Mucosa-associated lymphoma antigen 1 (MALT1) is a lymphoma oncogene that regulates signal transduction as a paracaspase and an adaptor protein. Yet, the role of MALT1 in other solid cancers such as melanoma is not well-understood. Here, we demonstrate that MALT1 is overexpressed in malignant melanoma cells, and predicts a poor disease-free survival. MALT1 inhibition via shRNA-mediated gene silencing or pharmacologically with MI-2 compound markedly reduced cell growth and migration of A2058 and A375 melanoma cell lines in vitro. Subcutaneous tumor growth analysis revealed that MALT1 gene silencing significantly reduced tumor growth and metastasis to the lung. Consistently, the subcutaneous tumors with MALT1 loss had increased cell apoptosis and decreased proliferation. In addition, these tumors showed signs of mesenchymal–epithelial transition as indicated by the upregulation of E-cadherin and downregulation of N-cadherin and β1-intergrin. Further molecular analysis revealed that MALT1 is required for c-Jun and nuclear factor-κB (NF-κB) activation by tumor necrosis factor-α. Forced expression of the c-Jun upstream activator MKK7 reversed the cell growth and migration defects caused by MALT1 loss. In contrast, NF-κB activation via expression of p65ER, a fusion protein containing NF-κB p65 and the tamoxifen-responsive mutant estrogen receptor, induced minimal effects on cell proliferation, but diminished cell death induced by MALT1 loss and TRAIL treatment. Together, these findings demonstrate that MALT1 promotes melanoma cell proliferation and motility through JNK/c-Jun, and enhances melanoma cell survival through NF-κB, underscoring MALT1 as a potential therapeutic target and biomarker for malignant melanoma.

Hepatorenal toxicities are an important side effect of anthracycline antibiotics. The objective of this study was to determine whether sesamin (Ses) protects against acute doxorubicin (DOX)-induced hepatorenal toxicities. Rats received daily treatment with either 0.5% carboxymethylcellulose (10 mL/kg) or Ses (10, 20 and 40 mg/kg) orally for 10 days, followed by an intravenous injection at day 8 of either saline (10 mL/kg) or DOX (20 mg/kg). Hepatorenal toxicity was assessed by measuring the levels of serum creatinine (Cre), blood urea nitrogen (BUN), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP). The protein expression of 4-hydroxynonenal (4-HNE) in hepatorenal tissues was evaluated using immunohistochemistry. The malondialdehyde (MDA) content and antioxidant activity in the kidney and liver tissues were also measured. The results suggest that pretreatment with Ses ameliorated DOX-induced liver and kidney injury by lowering the serum ALT, AST, ALP, Cre and BUN levels ( p < 0.05 or p < 0.01), and the histological damage to the liver and kidney tissues induced by DOX compared to control were also significantly attenuated by Ses. Furthermore, Ses significantly decreased the DOX-induced increase of MDA and 4-HNE and increased the activity of CAT, SOD and GPX compared to the DOX-treated rats ( p < 0.05 or p < 0.01), whereas the change of DOX + Ses (10 mg/kg) group is not significant compared to the DOX-treated group ( p > 0.05). These findings indicate that Ses elicits a typical protective effect against DOX-induced acute hepatorenal toxicity via the suppression of oxidative stress.

Oral cancer is one of the common cancers worldwide, among which over 90% are oral squamous cell carcinomas (OSCC). MicroRNAs act as critical regulators of cancer development and progression. MiR-103a-3p has been reported to be upregulated in OSCC patients and closely correlated to poor prognosis, yet its roles in the progression of OSCC remain undisclosed. In this study, we knocked down the expression of miR-103a-3p in two OSCC cell lines in vitro, and significantly repressed cell proliferation and cell cycle arrest at the G1 phase were observed, accompanied by decreased proliferating cell nuclear antigen, cyclin D1, cyclin B1 and increased PTEN levels. MiR-103a-3p inhibition also induced apoptosis as evidenced by increased apoptotic cells and upregulated cleaved caspase-9/casapase-3 expression. We established a xenograft model in nude mice and found that miR-103a-3p knockdown also suppressed tumor growth in vivo. Besides, the expression of regulator of calcineurin1 (RCAN1), known as its anti-tumor effect, was negatively correlated with the miR-103a-3p level in OSCC cells. We validated that RCAN1 was a downstream target of miR-103a-3p using the dual-luciferase assay. RCAN1 silencing reversed the cell proliferative inhibition, cell cycle arrest and cell apoptosis induced by miR-103a-3p knockdown. In addition, we found that long non-coding RNA LINC00675 acted as a sponge of miR-103a-3p and promoted the expression of miR-103a-3p targets RCAN1 and PTEN. In summary, miR-103a-3p inhibition represses proliferation and induces apoptosis of OSCC cells through regulating RCAN1, and miR-103a-3p may act as a novel diagnostic marker and therapeutic target for OSCC.