Dataset Information

SLC6A8 is involved in the progression of non-small cell lung cancer through the Notch signaling pathway.

ABSTRACT:

Background

Solute carrier family 6 member 8 (SLC6A8) is known to be involved in the development of human tumors; however, the effect of SLC6A8 on the growth of non-small cell lung cancer (NSCLC) remains unclear. Here, we explored the role and potential action mechanism of SLC6A8 in NSCLC.

Methods

We used public databases [Oncomine, Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA)] to explore the expression of SLC6A8 in NSCLC. Additionally, we used immunohistochemistry to detect the expression of SLC6A8 in NSCLC clinicopathological tissues (cancer and adjacent tissues) and Western blotting to detect the expression of SLC6A8 in NSCLC clinicopathological tissues, NSCLC cell lines (A549, H1299, H520, and H1975), and a normal epithelial cell line (BEAS-2B). Using overexpression and knockdown of the SLC6A8 gene, we analyzed the in vitro effects of SLC6A8 on the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of NSCLC and also the possible molecular mechanism with Notch signaling pathway.

Results

Bioinformatic analysis demonstrated that SLC6A8 is highly expressed in NSCLC and is related to poor prognosis. We found that the expression of the SLC6A8 protein in human lung cancer tissues was significantly higher than that in adjacent tissues. In addition, it was also significantly higher in lung cancer cell lines (A549, H1299, H520, and H1975) than that in normal lung epithelium-BEAS-2B. Moreover, SLC6A8 overexpression promotes the proliferation, migration and invasion in vitro in NSCLC, accompanied by the activation of notch signaling pathway and the up-regulation of MMP9 and E-cadherin proteins. Knocking down SLC6A8 can inhibit the above effects on cells.

Conclusions

SLC6A8 promotes the malignant progression of NSCLC and activates the Notch signaling pathway. Therefore, SLC6A8 is expected to become a molecular target for NSCLC treatment.

SUBMITTER: Feng Y

PROVIDER: S-EPMC7940877 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Many transcription factors involved in embryonic development and reactivated in tumors are considered potential prognostic biomarkers and novel therapeutic targets in various cancers. Sine oculis homeobox homolog 1 (SIX1), a developmentally restricted transcriptional regulator, plays a critical role during tumor initiation and development. However, the prognostic value and biological function of SIX1 in non-small cell lung cancer (NSCLC) remain unclear. Methods: Bioinformatic analyses were conducted to investigate the expression of SIX1 in cancer and adjacent normal tissues of NSCLC and further explore the correlations between SIX1 expression and clinical outcomes. Western blotting and RT-PCR analysis were performed to detect of SIX1 expression level in NSCLC cell lines and normal bronchial epithelial cell. EdU, CCK-8, clonal formation assay, wound healing and transwell assay were performed to explore the effects of gain- or loss-of-function of SIX1 on cellular proliferation, migration and invasion in vitro. Gene set enrichment analysis (GSEA) was used to identify the potential signaling pathways involved in SIX1 mediated biological function and the correlation was confirmed by western blotting and RT-PCR analysis. In vivo experiment was conducted to further validate the tumor-promoting effects of SIX1. Results: Bioinformatic analysis indicated that SIX1 was markedly upregulated in NSCLC tissues of and positively correlated with poor prognosis of patients with NSCLC. Ectopic expression of SIX1 facilitated proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of NSCLC cells. On the contrary, knocking down SIX1 exhibited the opposite effects. Mechanistic studies suggested that SIX1 activated the Notch pathway to promote the malignant biological behaviors of NSCLC, which could be reversed by inhibiting the Notch signaling with γ-secretase inhibitor. Conclusions: SIX1 could facilitate multiple malignant biological behaviors by activating the Notch signaling pathway and function as a promising prognostic biomarker.