Tumor suppressive microRNA-375 regulates lactate dehydrogenase B in maxillary sinus squamous cell carcinoma

Abstract

Abstract. The expression of is significantly reduced in cancer tissues of maxillary sinus squamous cell carcinoma (MSSCC). The aim of this study was to investigate the functional significance of miR-375 and a possible regulatory role in the MSSCC networks. Restoration of miR-375 significantly inhibited cancer cell proliferation and invasion in IMC-3 cells, suggesting that miR-375 functions as a tumor suppressor in MSSCC. Genome-wide gene expression data and luciferase reporter assays indicated that lactate dehydro genase B (LDHB) was directly regulated by miR-375. Cancer cell proliferation and invasion were significantly inhibited by transfection of si-LDHB into IMC-3 cells, suggesting that LDHB may play a role in MSSCC oncogenic function. In clinical MSSCC specimens, LDHB mRNA levels were up-regulated in cancer tissues, which were inversely correlated with the expression of miR-375. In addition, Kaplan-Meier curves and log-rank tests revealed that the high mRNA expression levels of LDHB had a significant adverse effect on survival rate. The identification of a cancer network regulated by the miR-375 tumor suppressor could provide new insights into the molecular mechanisms of MSSCC oncogenesis. IntroductionMaxillary sinus squamous cell carcinoma (MSSCC) is a malignant epithelial tumor originating in the respiratory mucosa of the maxillary sinus. MSSCC comprises 2-3% of all head and neck tumors, with an annual incidence of 0.5-1.0 per 100,000 people (1,2). Since the clinical symptoms of patients with MSSCC are very insidious, tumors are often diagnosed at advanced stages. Despite advances in multimodality therapy including surgery, radiotherapy and chemotherapy, the 5-year survival rate for MSSCC has remained ~50%. Although regional lymph node metastasis and distant metastasis are uncommon (20%), the high rate of locoregional recurrence (60%) contributes to poor survival (3). The results of epidemiological studies have suggested that occupational exposures to leather, wood dust, nickel, arsenic and formaldehyde are risk factors for MSSCC (4-6); a point of divergence from head and neck squamous cell carcinomas (HNSCC) of the tongue, oral cavity and pharynx. Few reports have performed genome analysis of MSSCC. Understanding the molecular oncogenic pathways underlying MSSCC could significantly improve diagnosis, therapy, and disease prevention.Growing evidence suggests that carcinogenesis is induced by overactivation of pro-oncogenic pathways and inactivation of tumor-suppressive pathways (7). In cancer pathways, normal regulatory mechanisms are disrupted by aberrant expression of microRNA (miRNA) (8). miRNAs are a class of small non-coding RNA molecules consisting of 19-22 nucleotides that are involved in a variety of biological processes including development, differentiation, apoptosis, and cell proliferation. They regulate gene expression through translational repression and mRNA cleavage (9). Bioinformatic predictions indicate that miRNAs regulate >30% of protein coding genes (10). So far, 1424 human miRNAs ha...

Stable shRNA Silencing of Lactate Dehydrogenase A (LDHA) in Human MDA-MB-231 Breast Cancer Cells Fails to Alter Lactic Acid Production, Glycolytic Activity, ATP or Survival

“…Heightened expression of LDHB may contribute to tumor acidity, and growth (24) known to occur in parallel to activated RTK-PI3K-AKT-mTOR signaling (25) and is observed in various types of cancer including bladder (26) merkel cell carcinoma (27) lung cancer (28) glioma (29) or maxillary sinus squamous cell carcinoma, most reporting its association with poor survival rates (30). …”

MicroRNA-375 Suppresses Extracellular Matrix Degradation and Invadopodial Activity in Head and Neck Squamous Cell Carcinoma

“…Ectopic overexpression of miR-375 impairs cell invasion of oral cavity, hypopharyngeal, nasopharyngeal, esophageal, breast, hepatocellular, cervical, and gastric cancer cells. 15,20,22,23,65–69 Our previous study 11 reported that stable increased miR-375 expression in both UMSCC1 and UMSCC47 cell lines results in diminished invasion in vitro. The invasive nature of HNSCC is often associated with locoregional invasion and metastasis to cervical lymph nodes.…”

Astaxanthin Inhibits PC-3 Xenograft Prostate Tumor Growth in Nude Mice

“…In the present study, we found a higher expression of miR-375 and miR-487b in the HA group, which indicated that high concentration of astaxanthin could suppress tumor growth by inducing overexpression of miR-375. Also, several studies have shown that the expression of miR-375 is significantly reduced in tumor tissues, and this miRNA functions as a tumor suppressor by targeting several oncogenic genes [48,49,50,51,52]. On the other hand, miR-487b has an important role as a tumor-suppressive by inhibiting cell proliferation, invasion, and migration, and has been mapped to 14q32.31 in metastatic PCa cells [53].…”