Autophagy related RHEB-CSF1R complex promotes tumor metastasis via advancing phosphorylation levels of PI3K, AKT, mTOR in pancreatic cancer

doi:10.3748/wjg.v32.i12.112725

Advanced Search

BPG is committed to discovery and dissemination of knowledge

Home / Archive / Volume 32, Issue 12

This Article

Peer-Review Report of This Article

CrossCheck and Google Search of This Article

Academic Rules and Norms of This Article

Supplementary Materials of This Article

Citation of this article

Corresponding Author of This Article

Research Domain of This Article

Article-Type of This Article

Open-Access Policy of This Article

Times Cited Counts in Google of This Article

Number of Hits and Downloads for This Article

Total Article Views (21)

All Articles published online

The chart showing PDF series, HTML series, Figures (1-11) series, Tables (1-2) series.

Item

Count

PDF

HTML

Figures (1-11)

Tables (1-2)

Sum=42

Publishing Process of This Article

The chart showing Browse series, Download series.

Item

Count

Browse

Download

Sum=24

Mar 28, 2026 (publication date) through Mar 19, 2026

Times Cited of This Article

Times Cited (0)

Journal Information of This Article

Publication Name

World Journal of Gastroenterology

ISSN

1007-9327

Publisher of This Article

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

Basic Study

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 Gastroenterol. Mar 28, 2026; 32(12): 112725
Published online Mar 28, 2026. doi: 10.3748/wjg.v32.i12.112725

Autophagy related RHEB-CSF1R complex promotes tumor metastasis via advancing phosphorylation levels of PI3K, AKT, mTOR in pancreatic cancer

Qian-Xi Deng, Kun Yang, Jin He, Jun-Feng Li, Xiao-Qing Li, Long Zou, Yi-Ming Li, Shu-Man Xu, Zheng Jiang, Lin-Ju Wu

Qian-Xi Deng, Long Zou, Yi-Ming Li, Department of Gastroenterology, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang 621000, Sichuan Province, China

Qian-Xi Deng, Kun Yang, Jin He, Jun-Feng Li, Xiao-Qing Li, Shu-Man Xu, Zheng Jiang, Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China

Lin-Ju Wu, Department of Anesthesiology, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang 621000, Sichuan Province, China

Co-corresponding authors: Zheng Jiang and Lin-Ju Wu.

Author contributions: Deng QX, Yang K, Wu LJ, and Jiang Z contributed to study conception and design; Deng QX, Yang K, He J, Li JF, Li XQ, Zou L, Li YM, and Xu SM contributed to data collection, analysis and interpretation of results; Deng QX, Yang K, and Wu LJ contributed to draft manuscript preparation; Wu LJ and Jiang Z contributed to critical revisions of the intellectual content, and contributed equally as co-corresponding authors; all authors reviewed the results and approved the final version of the manuscript.

Supported by Sichuan Medical and Health Care Promotion Institute Youth Research Project, No. KY2023QN0129; Research Project of Early Gastrointestinal Cancer Physician Co-Growth Program, No. GTCZ-2023-SC-06; and The Third Hospital of Mianyang Research Project, No. 202206.

Institutional review board statement: This study was ratified by the Ethics Committee of the Third Hospital of Mianyang, No. 2023(56).

Institutional animal care and use committee statement: All experimental procedures involving animals were certified by the Institutional Animal Care and Use Committee of Chongqing Medical University, No. IACUC-CQMU-2023-0104.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

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 generated and/or analyzed in this study are available in the Gene Expression Omnibus and The Cancer Genome Atlas databases.

Corresponding author: Lin-Ju Wu, Chief Physician, Department of Anesthesiology, The Third Hospital of Mianyang, Sichuan Mental Health Center, No. 190 East Jiannan Road, Youxian District, Mianyang 621000, Sichuan Province, China. wulinju2149@mysyy.cn

Received: September 3, 2025
Revised: October 21, 2025
Accepted: January 16, 2026
Published online: March 28, 2026
Processing time: 196 Days and 23.3 Hours

Abstract

BACKGROUND

Pancreatic cancer (PC) is a prevalent and highly malignant tumor. Reports indicate that autophagy exerts a dual role, potentially promoting or suppressing tumor progression at different stages of PC. Ras homolog enriched in brain (RHEB) is also recognized as a key gene regulating cellular autophagy through two distinct pathways.

AIM

To investigate RHEB’s role in PC metastasis and the underlying mechanisms.

METHODS

RHEB functions were validated using in vitro, cell counting kit-8 colony formation, and Transwell assays. RNA-seq and co-immunoprecipitation were then used to find proteins interacting with the gene before using transmission electron microscopy and immunofluorescence to validate the relationship between RHEB and autophagy. Western blot further validated the results at the protein level. Rescue experiments were subsequently performed to validate the detailed mechanism, with a distance liver metastasis model even established to explore RHEB’s effects in vivo. Multiple bioinformatic analysis tools were eventually utilized to elucidate RHEB’s mechanism and construct a prognostic signature.

RESULTS

RHEB promoted PC proliferation and metastasis in vitro. Higher RHEB expression was negatively correlated with longer survival times, with the gene also interacting directly with colony stimulating factor 1 receptor (CSF1R) to inhibit autophagy. The RHEB-CSF1R complex further advanced phosphorylation levels of phosphatidylinositol 3-kinase (PI3K), AKT serine/threonine kinase 1, and the mammalian target of rapamycin, as well as autophagy markers. The use of autophagy inhibitors confirmed that the RHEB-CSF1R complex could promote epithelial-mesenchymal transition markers expression levels. Finally, Transwell assays with CSF1R-overexpression/silencing, PI3K activator/inhibitor, and autophagy inhibitor revealed that these factors could affect PC metastasis phenotype.

CONCLUSION

This study found that RHEB lowered PC patients’ survival. RHEB expression promoted PC proliferation, migration, and invasive ability, but it also inhibited autophagy by upregulating and interacting with CSF1R, leading to PI3K, AKT serine/threonine kinase 1, and mammalian target of rapamycin phosphorylation. This, in turn, promoted PC metastasis by promoting epithelial-mesenchymal transition marker expression. The above results indicated that RHEB can be a promising biomarker for predicting prognosis and developing new treatment strategies in PC.

Keywords: Ras homolog enriched in brain; Colony stimulating factor 1 receptor; Autophagy; Phosphorylation of phosphatidylinositol 3-kinase; AKT serine/threonine kinase 1; Mammalian target of rapamycin; Pancreatic cancer; Metastasis

Core Tip: Ras homolog enriched in brain (RHEB), small GTPases, play a crucial role in regulating neuronal activity and have gained attention for their implications in cancer development, particularly in pancreatic cancer (PC). Clarifying the precise mechanism through which the autophagy-related gene RHEB promotes PC metastasis holds the potential for improving prognosis as well as for developing new prevention and treatment strategies. This study aims to elucidate the role of the autophagy-related gene RHEB in PC metastasis.