High expression of miR-145-3p associated with vascular and perineural invasion presence in cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) is a lethal malignancy of the bile ducts, where lymph node spread critically worsens survival and guides adjuvant chemotherapy decisions. Perineural and vascular invasions are linked to poor prognosis, with hypoxia driving vasculogenesis, angiogenesis, and metastasis. Vascular endothelial growth factor A (VEGFA) plays a key role in invasion and lymph node metastasis. It is regulated by microRNAs such as miR-145-3p and miR-101-3p, which can inhibit angiogenesis and influence EMT, cell migration, and metastasis. This study analyzed miR-145-3p, miR-101-3p, and VEGFA expression in CCA patients, focusing on their roles in invasion, differentiation, metastasis, and staging, alongside biological process enrichment for miR-145-3p target genes. A significant downregulation was observed for miR-145-3p, whereas miR-101-3p showed no changes. VEGFA was upregulated, underscoring its role in angiogenesis. Paradoxically, given its overall downregulation in CCA tissues, higher miR-145-3p levels were found in vascular and perineural invasion cases, suggesting interaction with the tumor microenvironment, possibly via TGF-β1. Elevated miR-145-3p expression in well-differentiated samples suggests it is a favorable prognostic marker and differentiation regulator. Biological enrichment analyses linked miR-145-3p targets to pathways driving vascular invasion, lymphangiogenesis, and TGF-β signaling. Perineural invasion involved nervous system development, MAPK signaling, axon guidance, and neurotrophin signaling, highlighting miR-145-3p's diverse roles in tumor progression and metastasis. Overall, our findings suggest that miR-145-3p acts as a multifaceted regulator in CCA, with potential as both a prognostic biomarker and therapeutic target. Future studies are warranted to elucidate its mechanistic contributions and clinical utility in guiding treatment strategies.