MiR-378a-5p inhibits angiogenesis of oral squamous cell carcinoma by targeting KLK4

Abstract

Oral squamous cell carcinoma (OSCC) is still a leading cause of cancer death owing to distant metastasis, which is largely facilitated by tumor angiogenesis. MicroRNA (miR)-378a-5p and Kallikrein-related peptidase 4 (KLK4) participate in tumorigenesis and tumor metastasis according to previous studies, yet the exact role they play in tumor angiogenesis remains poorly understood. The aim of the present study was to investigate the effect of miR-378a-5p and KLK4 on angiogenesis of OSCC. MTT assay showed that the expression level of miR-378a-5p was negatively correlated with the proliferation of OSCC cells. ELISA and western blot assay showed that downregulation of miR-378a-5p promoted VEGF expression. Tube formation and in vivo chicken chorioallantoic membrane (CAM) assay showed that inhibition of miR-378a-5p reduced tube formation of human umbilical vein endothelial cells (HUVECs) and newly formed microvessel. On the contrary, overexpression of KLK4 enhanced angiogenesis of OSCC cells with increased VEGF expression, tube formation activity of HUVECs and newly formed microvessel. Moreover, the dual-luciferase assay validated that KLK4 was a target gene of miR-378a-5p. MiR-378a-5p silencing induced tube formation was suppressed by the downregulation of KLK4. Besides, the activation of Wnt/β-catenin signaling pathway in miR-378a-5p antagomir transfected cells was also blocked by the KLK4 shRNA. To sum up, our study suggests that miR-378a-5p suppressed angiogenesis of OSCC at least partly by the regulation of KLK4.

LINC00514 promotes lipogenesis and tumor progression in esophageal squamous cell carcinoma by sponging miR‑378a‑5p to enhance SPHK1 expression

“…Pan et al ( 46 ) found that miR-378a-5p was reduced in renal tissues and renal cell carcinoma cells, and patients with a high miR-378a-5p level exhibited longer overall survival rates than those of patients with low miR-378a-5p levels. In addition, previous reports have demonstrated that miR-378a-5p is implicated in the regulation of metabolism and angiogenesis ( 43 , 47 ). The present study found low expression of miR-378a-5p in ESCC tissues, and this was closely associated with TNM stage and lymph node metastasis, suggesting that the LINC00514/miR-378a-5p signaling axis may be an important therapeutic target for patients with ESCC.…”

miR-378a-5p regulates CAMKK2/AMPK pathway to contribute to cerebral ischemia/reperfusion injury-induced neuronal apoptosis

“…For example, by binding to the 3'-UTR of suppressor of fused homolog (SUFU), miR-378a-5p promoted cell apoptosis in triple negative breast cancer [22]. In oral squamous cell carcinoma, miR-378a-5p was shown to be negatively associated with the cell proliferation and inhibited angiogenesis through binding to kallikrein-related peptidase 4 (KLK4), inhibiting tumorigenesis and tumor metastasis [23]. Therefore, the overexpression of miR-378a-5p benefits the prognosis of cancer patients.…”

Wnt/β‐catenin signaling pathway participates in the effect of miR‐626 on oral squamous cell carcinoma by targeting RASSF4

“…Zhu P et al reported that the interaction of hsa_circ_0004018 and miR‐626/DKK3 with HCC proliferation and migration and xenograft tumor growth involves the Wnt/β‐catenin signaling pathway 11 . Additionally, aberrations in Wnt/β‐catenin are common during human carcinogenesis, which suggests that Wnt/β‐catenin is a major target for the treatment of cancers, including OSCC 51 . Mechanistically, activation of the Wnt/β‐catenin pathway is triggered by the expression of the FZD1 receptor, and the elevation of β‐catenin also indicates the activation of Wnt signaling 52 .…”