Annexin10 promotes extrahepatic cholangiocarcinoma metastasis by facilitating EMT via PLA2G4A/PGE2/STAT3 pathway

Background: Cholangiocarcinoma (CCA), consisting of intrahepatic (IHCCA), perihilar (PHCCA), and distal (DCCA) CCA, is a type of highly aggressive malignancy with a very dismal prognosis. Potential biomarkers and drug targets of CCA are urgently needed. As a new member of the Annexin (ANXA) family, the role of ANXA10 in the progression and prognosis of CCA is unknown. Methods: Potential PHCCA biomarkers were screened by transcriptome sequencing of 5 pairs of PHCCA and adjacent tissues. The clinical significance of ANXA10 was evaluated by analyzing its correlation with clinicopathological variables, and the prognostic value of ANXA10 was evaluated with univariate and multivariate analyses. The function of ANXA10 in the epithelial-mesenchymal transition (EMT), proliferation, invasion and metastasis was detected with in vitro and in vivo experiments. Moreover, we screened the key molecule in ANXA10-induced CCA progression by mRNA sequencing and evaluated the correlation between PLA2G4A and ANXA10. The effect of PLA2G4A downstream signaling, including Cyclooxygenase 2, Prostaglandin E2(PGE2) and Signal transducer and activator of transcription 3(STAT3), on EMT and metastasis was further detected with in vitro and in vivo experiments. Findings: ANXA10 expression was upregulated in PHCCA and DCCA but not in IHCCA. High ANXA10 expression was significantly associated with poor tumor differentiation and prognosis. ANXA10 promoted the proliferation, migration and invasion of the PHCCA cells. PLA2G4A expression was regulated by ANXA10 and high PLA2G4A predicted poor prognosis in PHCCA and DCCA. ANXA10 facilitated EMT and promoted metastasis by upregulating PLA2G4A expression, thus increasing PGE2 levels and activating STAT3. Interpretation: ANXA10 was an independent prognostic biomarker of PHCCA and DCCA but not IHCCA. ANXA10 promoted the progression of PHCCA and facilitated metastasis by promoting the EMT process via the PLA2G4A/PGE2/STAT3 pathway. ANXA10, PLA2G4A and their downstream molecules, such as COX2 and PGE2, may be promising drug targets of PHCCA and DCCA. (c) 2019 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).