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

Stem Cell Research & Therapy - 2020
Wenlin Wu1, Chenxi Xu2, Xiaobo Zhang2, Yu An3, Le Shu2
1College of Oceanology and Food Science, Quanzhou Normal University, Quanzhou, 36200, Fujian Province, People’s Republic of China
2College of Life Science, Zhejiang University, Hangzhou, 310058, Zhejiang Province, People’s Republic of China
3Huffington Centre on Aging, Baylor College of Medicine, Houston, TX, 77030, USA

Tóm tắt

AbstractBackgroundMelanoma 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.

Từ khóa


Tài liệu tham khảo

Silvers DN. Focus on melanoma. J Dermatol Surg Oncol. 1976;2(2):108.

Perez MC, Orcutt ST, Zager JS. Current standards of surgical management in primary melanoma; 2017.

Luke JJ, et al. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol. 2017;14(8):463.

Lonardo E, Hermann PC, Heeschen C. Pancreatic cancer stem cells – update and future perspectives. Mol Oncol. 2010;4(5):431–42.

Frosina G. DNA repair and resistance of gliomas to chemotherapy and radiotherapy. Mol Cancer Res. 2009;7(7):989–99.

Baumann M, Krause M, Hill R. Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer. 2008;8(7):545–54.

Hainaut P. Targeting the hallmarks of cancer: towards a rational approach to next-generation cancer therapy. Curr Opin Oncol. 2013;25(1):50–1.

Lagadec C, et al. TrkA overexpression enhances growth and metastasis of breast cancer cells. Oncogene. 2009;28(18):1960–70.

Brewster, M.E., et al., Preclinical and clinical studies. 2015.

Krajewski S, et al. Immunohistochemical analysis of Mci-1 protein in human tissues. Am J Pathol. 1995;146:1309–19.

Perciavalle RM, Opferman JT. Delving deeper: MCL-1’s contributions to normal and cancer biology. Trends Cell Biol. 2013;23(1):22–9.

Annis MG, et al. There is more to life and death than mitochondria: Bcl-2 proteins at the endoplasmic reticulum. Biochim Biophys Acta. 2004;1644(2):115–23.

Akgul C. Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci. 2009;66(8):1326–36.

Shamas-Din A, et al. BH3-only proteins: orchestrators of apoptosis. Biochim Biophys Acta. 2011;1813(4):508–20.

D’Alessio M, et al. Oxidative Bax dimerization promotes its translocation to mitochondria independently of apoptosis. FASEB J. 2005;19(11):1504–6.

Placzek WJ, et al. A survey of the anti-apoptotic Bcl-2 subfamily expression in cancer types provides a platform to predict the efficacy of Bcl-2 antagonists in cancer therapy. Cell Death Dis. 2010;1(5):e40.

Cai Y, et al. A brief review on the mechanisms of miRNA regulation. Genomics Proteomics Bioinformatics. 2009;7(4):147–54.

Shimono Y, et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell. 2009;138(3):592–603.

Yang F, et al. Shrimp miR-S8 suppresses the stemness of human melanoma stem-like cells by targeting the transcription factor YB-1. Cancer Res. 2017;77(20):canres.1375.2017.

Céline G, Eileen W. BH3-only proteins in control: specificity regulates MCL-1 and BAK-mediated apoptosis. Genes Dev. 2005;19(11):1263–8.

Yuchun Luo NN, Fujita M. Isolation of human melanoma stem cells using ALDH as a marker. Curr Protoc Stem Cell Biol. 2013;26:Unit 3.8.

Karmakar S, et al. Abstract 2495: hPaf1/PD2 interacts with OCT3/4 in maintenance of the self-renewal process of ovarian cancer stem cells. Cancer Res. 2016;76(14 Supplement):2495.

Ding XW, Wu J-h, Jiang C-p. ABCG2: a potential marker of stem cells and novel target in stem cell and cancer therapy. Life Sci. 2010;86(17):631–7.

Wang ML, Chiou SH, Wu CW. Targeting cancer stem cells: emerging role of Nanog transcription factor. Onco Targets Ther. 2013;6(default):1207–20.

Chen CJ, et al. Abstract 1198: adaptation to ER stress as a driver of increased expression of Mcl-1 with melanoma progression. Cancer Res. 2010;70(8 Supplement):1198.

Lin J, et al. Regulation of cancer stem cell self-renewal by HOXB9 antagonizes ER stress-induced melanoma cell apoptosis via the miR-765-FOXA2 axis. J Invest Dermatol. 2018;138(7):1609–19.

Chang CW, et al. ROS-independent ER stress-mediated NRF2 activation promotes Warburg effect to maintain stemness-associated properties of cancer-initiating cells. Cell Death Dis. 2018;7(1):194.

Yoshida H, et al. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107(7):881–91.

Gomez-Cabrero A, Wrasidlo W, Reisfeld RA. IMD-0354 targets breast cancer stem cells: a novel approach for an adjuvant to chemotherapy to prevent multidrug resistance in a murine model. PLoS One. 2013;8(8):e73607.

Liu P, et al. Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells. Br J Cancer. 2013;109(7):1876–85.

Lim YC, et al. Cancer stem cell traits in squamospheres derived from primary head and neck squamous cell carcinomas. Oral Oncol. 2011;47(2):83–91.

Galli R. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64(19):7011–21.

Sandercock J, et al. First-line treatment for advanced ovarian cancer: paclitaxel, platinum and the evidence. Br J Cancer. 2002;87(8):815–24.

Yi L, et al. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther. 2012;11(8):1672–82.

Puthalakath H, et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell. 2007;129(7):1337–49.

Verfaillie T, Garg AD, Agostinis P. Targeting ER stress induced apoptosis and inflammation in cancer. Cancer Lett. 2013;332(2):249–64.

Gores GJ, Kaufmann SH. Selectively targeting Mcl-1 for the treatment of acute myelogenous leukemia and solid tumors. Genes Dev. 2012;26(4):305–11.

Fan F, et al. Targeting Mcl-1 for multiple myeloma (MM) therapy: drug-induced generation of Mcl-1 fragment Mcl-1128–350 triggers MM cell death via c-Jun upregulation. Cancer Lett. 2014;343(2):286–94.

Zangemeister-Wittke U, Huwiler A. Antisense targeting of Mcl-1 has therapeutic potential in gastric cancer. Cancer Biol Ther. 2006;5(10):1355–6.

Koong AC, Chauhan V, Romero-Ramirez L. Targeting XBP-1 as a novel anti-cancer strategy. Cancer Biol Ther. 2006;5(7):756–9.

Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33.

Thông tin
Thông tin xuất bản

Stem Cell Research & Therapy

Thông tin tác giả