Role of adiponectin signaling in cholangiocarcinoma

Introduction:

Adiponectin signaling plays a vital function in many biological processes in health and diseases. Recent studies have shown that adiponectin signaling contributed in carcinogenesis of cholangiocarcinoma (CC), the second most common primary hepatic malignancy. The aim of this study is to investigate the role of adiponectin signaling in CC by using a small molecular AdipoR agonist (2-(4-Benzoylphenoxy)-N-[1-(phenylmethyl)-4-piperidinyl]-acetamide) in vitro and in vivo.

Methods:

Anticancer effects of an AdipoR agonist were tested in vitro on intra- and extra-hepatic CC cell lines by different molecular methods (proliferation, migration, invasion, colony formation and apoptosis assay). Moreover, the regulations of cancer related signaling pathways were analyzed by Western blot, RT-PCR and RNAseq. Finally, anticancer effects were further evaluated using a CC engineered mouse model (Alb-Cre/KRAS^G12D/p53^L/L).

Results:

Cell proliferation, migration, invasion and colony formation were inhibited due to activating adiponectin signaling pathway. AdipoR agonist also induced CC cells going to apoptosis. EMT, AMPK, STAT3 and PARP signaling pathways were regulated under AdipoR agonist treatment. In addition, RNAseq profile data showed that abounding tumor suppressor genes were up-regulated and proto-oncogenes were down-regulated in treated cells compared to the control group. In CC engineered mice, survival was prolonged in the group treated with AdipoR agonist.

Conclusions:

Activating adiponectin signaling has potential anticancer effect by regulating different vital signaling pathways in cholangiocarcinogenesis in vitro and in vivo. Our data suggested that, targeting adiponectin signaling could be a new treatment option for patients with inoperable CC.