UHMK1 regulates VM formation in OSCC by interacting with STMN1

Oral squamous cell carcinoma (OSCC) is a common malignant tumor in the head and neck region and clinically characterized by relatively high invasiveness and a propensity for metastasis. Patients generally exhibit nonsatisfactory prognosis. Beyond the classical endothelium-dependent angiogenesis pathway, vasculogenic mimicry (VM), a nonclassical blood supply mechanism whereby tumor cells themselves form microcirculatory conduits, plays a significant role in tumor progression. However, the regulatory mechanism of VM formation remains to be fully understood. U2AF homologous motif kinase 1 (UHMK1) is a regulatory protein possessing serine/threonine kinase activity and RNA-binding capability and was found to be overexpressed in OSCC tissues in our previous research. The present study aimed to explore the association between UHMK1 expression in OSCC and VM formation and elucidate the potential molecular mechanisms by which UHMK1 regulates VM development. Immunohistochemistry (IHC) results demonstrated that UHMK1 upregulation in OSCC was significantly correlated with VM structure, and both were associated with poor clinical outcomes and shortened patient survival time. In vitro experiments revealed that UHMK1 knockdown markedly suppressed VM formation in OSCC cells. Bioinformatics prediction and co-immunoprecipitation (co-IP) assays confirmed the interaction between UHMK1 and stathmin1 (STMN1). Further investigations indicated that UHMK1 stabilized STMN1 protein expression by inhibiting its ubiquitin-proteasome degradation pathway, and these two might jointly activate the PI3K/AKT/mTOR signaling pathway to regulate VM formation. The current study revealed the key role of UHMK1-STMN1 in coregulating VM formation in OSCC, providing new insights into the tumor microenvironment and identifying potential targets for anti-angiogenic therapy.