MET overexpression in ovarian cancer via CD24-induced downregulation of miR-181a: A signalling for cellular quiescence-like state and chemoresistance in ovarian CSCs

Abstract

Increased expression of CD24 and MET, markers for cancer stem-like cells (CSCs), are each associated with ovarian cancer severity. However, whether CD24 and MET are co-expressed in ovarian CSCs and, if so, how they are related to CSC phenotype manifestation remains unknown. Our immunohistochemistry analysis showed that the co-expression of CD24 and MET was associated with poorer patient survival in ovarian cancer than those without. In addition, analyses using KM plotter and ROC plotter presented that the overexpression of CD24 or MET in ovarian cancer patients was associated with resistance to platinum-based chemotherapy. In our miRNA transcriptome and putative target genes analyses, miR-181a was downregulated in CD24-high ovarian cancer cells compared to CD24-low and predicted to bind to CD24 and MET 3'UTRs. In OV90 and SK-OV-3 cells, CD24 downregulated miR-181a expression by Src-mediated YY1 activation, leading to increased expression of MET. And, CD24 or MET knockdown or miR-181a overexpression inhibited the manifestation of CSC phenotypes, cellular quiescence-like state and chemoresistance, in OV90 and SK-OV-3 cells: increased colony formation, decreased G0/G1 phase cell population and increased sensitivity to Cisplatin and Carboplatin. Our findings suggest that CD24-miR-181a-MET may consist of a signalling route for ovarian CSCs, therefore being a combinatory set of markers and therapeutic targets for ovarian CSCs.

References

[1] Lupia M, Cavallaro U. Ovarian cancer stem cells: still an elusive entity? Mol Cancer. 2017;16(1):64.

[2] Agarwal R, Kaye SB. Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer. 2003;3(7):502-516.

[3] Pignata S, Cecere SC, Du Bois A, Harter P, Heitz F. Treatment of recurrent ovarian cancer. Ann Oncol. 2017;28:51-56.

[4] Housman G, Byler S, Heerboth S, et al. Drug resistance in cancer: an overview. Cancers (Basel). 2014;6(3):1769-1792.

[5] Zong X, Nephew KP. Ovarian cancer stem cells: role in metastasis and opportunity for therapeutic targeting. Cancers (Basel). 2019;11(7):934.

[6] Kenda Suster N, Virant-Klun I. Presence and role of stem cells in ovarian cancer. World J Stem Cells. 2019;11(7):383-397.

[7] Takebe N, Ivy SP. Controversies in cancer stem cells: targeting embryonic signaling pathways. Clin Cancer Res. 2010;16(12):3106-3112.

[8] Hung KF, Yang T, Kao SY. Cancer stem cell theory: are we moving past the mist? J Chin Med Assoc. 2019;82(11):814-818.

[9] Bowen NJ, Walker LD, Matyunina LV, et al. Gene expression profiling supports the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as ovarian cancer initiating cells. BMC Med Genomics. 2009;2:71.

[10] Bapat SA, Mali AM, Koppikar CB, Kurrey NK. Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res. 2005;65(8):3025-3029.

[11] Gao MQ, Choi YP, Kang S, Youn JH, Cho NH. CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene. 2010;29(18):2672-2680.

[12] Meng E, Long B, Sullivan P, et al. CD44+/CD24− ovarian cancer cells demonstrate cancer stem cell properties and correlate to survival. Clin Exp Metastasis. 2012;29(8):939-948.

[13] Altevogt P, Sammar M, Huser L, Kristiansen G. Novel insights into the function of CD24: a driving force in cancer. Int J Cancer. 2021;148(3):546-559.

[14] Muppala S, Mudduluru G, Leupold JH, Buergy D, Sleeman JP, Allgayer H. CD24 induces expression of the oncomir miR-21 via Src, and CD24 and Src are both post-transcriptionally downregulated by the tumor suppressor miR-34a. PloS One. 2013;8(3):e59563.

[15] Salaria S, Means A, Revetta F, Idrees K, Liu E, Shi C. Expression of CD24, a stem cell marker, in pancreatic and small intestinal neuroendocrine tumors. Am J Clin Pathol. 2015;144(4):642-648.

[16] Li C, Wu JJ, Hynes M, et al. c-met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology. 2011;141(6):2218-2227.e2215.

