Shrimp miR-965 induced the human melanoma stem-like cell apoptosis and inhibited their stemness by disrupting the MCL-1-ER stress-XBP1 feedback loop in a cross-species manner

Abstract

Background: Melanoma 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. Methods: Tumorsphere 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. Results: In 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 − 313to − 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. Conclusion: In 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.

BAY-885, a mitogen-activated protein kinase kinase 5 inhibitor, induces apoptosis by regulating the endoplasmic reticulum stress/Mcl-1/Bim pathway in breast cancer cells

“…Upregulation of Mcl-1 could attenuate the apoptosis induced by ER stress in melanoma cells [ 40 ]. A feedback loop between Mcl-1 and ER stress has also been identified [ 41 ]. Although previous studies found that inhibition of ERK5 induced apoptosis relied on the upregulation of Bim in different cells [ 18 , 19 ].…”

Investigations into the effects and related upstream/downstream regulatory mechanisms of long non-coding RNA WT1-AS in the maintenance and development of gastric cancer stem cells in vitro and in vivo

“…Thus, transcription factors that had the likelihood to bind with the promoter regions of WT1-AS were predicted. Among these transcription factors, TP53 [26,30] and XBP1 [27,28,31] were found to be implicated in the formation and development of cancer stem cells. Our experiments demonstrated that TP53 increase did not in uence WT1-AS expression in GSCs.…”

Double‐edged sword role of shrimp miRNA explains an evolutionary language between shrimp‐pathogen interactions that unties the knot of shrimp infection

“…(MCL-1-ER stress-XBP1) feedback loop, both suppress the tumour progression of human melanoma stem cells. 149,150 WSSV-induced MCL-1 antiviral shrimp miR-34 can inhibit the proliferation of human breast cancer cells and suppress human tumorigenesis. 151 Attempts have been made to vaccinate shrimp against large viral and bacterial pathogens.…”