Abstract
Aldehyde dehydrogenases (ALDHs) play an essential role in regulating malignant tumor progression; however, their role in cholangiocarcinoma (CCA) has not been elucidated. We analyzed the expression of ALDHs in 8 paired tumor and peritumor perihilar cholangiocarcinoma (pCCA) tissues and found that ALDH3B1 and ALDH3B2 were upregulated in tumor tissues. Further survival analysis in intrahepatic cholangiocarcinoma (iCCA, n = 27), pCCA (n = 87) and distal cholangiocarcinoma (dCCA, n = 80) cohorts have revealed that ALDH3B2 was a prognostic factor of CCA and was an independent prognostic factor of iCCA and pCCA. ALDH3B2 expression was associated with serum CEA in iCCA and dCCA, associated with tumor T stage, M stage, neural invasion and serum CA19-9 in pCCA. In two cholangiocarcinoma cell lines, overexpression of ALDH3B2 promoted cell proliferation and clone formation by promoting the G1/S phase transition. Knockdown of ALDH3B2 inhibited cell migration, invasion, and EMT in vitro, and restrained tumor metastasis in vivo. Patients with high expression of ALDH3B2 also have high expression of ITGB1 in iCCA, pCCA, and dCCA at both mRNA and protein levels. Knockdown of ALDH3B2 downregulated the expression of ITGB1 and inhibited the phosphorylation level of c-Jun, p38, and ERK. Meanwhile, knockdown of ITGB1 inhibited the promoting effect of ALDH3B2 overexpression on cell proliferation, migration, and invasion. ITGB1 is also a prognostic factor of iCCA, pCCA, and dCCA and double-positive expression of ITGB1 and ALDH3B2 exhibits better performance in predicting patient prognosis. In conclusion, ALDH3B2 promotes tumor proliferation and metastasis in CCA by regulating the expression of ITGB1 and upregulating its downstream signaling pathway. The double-positive expression of ITGB1 and ALDH3B2 serves as a better prognostic biomarker of CCA.
Highlights
Cholangiocarcinoma (CCA) is a cancer type arising from the biliary duct which is associated with poor prognosis [1]
Whether Aldehyde dehydrogenases (ALDHs) participate in the oncogenesis and progression of cholangiocarcinoma has not yet been evaluated
We compared the expression of 19 ALDHs in hilar cholangiocarcinoma and paired peritumor tissues by mRNA microarray
Summary
Cholangiocarcinoma (CCA) is a cancer type arising from the biliary duct which is associated with poor prognosis [1]. CCA accounts for about 3% of gastrointestinal cancers; the morbidity and mortality of cholangiocarcinoma, especially iCCA, are increasing worldwide [2,3,4]. The studies of biomarkers and drug targets of CCA are very rare, resulting in the slow processes of CCA targeted therapy. Both effective pre-and post-operational biomarkers are urgently needed for early diagnosis and individualized treatment of CCA [13,14,15]
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