Abstract
AbstractTo identify drivers of sarcoma cancer stem-like cells (CSCs), we compared gene expression using RNA sequencing between HT1080 fibrosarcoma and SK-LMS-1 leiomyosarcoma spheroids (which are enriched for CSCs) compared with the parent populations. The most overexpressed survival signaling-related gene in spheroids was phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3), a regulatory subunit of PI3K, which functions in tumorigenesis and metastasis. In a human sarcoma microarray, PIK3R3 was also overexpressed by 4.1-fold compared with normal tissues. PIK3R3 inhibition using shRNA in the HT1080, SK-LMS-1, and DDLS8817 dedifferentiated liposarcoma in spheroids and in CD133+ cells (a CSC marker) reduced expression of CD133 and the stem cell factor Nanog and blocked spheroid formation by 61–71%. Mechanistic studies showed that in spheroid cells, PIK3R3 activated AKT and ERK signaling. Inhibition of PIK3R3, AKT, or ERK using shRNA or inhibitors decreased expression of Nanog, spheroid formation by 68–73%, and anchorage-independent growth by 76–91%. PIK3R3 or ERK1/2 inhibition similarly blocked sarcoma spheroid cell migration, invasion, secretion of MMP-2, xenograft invasion into adjacent normal tissue, and chemotherapy resistance. Together, these results show that signaling through the PIK3R3/ERK/Nanog axis promotes sarcoma CSC phenotypes such as migration, invasion, and chemotherapy resistance, and identify PIK3R3 as a potential therapeutic target in sarcoma.
Funder
Memorial Sloan-Kettering Cancer Center
U.S. Department of Health & Human Services | National Institutes of Health
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology
Reference41 articles.
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.
2. Brennan MF, Antonescu CR, Maki RG. Management of soft tissue sarcoma. New York:Springer;2013.
3. Billingsley KG, Burt ME, Jara E, Ginsberg RJ, Woodruff JM, Leung DH, et al. Pulmonary metastases from soft tissue sarcoma: analysis of patterns of diseases and postmetastasis survival. Ann Surg. 1999, 229:602–10 discussion 610-602.
4. Singer S, Tap WD, Kirsch DG, Crago AM. Soft tissue sarcoma In: DeVita VT, Jr., Rosenberg SA, Lawrence TS, editors. Cancer: Principles and Practice of Oncology, 11 edn. Philadelphia: Lippincott Williams & Wilkins;2018. p. 1401–50.
5. Chang KK, Yoon C, Yi BC, Tap WD, Simon MC, Yoon SS. Platelet-derived growth factor receptor-alpha and -beta promote cancer stem cell phenotypes in sarcomas. Oncogenesis. 2018;7:47.
Cited by
15 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献