探討MAPK/ERK訊息傳遞相關之新穎微型RNA在黑色素瘤中BRAF抑制劑之抗藥性及其微環境之調控及作用(3/3)

The mitogen-activated protein kinase (MAPK/ERK) signaling occupies an essential role in many cancer progressions, including melanoma. BRAF is mutated frequently in melanoma (~60-80%) and this causes MAPK/ERK signaling activation. BRAF inhibitors such as PLX4032 (Vemurafenib) have improved overall survival in BRAF mutant melanoma patients, but the most patients will develop drug resistance within an average 7 months via reactivation of MAPK/ERK and alternative pathways. Notably, the activity of MAPK/ERK signaling can be modulated by microNA (miRNAs) derived from tumor microenvironment through extracellular vesicles. As consequence, these miRNAs contribute significantly to therapy responses.Our previous efforts had led to identify 22 miNAs associated with MAPKERK pathway. Most importantly, our studies demonstrated that miR-524-5p and miR-596 regulate MAPK/ERK signaling to suppress melanoma (Liu et al., Journal of Investigative Dermatology, 2018 and Oncotarget, 2014). Consistent with this premise, miR-524-5p overexpression led to reduce the development of PLX4032-resistant melanoma in vitro and in vivo through MAPK/ERK and PI3K/AKT signaling pathways. Interestingly, miR-524-5p level was higher in complete response compared partial response patients treated with BRAF inhibitors (Nguyen MH et al., Submitted). The significance of our work has been specifically recognized and mentioned in a review article by a leading scientist in the field (Masliah-Planchon, 2016). Given that the advantage of being the leading position in this subject, we will systematically delineate how these 22 miRNAs functionally interact with MAPK/ERK pathway. Specifically, we will evaluate whether these candidate miRNAs have the therapeutic effects for melanoma, and BRAF inhibitor-induced resistance and second tumorigenesis. Most importantly, the possible roles of tumor microenvironment in this regard will be investigated. For example, how these miRNAs influence the tumor microenvironment mechanistically. The ultimate goal of this proposal is to decipher the molecular network of candidate miRNAs in MAPK/ERK signaling; and hopefully, the knowledge we gain from this study can potentially be extended in the discovery of new prognosis or therapy targets for diseases.