Characterization of the intronic portion of cadherin superfamily members, common cancer orchestrators

Abstract

Cadherins are cell-cell adhesion proteins essential for the maintenance of tissue architecture and integrity, and their impairment is often associated with human cancer. Knowledge regarding regulatory mechanisms associated with cadherin misexpression in cancer is scarce. Specific features of the intronic-structure and intronic-based regulatory mechanisms in the cadherin superfamily are unidentified. This study aims at systematically characterizing the intronic portion of cadherin superfamily members and the identification of intronic regions constituting putative targets/triggers of regulation, using a bioinformatic approach and biological data mining. Our study demonstrates that the cadherin superfamily genes harbour specific characteristics in comparison to all non-cadherin genes, both from the genomic and transcriptional standpoints. Cadherin superfamily genes display higher average total intron number and significantly longer introns than other genes and across the entire vertebrate lineage. Moreover, in the human genome, we observed an uncommon high frequency of MIR (mammalian-wide interspersed repeats) and MaLR (mammalian-wide interspersed repeats, a subtype of LTR) regulatory-associated repetitive elements at 5¢-located introns, concomitantly with increased de novo intronic transcription. Using this approach, we identified cadherin intronic-specific sites that may constitute novel targets/triggers of cadherin superfamily expression regulation. These findings pinpoint the need to identify mechanisms affecting particularly MIR and MaLR elements located in introns 2 and 3 of human cadherin genes, possibly important in the expression modulation of this superfamily in homeostasis and cancer.

Digital PCR identifies changes in CDH1 (E-cadherin) transcription pattern in intestinal-type gastric cancer

“…In addition, intron 2, from which CDH1a arises, is a well-demonstrated cis regulatory element of CDH1 gene expression, containing multiple transcription initiation sites and evolutionary conserved elements, as well as enhancers and repeated sequences [ 6 , 14 , 15 , 16 ]. In particular, surrounding exon 1a different regulatory sequences have been identified, including CpG islands, DNaseI hypersensitive sites and CTCF (CCCTC-binding factor) insulator elements [ 15 ].…”

“…In addition to genetic determinants and miRNAs, an intron-mediated mechanism of CDH1 regulation has also been identified [ 13 , 14 , 15 ]. Indeed, intron 2, harboring an exceptionally high number of repetitive elements involved in exonization, can act as a cis -modulator of E-cadherin gene and protein expression [ 6 , 14 , 16 ]. In certain cell lines, intron 2 has been shown to give rise to a number of non-canonical transcripts, one of which, CDH1a , harbors properties that enable its translation into a protein isoform differing from the canonical E-cadherin in its N-terminal domain [ 15 ].…”

Transcription initiation arising from E-cadherin/CDH1 intron2: a novel protein isoform that increases gastric cancer cell invasion and angiogenesis†

“…While seeking for mechanisms regulating CDH1 expression during mouse development, colleagues (2003 and showed that murine CDH1 intron 2 deletions interfere with gene transcriptional activation and expression in a tissue specific manner (16,17), strongly supporting the existence of sequences, within those regions, that may act as cis-modulators of E-cadherin expression (18). Thus, there are unaccounted mechanisms for CDH1 inactivation in sporadic and inherited tumors, potentially involving intronic-dependent regulation of this locus.…”

E-cadherin roles in animal biology: A perspective on thyroid hormone-influence

“…1). Striking, cadherin superfamily genes display a higher average total intron number and significantly longer introns than other genes and across the entire vertebrate lineage [144]. Particularly, the human genome has an uncommon high frequency of MIR and MaLR regulatory-associated repetitive elements at 5’-located introns, concomitant with increased de novo intronic transcription.…”