Abstract
Simple SummaryA disintegrin and metalloprotease 12 (ADAM12) has been associated with tumor development and progression. The aim of the current study was to evaluate the impact of ADAM12 on cancer progression, prognosis, and therapeutic targets in colorectal cancer (CRC). Our results show that ADAM12 overexpression enhanced proliferation, inhibited apoptosis, and acted as a positive regulator of cell cycle progression in CRC cells. Phosphorylation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was decreased and that of Akt was increased by ADAM12 overexpression. These results were reversed upon ADAM12 knockdown. ADAM12 overexpression was significantly associated with the cancer stage, depth of invasion, lymph node metastasis, distant metastasis, and poor survival in CRC patients. In a mouse xenograft model, tumor area, volume, and weight were significantly greater for the ADAM12 overexpression group and significantly lower for the ADAM12 knockdown group. In conclusion, ADAM12 may serve as a promising biomarker and/or therapeutic target in CRC.A disintegrin and metalloprotease 12 (ADAM12) has been implicated in cell growth, tumor formation, and metastasis. Therefore, we evaluated the role of ADAM12 in colorectal cancer (CRC) progression and prognosis, and elucidated whether targeted downregulation of ADAM12 could lead to therapeutic sensitization. The effect of ADAM12 on tumor cell behavior was assessed in CRC cell lines, CRC tissues, and a mouse xenograft model. ADAM12 overexpression enhanced proliferation, inhibited apoptosis, and acted as positive regulator of cell cycle progression in CRC cells. Phosphorylation of PTEN was decreased and that of Akt was increased by ADAM12 overexpression. These results were reversed upon ADAM12 knockdown. ADAM12 overexpression was significantly associated with the cancer stage, depth of invasion, lymph node metastasis, distant metastasis, and poor survival in CRC patients. In a mouse xenograft model, tumor area, volume, and weight were significantly greater for the ADAM12-pcDNA6-myc-transfected group than for the empty-pcDNA6-myc-transfected group, and significantly lower for the ADAM12-pGFP-C-shLenti-transfected group than for the scrambled pGFP-C-shLenti-transfected group. In conclusion, ADAM12 overexpression is essential for the growth and progression of CRC. Furthermore, ADAM12 knockdown reveals potent anti-tumor activity in a mouse xenograft model. Thus, ADAM12 may serve as a promising biomarker and/or therapeutic target in CRC.
Highlights
Colorectal cancer (CRC) is one of the major causes of cancer-associated morbidity and mortality worldwide
To study the prognostic role of A disintegrin and metalloprotease 12 (ADAM12) in human colorectal cancer (CRC) progression, we immunohistochemically investigated the expression of ADAM12 protein in formalin-fixed, paraffinembedded tissue blocks obtained from 366 CRC patients
ADAM12 regulates prostatic cancer cell invasion through the NF-κB signaling pathway [37]. Consistent with these findings, we found that phosphorylation of PTEN was decreased and Akt was increased by overexpression of ADAM12 in human CRC cells
Summary
Colorectal cancer (CRC) is one of the major causes of cancer-associated morbidity and mortality worldwide. Despite significant advancements in diagnosis and therapy, fewer than 40% of cases are diagnosed when the cancer is still localized, and the prognosis of advanced CRC remains poor, with progressive behaviors, including cancer invasion and metastasis, being the major contributors to CRC-related morbidity and mortality [1,2,3]. This highlights the need to develop biomarkers to identify which persons will benefit the most from cancer surveillance and management. This family is involved in various physiological and pathological processes, including cellular development, modulation of inflammatory reactions, and formation and progression of cancer via the release of membrane-bound proteins, such as adhesion molecules, cytokines, chemokines, and growth factors [8,9,10]
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