Small proline rich protein 2a in benign and malignant liver disease

Abstract

STAT3-driven expression of small proline rich protein 2a (SPRR2a), which acts as an src homology 3 (SH3) domain ligand, induces biliary epithelial cell (BEC) epithelialmesenchymal transition (EMT), which, in turn, promotes wound healing. SPRR2a also quenches free radicals and protects against oxidative stress and DNA damage in nonneoplastic BEC. Sprr2a-induced EMT also increases local invasiveness of cholangiocarcinomas (CC), but prevents metastases. Understanding SPRR2a regulation of EMT has potential for therapeutic targeting in both benign and malignant liver disease. Molecular mechanisms responsible for SPRR2a-induced EMT were characterized, in vitro, and then evidence for utilization of these pathways was sought in human intrahepatic CC, in vivo, using multiplex labeling and software-assisted morphometric analysis. SPRR2a complexes with ZEB1 and CtBP on the microRNA (miR)-200c/141 promoter resulting in synergic suppression of miR-200c/141 transcription, which is required for maintenance of the BEC epithelial phenotype. SPRR2a induction promotes dephosphorylation and nuclear translocation of the SH3-domain containing protein GRB2 and an SH3-domain ligand in ZEB1 is required for SPRR2a-induced synergic suppression of miR-200c/141. Multiplex protein labeling of CC and morphometric analyses showed: 1) up-regulation of ZEB-1, and 2) down-regulation of CK19 in intrahepatic CC compared to nonneoplastic BEC, consistent with previous CC proteomic studies showing EMT during cholangiocarcinogenesis. Conclusion: SPRR2a modulates ZEB-1 signaling by way of miR-200c/141-associated EMT through SH3-domain networks and contributes to benign and malignant BEC wound-healing responses. (HEPATOLOGY 2014;59:1130-1143

ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma

“…Furthermore, they showed that mesenchymal markers such as ZEB1 and vimentin were more abundantly expressed, whereas an epithelial marker, E-cadherin, was much less abundantly expressed in hepatic stem cell-like ICC cases as compared with mature hepatocyte-like ICC cases in mRNA levels. Another finding reported that ZEB1 correlates with the differentiation status of ICC cells, furthermore, Mizuguchi showed that small proline-rich protein 2a complexes with ZEB1 repress mirR-200c/141 transcription in ICC cells, thereby inducing EMT 15. These results were support of our finding of the clinical significance of ZEB1 in ICC, and ZEB1 is recognised as a key molecule of the EMT in ICC.…”

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

“…Small proline rich protein 2a (SPRR2a) overexpression in CCA cells induced EMT, which in turn promotes invasiveness [59,120]. Further experiments showed that SPRR2A acts as a transcriptional corepressor with ZEB1 to repress miR-200c/141 transcription in CCA cells in order to maintain a mesenchymal phenotype [59].…”

“…Further experiments showed that SPRR2A acts as a transcriptional corepressor with ZEB1 to repress miR-200c/141 transcription in CCA cells in order to maintain a mesenchymal phenotype [59].…”

“…Nuclear ZEB1 was highly expressed in malignant iCCA cells compared to normal non-neoplastic epithelial cells and was associated with aggressive parameters and poorer OS [35,59]. High expression of ZEB2 was found in 51% of CCA and correlated with metastasis and poor prognosis [60].…”

Molecular hydrogen attenuates hypoxia/reoxygenation injury of intrahepatic cholangiocytes by activating Nrf2 expression

“…As a kind of important but delicate cells, cholangiocytes are also sensitive to oxidative stress and involved in the process of cholangiopathies [9,10]. Although an increasing number of studies have investigated intracellular mechanisms and therapeutic targets to prevent H/R-induced hepatocyte injury [3,11,12], only a few have focus on H/R-induced cholangiocyte injury.…”