ADAM9 Isoform Switching in Oesophageal Cancer

Abstract

Alternative splicing (AS) generates various structurally and functionally different protein isoforms. AS plays an important role in cancers by triggering hallmarks of cancer from a progression of primary tumour cells (tumorigenesis) to metastasis of secondary tumour cells to distant organs. Oesophageal cancer (EC) is one of the deadliest and least studied cancers worldwide because of its aggressive nature and low mortality rate. It remains a

public health concern worldwide (Holmes and Vaughan, 2007). ADAM9 is a membrane- anchored protein that is involved in various physiological and regulatory functions.

Proteolytically, ADAM9 is involved in EGFR signalling by processing EGFR ligands HB- EGF) whereas non-proteolytically interacts with integrins and is involved in cell adhesion

and cancer invasion. Expression levels of the two alternatively spliced transcripts of ADAM9 have an opposing role in breast cancer. This study was designed to provide a clear understanding if switching exists between L and S forms and ADAM9 enrichment in oesophageal cancer. Transcriptome assembly and reconstruction analysis revealed that ADAM9 is significantly upregulated, L transcript has high coverage than S transcript in oesophageal cancer. Dexseq statistical analysis revealed the differential transcript usage of L and S -form, which shows the increased usage of L-form compared to S-form. Furthermore, interacting partners for ADAM9 were identified. Moreover, enrichment analysis was performed, which revealed focal adhesion as the enriched process in all three datasets. This shows that ADAM9 is involved in ECM interactions occurring at specialized zones called focal adhesions. These focal adhesions are rich in integrin adhesion receptors which play an essential role in bi-directional transmembrane communication by connecting cell cytoskeletons to the extracellular membrane matrix in response to these focal adhesion signalling, the cell initiates diverse processes, including cell growth or death, cell motility and cytoskeleton reorganisation. Thus, this study enhanced the understanding of the proteolytic and non-proteolytic roles of ADAM9 and its isoforms in oesophageal cancer; however, a specific pathway in which ADAM9 is involved still needs to be discovered. Moreover, the stage-specific role of S and L-form is yet to be studied using stage-specific data.