Abstract
E-cadherin is a cell-cell adhesion protein encoded by CDH1 tumor-suppressor gene. CDH1 inactivating mutations, leading to loss of protein expression, are common in gastric cancer of the diffuse histotype, while alternative mechanisms modulating E-cadherin expression characterize the more common intestinal histotype. These mechanisms are still poorly understood. CDH1 intron 2 has recently emerged as a cis-modulator of E-cadherin expression, encoding non-canonical transcripts. One in particular, CDH1a, proved to be expressed in gastric cancer cell lines, while being absent in the normal stomach. For the first time, we evaluated by digital PCR the expression of CDH1 and CDH1a transcripts in cancer and normal tissue samples from 32 patients with intestinal-type gastric cancer. We found a significant decrease in CDH1 expression in tumors compared to normal counterparts (P = 0.001), which was especially evident in 76% of cases. CDH1a was detected at extremely low levels in 47% of tumors, but not in normal mucosa. A trend was observed of having less CDH1 in tumors expressing CDH1atranscript. The majority of tumors with both a decrease in CDH1 and presence of CDH1a also showed a decrease in miR-101 expression levels. On the whole, the decrease of CDH1 transcript, corresponding to the canonical protein, and the presence of CDH1a, corresponding to an alternative isoform, are likely to perturb E-cadherin-mediated signaling and cell-cell adhesion, thus contributing to intestinal-type gastric carcinogenesis.
Highlights
Gastric cancer (GC) is a heterogeneous disease, with two major histological subtypes, “intestinal” (IGC) and “diffuse” (DGC) [1], that vary in terms of both clinicpathological profiles and molecular pathogenesis [2]
Gene expression was investigated by quantifying with digital PCR the canonical transcript and one non-canonical transcript arising from intron 2; this last has properties enabling its translation into a protein isoform differing from the canonical E-cadherin in its N-terminal domain [15]
The importance of E-cadherin in the manifestation of gastric cancer is highlighted by findings supporting the dysregulation of this protein in both the intestinal and diffuse GC histotypes
Summary
Gastric cancer (GC) is a heterogeneous disease, with two major histological subtypes, “intestinal” (IGC) and “diffuse” (DGC) [1], that vary in terms of both clinicpathological profiles and molecular pathogenesis [2]. Different genetic and epigenetic lesions underlie the carcinogenic processes involved [2] and subtype-specific molecular signatures have been identified by whole-genome sequencing and gene expression and methylation profiling [3, 4, 5]. Beyond these subtypespecific features, comprehensive molecular approaches highlighted that adherens junctions and focal adhesions are driver pathways in gastric carcinogenesis, with alterations in genes associated with these pathways occurring in most GC cases [3, 4, 5]. The protein has been implicated in cell survival, proliferation and migration, and its loss/aberrant expression has a key role in tumor invasion and metastasis [7, 8]
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