STRA6 Promotes Thyroid Carcinoma Progression via Activation of the ILK/AKT/mTOR Axis in Cells and Female Nude Mice

• Published in: Endocrinology (Philadelphia) Vol. 164; no. 3; p. 1
• Main Authors: He, Weiman, Cheng, Zhen, Huo, Zijun, Lin, Bo, Wang, Xuejie, Sun, Yijia, Yu, Shuang, Cao, Siting, Xue, Junyu, Liu, Rengyun, Lv, Weiming, Li, Yanbing, Hong, Shubin, Xiao, Haipeng
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.03.2023
• Subjects: AKT protein; Animals; Cancer; Carcinoma; Cell Line, Tumor; Cell Proliferation - genetics; Disease Models, Animal; Endocrinology; Ethylenediaminetetraacetic acid; Female; Gene sequencing; Genomics; Health aspects; Humans; ILK protein; Immunohistochemistry; Immunoprecipitation; In vivo methods and tests; Integrins; Kinases; Lipid metabolism; Lipids; Lymph nodes; Membrane proteins; Membrane Proteins - genetics; Metastases; Metastasis; Mice; Mice, Nude; Molecular modelling; Nanoparticles; Prognosis; Protein binding; Protein kinases; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin; Retinoids; RNA; RNA sequencing; RNA, Small Interfering; Signal transduction; siRNA; Therapeutic targets; Thyroid; Thyroid cancer; Thyroid carcinoma; Thyroid Neoplasms - genetics; TOR protein; TOR Serine-Threonine Kinases - metabolism; Xenotransplantation; China; nanoparticle; thyroid carcinoma; ILK/AKT/mTOR axis; lipid metabolism; STRA6
• ISSN: 1945-7170; 0013-7227; 1945-7170
• DOI: 10.1210/endocr/bqac215

Abstract Background Metastasis has emerged to be an important cause for poor prognosis of thyroid carcinoma (TC) and its molecular mechanisms are not fully understood. STRA6 is a multifunctional membrane protein widely expressed in embryonic and adult tissues. The function and mechanism of STRA6 in TC remain elusive. Objective We aimed to explore the role of STRA6 in TC progression and provide a therapeutic target for TC. Methods The expression and clinicopathological relevance of STRA6 were explored in TC. Stable STRA6-knockdown TC cells were established and used to determine the biological function of STRA6 in vitro and in vivo. RNA sequencing and co-immunoprecipitation were performed to unveil the molecular mechanism of STRA6 in TC progression. The potential of STRA6 as a therapeutic target was evaluated by lipid nanoparticles (LNPs) containing siRNA. Results STRA6 was upregulated in TC and correlated with aggressive clinicopathological features, including extrathyroidal extension and lymph node metastasis, which contributed to the poor prognosis of TC. STRA6 facilitated TC progression by enhancing proliferation and metastasis in vitro and in vivo. Mechanistically, STRA6 could interact with integrin-linked kinase (ILK) and subsequently activate the protein kinase B/mechanistic target of rapamycin (AKT/mTOR) signaling pathway. We further unveiled that STRA6 reprogrammed lipid metabolism through SREBP1, which was crucial for the metastasis of TC. Moreover, STRA6 siRNA delivered by LNPs significantly inhibited cell growth in xenograft tumor models. Conclusions Our study demonstrates the critical roles of STRA6 contributing to TC progression via the ILK/AKT/mTOR axis, which may provide a novel prognostic marker as well as a promising therapeutic target for aggressive TC.