Aberrant SLC6A14 Expression Promotes Proliferation and Metastasis of Colorectal Cancer via Enhancing the JAK2/STAT3 Pathway

Hongli Mao; Jinxiu Sheng; Jinlin Jia; Chang Wang; Shanfeng Zhang; Hongle Li; Fucheng He

doi:10.2147/OTT.S288709

Aberrant SLC6A14 Expression Promotes Proliferation and Metastasis of Colorectal Cancer via Enhancing the JAK2/STAT3 Pathway

Onco Targets Ther. 2021 Jan 13:14:379-392. doi: 10.2147/OTT.S288709. eCollection 2021.

Authors

Hongli Mao¹, Jinxiu Sheng¹, Jinlin Jia¹, Chang Wang¹, Shanfeng Zhang², Hongle Li³, Fucheng He¹

Affiliations

¹ Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
² The Laboratory Center for Basic Medicine, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
³ Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.

Abstract

Background: Solute carrier family 6 member 14 (SLC6A14) is a high-capacity amino acid transporter in mammalian cells. It has gained increasing attention for its potential involvement in the progression and metabolic reprogramming of various malignant tumors. However, the role of SLC6A14 in colorectal cancer (CRC) remains unclear.

Methods: Real-time polymerase chain reaction (qRT-PCR), immunoblotting and immunohistochemistry were carried out to detect the expression level of SLC6A14 in human CRC tissues and CRC-derived cell lines. HCT-116 and Caco-2 cell lines were selected to conduct in vitro functional studies. Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, cell migration and invasion assays were performed to investigate the role of SLC6A14 in CRC cells. Besides, azoxymethane/dextran sulfate sodium salt (AOM/DSS)-induced CRC and tumor xenograft models were constructed to explore the effects of SLC6A14 blockade or overexpression during tumor progression in vivo.

Results: SLC6A14 was substantially increased in human CRC samples and higher levels of SLC6A14 was correlated with advanced tumor stage, lymph node metastasis and dismal survival of CRC patients. SLC6A14 markedly promoted cell growth, inhibited cell apoptosis, and exacerbated migration and invasion of CRC cells in vitro. Mechanistically, SLC6A14 aggravated these malignant phenotypes through activating JAK2/STAT3 signaling pathway, and inhibiting JAK2/STAT3 signaling with specific inhibitors could reverse SLC6A14-mediated tumorigenic effects. Besides, two different animal studies verified the tumor-promoting effect of SLC6A14 in CRC.

Conclusion: Our data illustrated the crucial function of SLC6A14 during CRC progression, suggesting SLC6A14/JAK2/STAT3 axis may serve as novel therapeutic targets for patients with CRC.

Keywords: CRC; SLC6A14; STAT3; colorectal cancer; migration; proliferation.

Grants and funding

This project was supported by the Medical Science and Technology Joint Construction Project of Henan province of China (Grant No. 201901102) and the Science and Technology Project of Henan province of China (Grant No. 192102310133).