Abstract
BackgroundMelanoma is a type of aggressive skin cancer with a poor survival rate. The resistance to conventional therapy of this disease is, at least in part, attributed to its cancer stem cell population. However, the mechanism of survival and stemness maintenance of cancer stem cells remains to be investigated.MethodsTumorsphere formation assay was used to study the stem-like property of melanoma stem-like cells (MSLC). Chromatin immunoprecipitation (ChIP), promoter luciferase reporter assay were included for exploring the role of MCL-1 in MSLC and electrophoretic mobility shift assay were used to evaluate the interaction between shrimp miR-965 and human Ago2 protein. Melanoma xenograft nude mice were used to study the inhibition of tumor development.ResultsIn the present study, our results showed that myeloid cell leukemia sequence 1 (MCL-1) knocking down induced ER stress and apoptosis, and the expression reduction of stemness associated genes in MSLC, which implied a significant role of MCL-1 in MSLC. Further study indicated that ER stress agonist (tunicamycin) treatment in MSLC results in the translocation of XBP1, an ER stress sensor, into the nucleus to induce MCL-1 expression through direct binding to the − 313- to − 308-bp region of MCL-1 promoter. In addition, we found that a shrimp-derived miRNA (shrimp miR-965) could interact with the human Ago2 protein and suppressed the human MCL-1 expression by binding to the 3′ UTR of MCL-1 mRNA, thereby inhibiting the MSLC proliferation and stemness in vitro and in vivo in a cross-species manner.ConclusionIn conclusion, we identified an important role of MCL-1-ER stress-XBP1 feedback loop in the stemness and survival maintenance of MSLC, and shrimp miR-965, a natural food derived miRNA, could regulate MSLC stemness and survival by targeting MCL-1 and disrupting the balance of MCL-1-ER stress-XBP1 feedback loop. In conclusion, this study indicated an important mechanism of the regulation of MSLC stemness and survival, otherwise it also demonstrated the significance of cross-species-derived miRNA as promising natural drugs in melanoma therapy.
Highlights
Melanoma is a type of aggressive cancer featuring high mortality
myeloid cell leukemia sequence 1 (MCL-1) is upregulated in melanoma stem-like cells (MSLC) MCL-1 is an anti-apoptotic B cell lymphoma-2 (Bcl-2) family member that is overexpressed in many types of tumors
The results showed that the Cancer stem cells (CSC)-associated genes (Oct-3/4, Nanog, aldehyde dehydrogenase 1 (ALDH1), and ABCG2) [21,22,23,24] were significantly downregulated when MCL-1 was silenced with siRNA (Fig. 2c), indicating the involvement of MCL-1 in the stemness of the MSLC
Summary
Melanoma is a type of aggressive cancer featuring high mortality. Despite the fact that melanoma only explains 10% of skin cancers, it is accountable for 80% of skin cancer deaths [1, 2]. Resistance to therapeutic agents presented in cancers including melanoma raised new challenges to the further improvement of cancer therapy [3]. The antiapoptotic BCL-2 proteins include MCL-1, BCL-2 (BCL2 apoptosis regulator), BCL-W (BCL2 like 2), and BCL-XL (BCL2-like 1), while such as BAK (BCL-2 homologous antagonist killer) and BAX (BCL-2 associated X protein) were pro-apoptotic BCL-2 proteins. The interactions among these proteins determine the fate of cells [13,14,15]. The mechanism of survival and stemness maintenance of cancer stem cells remains to be investigated
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