Alternative splicing, a phenomenon by which a single gene generates multiple forms of mRNA that can be translated into diverse proteins , is responsible for an estimated 10–20% of all cancer-related gene alterations [5, 22, 23]. Both the ubiquitous normal transcripts and the unique splice variants generated from these alteration events are frequently expressed simultaneously in cancerous cells and tissues [6, 7, 24]. As such, those variants expressed as cancer-specific transcripts are possible candidate biomarkers [6, 7]. This study revealed that while the splice variants 6a, 6b, and 6c of the ARHGDIB gene are expressed in pancreas, stomach, colon, and breast cancer cell lines and in normal placental tissue but not in other types of normal tissue, the known form of ARHGDIB is ubiquitously expressed in many types of normal tissue and cancer cells. A similarly restricted profile has also been observed for PLAC1. PLAC1, reported to be the first member of a new class of antigens that specifically relates placentation to cancer [25, 26], has been observed to be ectopically activated in many human cancers and is essentially involved in malignant cell processes . These ARHGDIB variants can be considered potential biomarkers based on the similarity between ARHGDIB and PLAC1 reported in previous studies, as well as the observation of high levels of expression of the variants 6a, 6b, and 6c in placental and cancer cells and their relatively restricted expression in normal tissues in this study.
Splice variants are often translated into structurally defective proteins in cancer cells, affecting the functioning of the original protein [7, 27]. In a previous study, the authors of this study focused on examining splice variants and variant-derived protein isoforms to identify candidate biomarkers . However, the current study revealed that the variants 6a, 6b, and 6c and the normal transcript share a common protein-coding region and that these variants are slightly translated into the intact ARHGDIB protein. These results suggest that the structurally defective protein isoforms of ARHGDIB derived from the variant 6 series are not expressed in cancer cells and the placenta, thereby indicating that the mRNA of the cancer-specific variant 6 series may be a more suitable biomarker than the ARHGDIB protein.
In general, mRNA stability is related to UTR length as well as secondary structure , as both influence the regulation of protein expression . In this study, the 5′ and 3′ UTRs of the variant 6 series were observed to clearly differ from those of the normal ARHGDIB, resulting in the decreased mRNA stability of these variants, while the translation efficiency of the variants into intact ARHGDIB protein was observed to be distinctly low. These findings suggest that the mRNA stability of the novel variants identified in this study may be involved in the regulation of protein expression.