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Nonopioid Sigma1 receptor (Sig1R), which regulates various metabolism functions, has been implicated in cancers; yet, its role in hilar cholangiocarcinoma remains unclear. In the present study, we examined Sig1R expression in hilar cholangiocarcinoma (HC) tissues and explored its possible clinical values. Tissue microarray blocks containing 92 HC tissues and matched non-cancerous bile duct tissues were examined immunohistochemically for expression of Sig1R protein. Overexpression of Sig1R was found in 43 (46.7%) of the 92 primary tumor tissues. Overexpression of Sig1R was significantly associated with poor/undifferentiation (P = 0.011), tumor invasion (P = 0.001), lymph node metastasis (P = 0.047), and advanced disease stage (P = 0.024) of HC patients. Kaplan-Meier analysis showed that patients overexpressing Sig1R had an earlier recurrence and worse overall survival than those not overexpressing Sig1R. Cox regression analysis revealed that Sig1R was an independent factor to predict HC recurrence and prognosis of HC patients. Our results suggest that Sig1R is frequently activated in human HC tissue and overexpression of Sig1R might serve as a predictor for tumor recurrence and a prognostic biomarker for HC patients.

Avasimibe is a bioavailable acetyl-CoA acetyltransferase (ACAT) inhibitor and shows a good antitumor effect in various human solid tumors, but its therapeutic value in cholangiocarcinoma (CCA) and underlying mechanisms are largely unknown. In the study, we proved that avasimibe retard cell proliferation and tumor growth of CCAs and identified FoxM1/AKR1C1 axis as the potential novel targets of avasimibe. Aldo-keto reductase 1 family member C1 (AKR1C1) is gradually increased along with the disease progression and highly expressed in human CCAs. From survival analysis, AKR1C1 could be a vital predictor of tumor recurrence and prognostic factor. Enforced Forkhead box protein M1 (FoxM1) expression results in the upregulation of AKR1C1, whereas silencing FoxM1 do the opposite. FoxM1 directly binds to promoter of AKR1C1 and triggers its transcription, while FoxM1-binding site mutation decreases AKR1C1 promoter activity. Moreover, over-expressing exogenous FoxM1 reverses the growth retardation of CCA cells induced by avasimibe administration, while silencing AKR1C1 in FoxM1-overexpressing again retard cell growth. Furthermore, FoxM1 expression significantly correlates with the AKR1C1 expression in human CCA specimens. Our study demonstrates a novel positive regulatory between FoxM1 and AKR1C1 contributing cell growth and tumor progression of CCA and avasimibe may be an alternative therapeutic option for CCA by targeting this FoxM1/AKR1C1 signaling pathway. [ABSTRACT FROM AUTHOR]

The inorganic pyrophosphatase gene (PPA1) encodes inorganic pyrophosphatase, an enzyme that catalyzes the hydrolysis of inorganic pyrophosphate to orthophosphate, and has been revealed to be dysregulated in several types of human cancer. However, the role of PPA1 in intrahepatic cholangiocarcinoma (ICC) has not yet been determined. The present study detected PPA1 expression and investigated its clinical significance in ICC. Tissue microarray blocks containing 93 ICC specimens were constructed. The protein expression of PPA1 in these specimens was detected by immunohistochemistry. PPA1 was overexpressed in 49.5% of the ICC specimens and was significantly associated with large tumor size, positive margins, T stage, lymph nodal metastases, poorly differentiated tumors and advanced disease stage. Furthermore, PPA1 expression was an indicator of future recurrence and poor survival in patients with ICC. Increased expression of PPA1 is a common event in human ICC and is significantly associated with a poor outcome in patients with ICC, suggesting a potential role for PPA1 in the development and progression of ICC. [ABSTRACT FROM AUTHOR]