Abstract
Metastatic melanoma is the most aggressive form of skin cancer and is refractory to therapy. MicroRNAs have been recently discovered as novel molecules that provide therapeutic benefits against melanoma. This work aims to examine the effects of miR-26a and let-7a on the growth and invasiveness of malignant melanoma in vitro and in vivo. In addition, we elucidate the mechanism of action by identifying the target gene of miR-26a. Both miR-26a and let-7a inhibited proliferation and invasiveness and halted the cell cycle at the G1/G0 phase in SKMEL-28 and WM1552C malignant melanoma cell lines. Moreover, miR-26a potently induced apoptosis and downregulated the expressions of microphthalmia-associated transcription factor (MITF) and MAP4K3 in both cell lines. The luciferase reporter assay demonstrated that miR-26a suppresses MITF expression by binding the 3′-UTR, suggesting that MITF is a bona fide target of miR-26a. SiRNA knockdown of the MITF gene confirmed that miR-26a reduced cell viability and induced apoptosis by regulating MITF. Using a murine model, we also found miR-26a significantly retarded the growth of melanoma tumors in vivo. In conclusion, miR-26a and let-7a suppressed the growth and invasiveness of melanoma cells, suggesting that miR-26a and let-7a may represent novel therapies for malignant melanoma.
Highlights
The incidence of metastatic melanoma, the deadliest skin cancer, has increased in the past two decades
It was reported that miR-26a induced apoptosis of melanoma cells by directly targeting the silencer of death domains (SODDs), which has a vital role in preventing apoptosis in the sensitive cell lines of melanoma.[13]
The expression of miR-26a and let-7a was detected by qRT-PCR in SKMEL-28 and WM1552C melanoma cell lines
Summary
The incidence of metastatic melanoma, the deadliest skin cancer, has increased in the past two decades. It is estimated that 76 380 new melanoma cases will be diagnosed in 2016.1. The prognosis of melanoma is poor, with the lower than 20% of. 5-year survival rates for patients who harbor metastatic melanoma.[2,3] Since about 50% patients with melanoma have been found to harbor the activating BRAFV600E mutation,[4] the current targeted therapy focuses on RAS-RAF-MEK-ERK signaling pathway.[5] Even though the initial response to BRAF inhibitors (vemurafenib and dabrafenib) and MEK inhibitors (trametinib and cobimetinib) is impressive, resistance usually develops in the patients within 6–8 months.[6] looking for alternative effective therapies for the metastasized melanoma is an imperative task. It was reported that miR-26a induced apoptosis of melanoma cells by directly targeting the silencer of death domains (SODDs), which has a vital role in preventing apoptosis in the sensitive cell lines of melanoma.[13]
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