SOX4, an epithelial–mesenchymal transition inducer, transactivates ADAM28 gene expression and co‐localizes with ADAM28 at the invasive front of human breast and lung carcinomas

Abstract

ADAM28 (a disintegrin and metalloproteinase 28) is abundantly expressed by carcinoma cells in the human breast and non-small cell lung carcinomas, and plays a role in carcinoma cell growth and metastasis. Although Src is an inducer of ADAM28 gene expression through the PI3K/AKT/mTOR and MEK/ERK pathways, direct transcriptional regulators for ADAM28 gene expression remain unknown. In this study, we performed the luciferase reporter assay and found that SOX4 (SRY-related HMG-box 4), an inducer of epithelial-mesenchymal transition (EMT), is a transcriptional activator for the ADAM28 gene. This activation required the SOX4-binding consensus sequence at the 5'-untranslated region of the mouse and human ADAM28 genes. Forced expression of SOX4 promoted the ADAM28 gene expression and migration in human breast and lung carcinoma cell lines. In the human breast and lung carcinoma tissues, ADAM28 and SOX4 were co-expressed at the invasive front of carcinoma cell nests. Our data demonstrate that SOX4 transactivates ADAM28 gene expression through direct binding to the ADAM28 promoter region and suggest the possibility that ADAM28 plays a role in invasion through SOX4-mediated EMT in the human breast and lung carcinomas.

ADAM28: Another ambivalent protease in cancer

“…Moreover, co-localization of SOX4 and ADAM28 has been observed at the invasive front of human breast and lung carcinoma tissues. Altogether, these results demonstrate that ADAM28, which is transactivated by SOX4, promotes cell invasion of breast and lung carcinoma cells [74]. One can hypothesize that ADAM28 participates in SOX4-mediated EMT at invasive sites of tumors but the link remains to be clearly established (Fig.…”

“…loss of cell polarity and cell-cell adhesion) and the transcription factor SOX4 (SRY-related HMG-box 4) is now reported as one of the master regulators of EMT [73]. Co-transfection of COS-7 cells with ADAM28 promoter construct and SOX4 expression vector indicates that SOX4 activates ADAM28 reporter gene expression via its interaction with ADAM28 promoter [74]. Overexpression of SOX4 in lung and breast carcinoma cells enhances ADAM28 expression resulting in increased tumor cells migration.…”

Adamalysines as Biomarkers and a Potential Target of Therapy in Colorectal Cancer Patients: Preliminary Results

“…The cellular response to IGF is regulated by its binding to IGFBP, and the combination with IGFBP is stronger than the IGF affinity for the receptors. The biologically active IGF1 is one of the strongest growth factors in the activation of the ERK pathway, which is important for the development of CRC [14, 15]. IGFs, especially in association with obesity and insulin resistance, also have an impact on the increased risk of breast cancer [16].…”

Retracted Article: Long noncoding RNA ANRIL knockdown increases sensitivity of non-small cell lung cancer to cisplatin by regulating the miR-656-3p/SOX4 axis

“…SOX4 as an inducer of EMT could promote metastasis and development of cancers. 19,34 Furthermore, a number of evidences have been reported on the promoting role of SOX4 in chemoresistance in multiple cancers, including NSCLC. 20,35,36 Here we conrmed SOX4 as a target of miR-656-3p in NSCLC cells and further showed that ANRIL could regulate SOX4 expression by competitively binding miR-656-3p.…”