10.4251/wjgo.121485

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World Journal of Gastrointestinal Oncology

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1948-5204

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastrointest Oncol. Nov 15, 2026; 18(11): 121485
Published online Nov 15, 2026. doi: 10.4251/wjgo.121485

HMGA2 promotes epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma via transforming growth factor-β/small mothers against decapentaplegic 2

Yan-Ning Zhang, Jin-Yong Hao, Xia Lei, Peng-Fei Wang, Shao-Ce Xu, Xiao-Jun Huang

Yan-Ning Zhang, Jin-Yong Hao, Xia Lei, Peng-Fei Wang, Xiao-Jun Huang, Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou 730000, Gansu Province, China

Shao-Ce Xu, Department of Pathology, Lanzhou University Second Hospital, Lanzhou 730000, Gansu Province, China

Author contributions: Zhang YN, Hao JY and Huang XJ conceived and designed the study; Zhang YN, Lei X, and Xu SC conducted the experiments; Zhang YN and Hao JY performed the literature search and wrote the manuscript; Zhang YN and Wang PF conducted statistical analysis of the data; Hao JY and Haung XJ provided funding support; all authors have read and approved the final manuscript.

AI contribution statement: AI tools were not used to generate original scientific data, perform independent scientific analyses, or draw scientific conclusions.

Supported by Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital, No. CY2023-MS-A09; and College Teachers Innovation Fund of Gansu Province, China, No. 2025B-019.

Institutional review board statement: The retrospective clinical study was approved by the Ethics Committee of Lanzhou University Second Hospital (approval No. 2023A-561). All clinical data were anonymized, and the study did not interfere with patient diagnosis or treatment.

Institutional animal care and use committee statement: The animal experiments using BALB/c nude mice were performed in accordance with institutional animal care guidelines and were approved by the Ethics Committee of Lanzhou University Second Hospital (approval No. D2023-382).

Conflict-of-interest statement: The authors declare that they have no conflict of interest.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Corresponding author: Xiao-Jun Huang, MD, Doctor, Department of Gastroenterology, Lanzhou University Second Hospital, No. 82 Cuiying Gate, Chengguan District, Lanzhou 730000, Gansu Province, China. huang_xiaojunn@163.com

Received: April 7, 2026
Revised: July 1, 2026
Accepted: October 12, 2026
Published online: November 15, 2026
Processing time: 215 Days and 16.6 Hours

Abstract

BACKGROUND

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant biliary tract tumor with strong invasiveness, high metastatic potential and poor prognosis. HMGA2 contributes to tumorigenesis and malignant progression in multiple cancers, but its clinical significance, biological functions, and molecular mechanisms in ICC remain unclear.

AIM

To investigate the clinical significance, biological functions, and molecular mechanisms of HMGA2 in ICC progression.

METHODS

HMGA2 expression was evaluated by immunohistochemistry in postoperative tumor specimens from 61 patients with ICC and its associations with clinicopathological features and survival were analyzed. ICC cell lines with HMGA2 knockdown or overexpression were established. Cell proliferation, migration, and invasion were assessed using the cell counting kit-8, 5-ethynyl-2’-deoxyuridine incorporation, wound-healing, and Transwell assays. Xenograft experiments evaluated in vivo tumor growth. Western blotting was conducted to detect the expression of HMGA2, transforming growth factor-β (TGF-β)/small mothers against decapentaplegic 2 (Smad2) pathway-related proteins, and epithelial-mesenchymal transition (EMT)-associated markers.

RESULTS

HMGA2 positivity was associated with poor overall survival (P = 0.009) and remained an independent prognostic factor [hazard ratio (HR) = 2.271, 95% confidence interval (CI): 1.163-4.437, P = 0.016], along with vascular invasion (HR = 2.040, 95%CI: 1.083-3.844, P = 0.027). Cell counting kit-8 assays showed that HMGA2 overexpression significantly increased ICC cell viability at 24 hours, 48 hours, and 72 hours, whereas HMGA2 knockdown reduced cell viability. 5-ethynyl-2’-deoxyuridine assays further confirmed enhanced proliferation after HMGA2 overexpression (21.20% ± 1.27% vs 17.23% ± 0.95%, P = 0.0073) and reduced proliferation after HMGA2 knockdown (47.77% ± 1.16% vs 55.47% ± 1.33%, P = 0.0006). HMGA2 also promoted migration, invasion, xenograft growth, and TGF-β/Smad2-mediated EMT.

CONCLUSION

HMGA2 predicts poor prognosis and promotes ICC progression by activating the TGF-β/Smad2/EMT axis, supporting its potential as a biomarker and therapeutic target.

Keywords: Intrahepatic cholangiocarcinoma; HMGA2; Transforming growth factor-β; Small mothers against decapentaplegic 2 signaling; Epithelial-mesenchymal transition

Core Tip: This study demonstrates that HMGA2 is overexpressed in intrahepatic cholangiocarcinoma (ICC) and independently predicts poor prognosis. Functional experiments showed that HMGA2 promotes ICC cell proliferation, migration, invasion, and tumor growth. Mechanistically, HMGA2 activates the transforming growth factor-β/small mothers against decapentaplegic 2 signaling pathway and induces epithelial-mesenchymal transition, thereby driving ICC progression. These findings highlight HMGA2 as a potential prognostic biomarker and therapeutic target for ICC.