MicroRNA-378-3p/5p suppresses the migration and invasiveness of oral squamous carcinoma cells by inhibiting KLK4 expression

Abstract

Distant metastasis frequently occurs in oral squamous cell carcinoma (OSCC) and contributes to the adverse prognosis for patients with OSCC. However, the potential mechanisms behind the metastasis have not yet been clarified. This study investigated the role of miR-378 in the migration and invasiveness of OSCC in vitro and in vivo. According to our results, the migration and invasiveness of OSCC cells were increased in cells overexpressing miR-378, and reduced in cells where miR-378-3p/5p was silenced. In addition, overexpression of miR-378 suppressed the expressions and activities of matrix metalloproteinase 9 (MMP-9) and MMP-2. Epithelial–mesenchymal transition (EMT) was restrained by overexpression of miR-378, as evidenced by an increase in E-cadherin expression and decrease in N-cadherin and uPA expression. However, knockdown of miR-378-3p/5p produced the opposite results. Moreover, kallikrein-related peptidase 4 (KLK4) was confirmed to be a target gene of miR-378. Overexpression of KLK4 reversed the induced decrease in migration and invasiveness of cells overexpressing miR-378 by upregulating the levels of MMP-9, MMP-2, and N-cadherin, and downregulating the level of E-cadhrin. Finally, the number of metastasis nodules in the lung tissues of nude mice was reduced by overexpression of miR-378, whereas the number of metastases increased with knockdown of miR-378. Taken together, our results suggest that the miR-378–KLK4 axis is involved in the mechanisms behind the migration and invasiveness of OSCC cells. Targeting the miR-378–KLK4 axis may be an effective measure for treating OSCC.

Prognostic value of microRNA‑378 in esophageal cancer and its regulatory effect on tumor progression

“…This may provide novel diagnostic and therapeutic options for the future clinical management of human gastric cancer (37). Taken together, the results of the present study are consistent with previous findings (35,38,39).…”

miR‑144‑3p inhibits tumor cell growth and invasion in oral squamous cell carcinoma through the downregulation of the oncogenic gene, EZH2

“…For example, miR-188 overexpression has been reported to inhibit OScc cell growth and invasion by targeting SIX1 (26). cui et al revealed that miR-378-3p/5p suppressed OScc metastasis by inhibiting kallikrein-related peptidase 4 (KLK4) expression (6). ding et al demonstrated that miR-145 overexpression suppressed the growth of OScc xenograft tumors in vivo (27).…”

“…MicroRNAs (miRNAs or miRs) are short, non-coding RNAs that can bind to the 3'-untranslated region (3'-UTR) of target mRNAs to regulate gene expression, leading to the degradation of target mRNAs or translational inhibition of functional proteins (4). Emerging evidence indicates that miRNAs are extensively involved in the development of OScc, functioning as oncogenes or tumor suppressors, depending on the target genes (5)(6)(7). For instance, chou et al demonstrated that miR-486 overexpression led to growth inhibition and apoptosis induction by targeting discoidin domain receptor-1 (ddR1) in oral cancer cells (8).…”

Depicting the Implication of miR-378a in Cancers

“…miR-378a was identified as an onco-RNA in various tumors, including lung cancer, 22 , 25 , 27 - 29 ovarian cancer, 30 - 32 cervical cancer, 33 nasopharyngeal carcinoma, 34 melanoma, 35 osteosarcoma, 36 cholangiocarcinoma, 37 acute myeloid leukemia, 38 chronic myeloid leukemia, 21 and Burkitt lymphoma. 39 In contrast, it acted as an tumor suppressor in gastric cancer, 40 colorectal cancer, 41 liver cancer, 42 glioblastoma, 43 prostate cancer, 44 breast cancer (BC), 45 medulloblastoma (MB), 46 pituitary adenoma (PA), 47 oral squamous cell carcinomas, 48 bladder cancer, 49 esophageal carcinoma, 50 rhabdomyosarcoma (RMS), 51 and retinoblastoma (RB). 52 Compared with normal tissues and no lymph node metastasis cancer tissues, miR-378a was upregulated in cervical cancer tissues, especially in CIN III and lymph node metastasis cervical cancer.…”