MicroRNA-99a-3p/GRP94 axis affects metastatic progression of human papillary thyroid carcinoma by regulating ITGA2 expression and localization

Author:

Gao Yun1,Pan Yi1,Wang Tingting1,Yao Ying2,Yuan Wenbo2,Zhu Xue3ORCID,Wang Ke3

Affiliation:

1. Department of Internal Medicine, Jiangyuan Hospital Affiliated to Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China

2. Department of Pharmacy, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, China

3. NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China

Abstract

Abstract Papillary thyroid cancer (PTC) usually has favorable prognosis; however, distant metastasis is a leading cause of death associated with PTC. MicroRNA-99a-3p (miR-99a-3p) is a member of the miR-99 family that is shown to be a tumor suppressor in various human cancers including the anaplastic thyroid cancer, another type of thyroid cancer. The Cancer Genome Atlas database and our previous study reported that miR-99a-3p is downregulated in human PTC tissues as well as human papillary thyroid carcinoma B-CPAP and TPC-1 cell lines. However, its pathological role in PTC remains unclear, especially its impact on PTC metastasis. In the present study, the role of miR-99a-3p in PTC metastasis was molecularly evaluated in in vitro and in vivo models. Our functional study revealed that overexpressing miR-99a-3p significantly suppresses epithelial-mesenchymal transition (EMT) and anoikis resistance as well as migration and invasion of B-CPAP and TPC-1 cells. The mechanical study indicated that glucose-regulated protein 94 (GRP94) is the direct target of miR-99a-3p. Moreover, GRP94 overexpression reverses the inhibitory effect of miR-99a-3p on PTC metastasis. In addition, the miR-99a-3p/GRP94 axis exerts its effect via inhibiting the expression and cytoplasmic relocation of integrin 2α (ITGA2). Furthermore, in vivo experiments confirmed that miR-99a-3p significantly inhibits tumor growth and lung metastasis in PTC xenograft mice. Overall, our findings suggested that the miR-99a-3p/GRP94/ITGA2 axis may be a novel therapeutic target for the prevention of PTC metastasis.

Funder

Six Talent Peaks Project in Jiangsu Province

Project of Wuxi Municipal Science and Technology Bureau

Young Talent’s Subsidy Project in Science and Education of the Department of Public Health of Jiangsu Province

Six-one Scientific Research Project

Publisher

China Science Publishing & Media Ltd.

Subject

General Medicine,Biochemistry,Biophysics

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