ADAM10 is a key player in the diagnosis, prognosis and metastasis of non-small cell lung cancer (NSCLC)

Abstract

A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) plays critical roles in various cancer-associated biological events, such as cell multiplication, migration, and metastasis. This study employs both the TCGA database and patient samples to demonstrate that ADAM10 is highly expressed in non-small cell lung cancer (NSCLC) compared with normal tissue at different stages. Increased ADAM10 expression is positively correlated with decreased overall and recurrence-free survival. On the functional front, overexpression of ADAM10 promotes lung cancer cell progression, migration, and invasion, whereas downregulation of ADAM10 inhibits these processes. Mechanically, ADAM10 modulates the expression of Notch1, MMP9 and EMT markers such as Vimentin, N-cadherin, and E-cadherin. Overall, our findings suggest that ADAM10 may be a promising therapeutic and prognostic marker for NSCLC, emphasizing the importance of regulating its expression.

Keywords: DAM10; Non-small cell lung cancers; Prognostics.

Figure 1

ADAM10 expression may increase in lung cancer tissues. A. ADAM10 expression may increase in the non-small cell lung cancer (NSCLC) tissues by TCGA analysis. B. ADAM10 expression may increase in the different stages of NSCLC tissues. C. Western blot of ADAM10 expression increase in five human NSCLC cell lines compared with the normal human bronchial epithelial cell line. Quantitative results for ADAM10 expression. D. Western blot of ADAM10 expression may increase in the Chinese lung cancer tissues and paired adjacent non-cancerous tissue. The number beneath each pair of bands in the blots indicates relative expression ratios. Ratios less than 1 signify decreased expression, a ratio equal to 1 represents unchanged expression, and a ratio greater than 1 indicates increased expression in cancerous samples. (N, adjacent non-cancerous tissues; Ca, cancerous tissues;). And quantitative results for ADAM10 expression in the Chinese lung cancer tissues.

Figure 2

High ADAM10 expression positively correlated with poor survival. A. Survival for ADAM10 expression in NSCLC by meta-analysis. High ADAM10 expression has significant association with positive survival outcomes in NSCLC patients. B. Overall survival (OS) and (relapse-free survival) RFS for ADAM10 expression in NSCLC by Kaplan-Meier Plotter. CI indicates confidence interval, SMD indicates standardized mean difference, seTE indicates standard error of treatment effect, HR indicates hazard ratio, TE indicates estimated treatment effect.

Figure 3

Overexpression for ADAM10 promotes growth, migration, and invasion in lung cancer cells. A & F. Overexpression for ADAM10 in lung cancer cells H1299 and A549, respectively. B & G. Overexpression for ADAM10 promotes growth in lung cancer cells H1299 and HA549, respectively. C & H. Overexpression for ADAM10 promotes migration in lung cancer cells H1299 and A549 (magnification: X100), respectively. D & I. Would healing assay shows overexpression for ADAM10 that promotes migration in time-dependents in lung cancer cells H1299 and A549 (magnification: X40), respectively. E & J. Overexpression for ADAM10 promotes invasion in lung cancer cells H1299 and A549, respectively.

Figure 4

Inhibition of ADAM10 prevents migration and invasion in lung cancer cells. A & C. Inhibitor GI254023X for ADAM10 prevents migration and invasion in H1299 and A549 cells (magnification: X100). * P<0.05, ** P <0.01. And quantitative results. B & D Expression level for ADAM10 in H1299 and A549 cells. And quantitative results. E & F. ADAM10 inhibitor (GI254023X) exhibits dose-dependent effect in H1299 and A549 cells. Right lanes: The quantitative results.

Figure 5

ADAM10 expression and EMT regulation in lung cancer cell lines. A. ADAM10 inhibitor GI254023X regulates the expressions of EMT markers and Notch1, MMP9. B. Quantitative results for panel A. C. Overexpression of ADAM10 regulates the expressions of and EMT markers and Notch1, MMP9. D. Quantitative results for panel C. *, P<0.05, **, P<0.01.

Figure 6

Working model for ADAM10 in lung cancer. ADAM10 is overexpressed in lung cancer, resulting in an overall increase in its activity and cleavage of oncogenic substrates such as Notch1, N-cadherin, and E-cadherin, which increases in MMP9 and Vimentin levels. The enhanced activation of the Notch signaling pathway also occurs and ultimately contributes to the EMT development in NSCLC. Note: The figure was drawn with BioRender web-based tool with permission (https://BioRender.com), publication license number: MG27UDUXF4.