[17] Chan SH, Tsai KW, Chiu SY, et al. Identification of the novel role of CD24 as an oncogenesis regulator and therapeutic target for triple-negative breast cancer. Mol Cancer Ther. 2019;18(1):147-161.

[18] Li Y, Li A, Glas M, et al. c-met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc Natl Acad Sci U S A. 2011;108(24):9951-9956.

[19] van Leenders GJ, Sookhlall R, Teubel WJ, et al. Activation of c-MET induces a stem-like phenotype in human prostate cancer. PloS One. 2011;6(11):e26753.

[20] Wood GE, Hockings H, Hilton DM, Kermorgant S. The role of MET in chemotherapy resistance. Oncogene. 2021;40(11):1927-1941.

[21] Tang MK, Zhou HY, Yam JW, Wong AS. c-met overexpression contributes to the acquired apoptotic resistance of nonadherent ovarian cancer cells through a cross-talk mediated by phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2. Neoplasia. 2010;12(2):128-138.

[22] Zhan H, Tu S, Zhang F, Shao A, Lin J. MicroRNAs and Long non-coding RNAs in c-met-regulated cancers. Front Cell Dev Biol. 2020;8:145.

[23] Messeguer X, Escudero R, Farre D, Nunez O, Martinez J, Alba MM. PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics. 2002;18(2):333-334.

[24] Reese MG. Application of a time-delay neural network to promoter annotation in the Drosophila melanogaster genome. Comput Chem. 2001;26(1):51-56.

[25] Lanczky A, Gyorffy B. Web-based survival analysis tool tailored for medical research (KMplot): development and implementation. J Med Internet Res. 2021;23(7):e27633.

[26] Fekete JT, Gyorffy B. ROCplot.org: validating predictive biomarkers of chemotherapy/hormonal therapy/anti-HER2 therapy using transcriptomic data of 3,104 breast cancer patients. Int J Cancer. 2019;145(11):3140-3151.

[27] Eyvazi S, Kazemi B, Dastmalchi S, Bandehpour M. Involvement of CD24 in multiple cancer related pathways makes it an interesting new target for cancer therapy. Curr Cancer Drug Targets. 2018;18(4):328-336.

[28] Wang GZ, Goff SP. Regulation of Yin Yang 1 by tyrosine phosphorylation. J Biol Chem. 2015;290(36):21890-21900.

[29] Wang J, Cheng JX. c-met inhibition enhances chemosensitivity of human ovarian cancer cells. Clin Exp Pharmacol Physiol. 2017;44(1):79-87.

[30] Nakamura K, Terai Y, Tanabe A, et al. CD24 expression is a marker for predicting clinical outcome and regulates the epithelial-mesenchymal transition in ovarian cancer via both the Akt and ERK pathways. Oncol Rep. 2017;37(6):3189-3200.

[31] Dong X, Yuan L, Yao L. Recurrence of ovarian squamous cell carcinoma with MET gene copy number variation: a case report and review of literature. J Ovarian Res. 2020;13(1):62.

[32] Zuo L, Li X, Zhu H, Li A, Wang Y. Expression of miR-181a in circulating tumor cells of ovarian cancer and its clinical application. ACS Omega. 2021;6(34):22011-22019.

[33] Parikh A, Lee C, Joseph P, et al. microRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial-mesenchymal transition. Nat Commun. 2014;5:2977.

[34] Beaufort CM, Helmijr JC, Piskorz AM, et al. Ovarian cancer cell line panel (OCCP): clinical importance of in vitro morphological subtypes. PloS One. 2014;9(9):e103988.

[35] O'Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445(7123):106-110.

[36] Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100(7):3983-3988.

[37] Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65(23):10946-10951.

[38] Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64(19):7011-7021.

[39] Kim HJ, Yoon A, Ryu JY, et al. c-MET as a potential therapeutic target in ovarian clear cell carcinoma. Sci Rep. 2016;6:38502.

[40] Kim JH, Jang HJ, Kim HS, Kim BJ, Park SH. Prognostic impact of high c-met expression in ovarian cancer: a meta-analysis. J Cancer. 2018;9(19):3427-3434.

[41] Shiozawa Y, Nie B, Pienta KJ, Morgan TM, Taichman RS. Cancer stem cells and their role in metastasis. Pharmacol Ther. 2013;138(2):285-293.

RIGHTS & PERMISSIONS

2023 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.