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bioRxiv · 10.1101/2025.09.10.672939

RhoV Promotes Proliferation, Migration, and MAPK Activation in Pancreatic Ductal Adenocarcinoma

Wu, S.·Feng, J.·Wang, T.·Hwa, K.·Gao, S.·Xiao, Y.·Yang, D.·Li, X.·Li, Z.·Liu, R.·Liu, Y.·Zhou, X.·Lu, Y.·Huang, C.-K.·Lu, S.
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Abstract

Background and AimsPancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by diagnosis at advanced stages, limited therapeutic options, and frequent resistance to therapies. Although oncogenic KRAS mutations are central drivers of PDAC, alternative pathways indisputably contribute to its tumorigenesis and progression. RhoV, a member of the Rho family of small GTPases, has been implicated in tumor development in other cancer types, such as breast cancer and lung adenocarcinoma; however, its role in PDAC remains unclear. MethodsIn this study, we investigated the expression and functional impact of RhoV on PDAC. Analysis of publicly available datasets and immunohistochemical profiling of 114 PDAC patient specimens were used to evaluate the expression of RhoV in PDAC and its prognostic impact. Overexpression and CRISPR-Cas9-mediated knockout of RhoV were established in three pancreatic cancer cell lines. Functional analyses, such as cell proliferation, migration, invasion, colony formation, spheroid growth, and mouse xenograft, were used to evaluate the role of RhoV in PDAC cells. ResultsRhoV overexpression was associated with reduced overall and recurrence-free survival in public datasets and our own patient cohort. Functional assays demonstrated that RhoV overexpression promoted PDAC cell proliferation, colony formation, and spheroid growth, whereas knockout of RhoV suppressed these changes. Moreover, RhoV enhanced PDAC cell migration and invasion in vitro, accompanied by downregulation of E-cadherin and upregulation of N-cadherin and vimentin, indicating induction of epithelial-mesenchymal transition. Mechanistically, RhoV overexpression activated key MAPK pathway components, including phosphorylation of ERK, JNK, and p38. In vivo, xenograft models confirmed that RhoV drives tumor growth and increases tumor burden. ConclusionThese results establish RhoV as a novel oncogenic factor in PDAC progression and highlight its potential as a biomarker and therapeutic target, warranting further investigation into combinatorial targeting strategies to overcome KRAS inhibitor resistance.

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Wu, S., Feng, J., Wang, T., Hwa, K., Gao, S., Xiao, Y., Yang, D., Li, X., Li, Z., Liu, R., Liu, Y., Zhou, X., Lu, Y., Huang, C.-K., Lu, S.. 2025-09-16. RhoV Promotes Proliferation, Migration, and MAPK Activation in Pancreatic Ductal Adenocarcinoma. https://doi.org/10.1101/2025.09.10.672939

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