ADAM9 Mediates Triple-Negative Breast Cancer Progression via AKT/NF-κB Pathway

Abstract

Upregulation of a disintegrin and metalloprotease 9 (ADAM9) is correlated with progression of cancers, such as prostate, bladder, and pancreatic cancers. However, its role in triple-negative breast cancer (TNBC) is still unclear. Our study aimed to investigate whether ADAM9 is upregulated and promoted the aggressiveness in TNBC. Breast cancer cell lines and patient specimens were used to evaluate the ADAM9 expression by western blotting and immunohistochemistry staining, respectively. Compared with the non-TNBC, ADAM9 expression was significantly increased in TNBC cells and TNBC patient specimens. Based on the data acquired from public databases, the correlation between ADAM9 expression and breast cancer patient survival was analyzed by Kaplan-Meier method. It was shown that ADAM9 overexpression was significantly correlated with poorer survival in patients with TNBC. Furthermore, ADAM9 in TNBC cells was knocked down by small interference RNA and then studied by the MTT/colony formation assay, wound healing assay and transwell invasion assay on the cell proliferation, migration, and invasion, respectively. We found that inhibiting ADAM9 expression suppressed TNBC cell proliferation, migration, and invasion by lowering the activation of AKT/NF-κB pathway. Our results demonstrated that ADAM9 is an important molecule in mediating TNBC aggressiveness and may be a potential useful therapeutic target in TNBC treatment.

Metalloprotease ADAM9 cleaves ephrin-B ligands and differentially regulates Wnt and mTOR signaling downstream of Akt kinase in colorectal cancer cells

“…A previous study has associated ADAM9 function in Akt regulation with EGFR activation ( 42 ). However, HCT116 cells contain a constitutively active PI3K mutation ( Table S1 ), rendering Akt activity in these cells insensitive to growth factor stimulation ( 43 ), and a recent report shows that ADAM9 activates Akt independently of EGFR ( 44 ). We have shown that KD of ADAM9 results in increased levels of intact ephrin-B1 and active EphB3 receptor ( Figs.…”

“…We found that ADAM9 mRNA is also elevated in CRC tissues and identified Akt and downstream Wnt and mTOR signaling as the main targets for ADAM9 in CRC cells. Two published works have linked ADAM9 to Akt activity in esophageal squamous cell carcinoma and triple-negative breast cancer, respectively ( 42 , 44 ). Together with our results, these suggest that ADAM9 is a key Akt regulator in various tumors.…”

RNA-Based Therapeutics: Current Developments in Targeted Molecular Therapy of Triple-Negative Breast Cancer

“…• siRNA targets: ADAM9 [87]; AKT2 [88]; EGFR [89]; CD44 [90]; BRD4 [91]; IKBKE [61]; ICAM1 [92]; TTK, CDC20 [93]; POLR2A [94]; survivin [64]; MTOR (mTORC2) [95]; oncogenic lncRNAs TMPO-AS1 [96]/DANCR [97]; CD44 [98]; EIF4E (eIF4E) [99]; ZRANB1 [100] • shRNA targets: EZH2 [100]; LGALS1 (galectin-1) [101]; USP39 [102] There has been significant progress in developing RNA-based therapies for a wide variety of diseases, although primarily preclinically for TNBC to date. Although there are several promising early-stage studies for TNBC using RNAi and RNA immunotherapy as was described in Section 1.3, and combinatorial RNA-based therapies, described in Section 1.4, it is important to recognize that there is still a significant amount of work until these therapeutic agents/strategies will advance to clinical evaluation.…”

Natural Products with Activity against Lung Cancer: A Review Focusing on the Tumor Microenvironment

“…Liu et al also proved that the combination of Fei-Liu-Ping ointment with celecoxib inhibits the tumor inflammatory microenvironment in an LLC xenograft model [ 78 ]. Disintegrin and a metalloproteinase (ADAM9), a type I transmembrane protein, are overexpressed in various cancers, including lung cancer [ 135 , 136 , 137 ]. Lin et al proved that a secreted form of ADAM9 promotes cancer invasion through tumor-stromal interactions [ 137 ].…”