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

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 the 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 on 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, 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 that SLC6A14 played in the promotion of CRC, suggesting SLC6A14/JAK2/STAT3 axis may serve as novel therapeutic targets for patients with CRC.

On the origin of metastases: Induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm

“…Gene and predicted protein-protein interaction (PPI) enrichment analyses of RNA-seq data for of PAME CC14 (hereafter STS PAMEs unless otherwise noted) and control cells (see Figures 2A, left, and S2A for top 25 gene lists) revealed cytokine signaling, inflammatory/immune responses, and extracellular matrix organization in the upregulated (UP) cohort (Figures 2A,right,and S2C),including INSL4,CXCL1,3,6,8,10,IL1A,15,18,23,32,and CCL20,28, which can form a cytokine storm. PAMEs also expressed UP genes previously implicated in metastasis (e.g., L1CAM, SLC6A11, and YAP; Ganesh et al, 2020;Thompson, 2020;Mao et al, 2021). Similar analyses of downregulated (DOWN) genes highlighted DNA methylation, chromatin assembly, senescence, Notch signaling, and the repression of factors involved in intestinal lineage differentiation: ATOH1, CDX2, PAX4, and NEUROG3 (Figures S2A, S2B, and S2D; data not shown).…”

SLC6A14 promotes cell migration and inhibits autophagy in gastric cancer by regulating JAK2/STAT3 signaling

“…In addition, blocking of JAK2/STAT3 signaling promoted autophagy in GC [18]. Moreover, SLC6A14 upregulated p-JAK2 and p-STAT3 and stimulated tumor proliferation and metastasis in colorectal cancer cells [11]. It has been shown that knockdown of SLC6A14 decreased JAK2 and STAT3 phosphorylation in GC cells.…”

“…Inhibition of JAK2/STAT3 blocked proliferation of GC, reduced inflammation, and promoted apoptosis [10]. Moreover, SLC6A14 enhanced colorectal cancer cell proliferation and metastasis through activation of JAK2/STAT3 [11]. Therefore, SLC6A14 may also regulate GC through JAK2/STAT3 signaling.…”