CCN1 is critical for acid-induced esophageal epithelial cell transformation.
CCN1 is a matricellular protein involved in both wound healing and cancer cell invasion. Increased CCN1 expression has been associated with the development of Barrett's esophagus and the increased risk of progression to esophageal adenocarcinoma. In both cases, acid reflux is a major contributor. Low pH has been shown to induce CCN1 gene expression in esophageal epithelial cells. Here we demonstrated that both CCN1 and low pH could cause esophageal epithelial cell transformation, including loss of E-cadherin, disruption of cell-cell junctions, and expression of mesenchymal markers. Furthermore, knockdown of CCN1 through RNA interference sufficiently attenuated acid-driven cell phenotypic changes, while over-expression of CCN1 exacerbated these effects, indicating a critical role of CCN1 in acid-induced esophageal epithelial cell transformation. Given the pivotal role of low pH in gastro-esophageal reflux disease and its progression towards esophageal adenocarcinoma, our study identified CCN1 as a key molecule mediating this process.
Modak
Cristina
C
VA Long Beach Healthcare System, 5901 E. Seventh Street, Long Beach, CA 90822, USA.
Mouazzen
Wasim
W
Narvaez
Reinier
R
Reavis
Kevin M
KM
Chai
Jianyuan
J
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D022005:Adherens Junctions / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D015820:Cadherins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055515:Cysteine-Rich Protein 61 / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005744:Gastric Acid / Q000378:metabolism*; D005764:Gastroesophageal Reflux / Q000150:complications* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference
D014408:Biomarkers, Tumor; C501848:CCN1 protein, human; D015820:Cadherins; D055515:Cysteine-Rich Protein 61