Interferon-induced protein with tetratricopeptide repeats 3 may be a key factor in primary biliary cholangitis

Accumulating studies suggest that senescent biliary epithelial cells (BECs) produce senescence-associated secretory phenotypes (SASPs) and play various roles in the pathogenesis of primary biliary cholangitis (PBC) and other cholangiopathies. We examined comprehensive profiles of senescent BECs and its contribution to the pathogenesis of PBC taking advantage of microarray analysis. cDNA microarray analysis revealed that 1841 genes including CCL2, IFIT3, CPQ were commonly up-regulated in senescent BECs cultured in serum depleted media or media with glycochenodeoxycholic acid. Knockdown of IFIT3 significantly suppressed cellular senescence (p < 0.01) and significantly increased apoptosis (p < 0.01) in BECs treated with serum depletion or glycochenodeoxycholic acid. Significantly increased expression of IFIT3 was seen in senescent BECs in small bile ducts showing cholangitis and in ductular reactions in PBC, compared to control livers (p < 0.01). An inadequate response to UDCA was inversely correlated to the increased expression of IFIT3 in small bile duct in PBC (p < 0.05). In conclusion, the expression of various genes related to immunity and inflammation including SASPs were increased in senescent BECs. Upregulated IFIT3 in senescent BECs may be associated with the pathogenesis of PBC and may be a possible therapeutic target in PBC.

Typing FGFR2 translocation determines the response to targeted therapy of intrahepatic cholangiocarcinomas

Chromosomal translocations involving fibroblast growth factor receptor 2 (FGFR2) gene at the breakpoints are common genetic lesions in intrahepatic cholangiocarcinoma (ICC) and the resultant fusion protein products have emerged as promising druggable targets. However, predicting the sensitivity of FGFR2 fusions to FGFR kinase inhibitors is crucial to the prognosis of the ICC-targeted therapy. Here, we report identification of nine FGFR2 translocations out of 173 (5.2%) ICC tumors. Although clinicopathologically these FGFR2 translocation bearing ICC tumors are indistinguishable from the rest of the cohort, they are invariably of the mass-forming type originated from the small bile duct. We show that the protein products of FGFR2 fusions can be classified into three subtypes based on the breaking positions of the fusion partners: the classical fusions that retain the tyrosine kinase (TK) and the Immunoglobulin (Ig)-like domains (n = 6); the sub-classical fusions that retain only the TK domain without the Ig-like domain (n = 1); and the non-classical fusions that lack both the TK and Ig-like domains (n = 2). We demonstrate that cholangiocarcinoma cells engineered to express the classical and sub-classical fusions show sensitivity to FGFR-specific kinase inhibitors as evident by the suppression of MAPK/ERK and AKT/PI3K activities following the inhibitor treatment. Furthermore, the kinase-deficient mutant of the sub-classical fusion also lost its sensitivity to the FGFR-specific inhibitors. Taken together, our study suggests that it is essential to determine the breakpoint and type of FGFR2 fusions in the small bile duct subtype of ICC for the targeted treatment.

Peritumoral ductular reaction can be a prognostic factor for intrahepaticcholangiocellular carcinoma

Background: Peritumoral ductular reaction (DR) was reported to be related to the prognosis of combined hepatocellular-cholangiocarcinoma and hepatocellular carcinoma. Non-mucin-producing intrahepatic cholangiocarcinoma (ICC) which may be derived from small bile duct cells or liver progenitor cells (LPCs) was known to us. However, whether peritumoral DR is also related to non-mucin-producing ICCs remains to be investigated. Methods: Forty-seven patients with non-mucin-producing ICC were eventually included in the study and clinicopathological variables were collected. Immunohistochemical analysis and immunofluorescence staining for cytokeratin 19, proliferating cell nuclear antigen, and α-smooth muscle actin were performed in tumor and peritumor liver tissues.Results: A significant correlation existed between peritumoral DR and local inflammation and fibrosis. (r = 0.357, 95% CI, 0.037-0.557; P = 0.008 and r = 0.742, 95% CI, 0.580-0.849; P < 0.001, respectively). Patients with obvious peritumoral DR had high recurrence rate (81.8% vs 56.0%, P = 0.058) and poor overall and disease-free survival time (P = 0.01 and P = 0.03, respectively) comparing with mild peritumoral DR. Compared with the mild peritumoral DR group, the proliferation activity of LPCs/ cholangiocytes was higher in obvious peritumoral DR, which, however, was not statistically significant. (0.43±0.29 vs 0.28±0.31, P = 0.172). Furthermore, the correlation analysis showed that the DR grade was positively related to the portal/septalα-SMA level (r = 0.359, P = 0.001).Conclusions: Peritumoral DR was associated with local inflammation and fibrosis. Patients with non-mucin-producing ICC having obvious peritumoral DR had a poor prognosis. Peritumoral DR could be a prognostic factor for ICC. However, the mechanism should be further investigated.

Peritumoral ductular reaction can be a prognostic factor for intrahepatic cholangiocellular carcinoma

Background: Peritumoral ductular reaction (DR) was reported to be related to the prognosis of combined hepatocellular-cholangiocarcinoma and hepatocellular carcinoma. Non-mucin-producing intrahepatic cholangiocarcinoma (ICC) which may be derived from small bile duct cells or liver progenitor cells (LPCs) was known to us. However, whether peritumoral DR is also related to non-mucin-producing ICCs remains to be investigated. Methods: Forty-seven patients with non-mucin-producing ICC were eventually included in the study and clinicopathological variables were collected. Immunohistochemical analysis and immunofluorescence staining for cytokeratin 19, proliferating cell nuclear antigen, and α-smooth muscle actin were performed in tumor and peritumor liver tissues.Results: A significant correlation existed between peritumoral DR and local inflammation and fibrosis. (r = 0.357, 95% CI, 0.037-0.557; P = 0.008 and r = 0.742, 95% CI, 0.580-0.849; P < 0.001, respectively). Patients with obvious peritumoral DR had high recurrence rate (81.8% vs 56.0%, P = 0.058) and poor overall and disease-free survival time (P = 0.01 and P = 0.03, respectively) comparing with mild peritumoral DR. Compared with the mild peritumoral DR group, the proliferation activity of LPCs/ cholangiocytes was higher in obvious peritumoral DR, which, however, was not statistically significant. (0.43±0.29 vs 0.28±0.31, P = 0.172). Furthermore, the correlation analysis showed that the DR grade was positively related to the portal/septalα-SMA level (r = 0.359, P = 0.001).Conclusions: Peritumoral DR was associated with local inflammation and fibrosis. Patients with non-mucin-producing ICC having obvious peritumoral DR had a poor prognosis. Peritumoral DR could be a prognostic factor for ICC. However, the mechanism should be further investigated.