Calcium-sensing receptor promotes tumor proliferation and migration in human intrahepatic cholangiocarcinoma by targeting ERK signaling pathway.

The Calcium-sensing receptor (CaSR) is functionally expressed in the biliary epithelial cells and it has been verified to possess various regulatory functions in several different forms of human cancers. But its pathological role in human intrahepatic cholangiocarcinoma (ICC) development remains obscure. Here, we confirmed that CaSR expression was up-regulated in ICC tumor specimens and cell lines, which was positively correlated with number of tumors, lymph node metastasis and poor prognosis of ICC patients. CaSR activation induced by CaCl₂ or Calindol (a selective CaSR agonist) markedly facilitated cell proliferation and migration in ICC cells, while knockdown of CaSR or NPS2143 treatment (a CaSR antagonist) dramatically suppressed the above effects. We also demonstrated that alteration of CaSR activity mediated tumorigenesis and growth of ICC in vivo. Mechanistically, CaSR activation could promote cell cycle progression and induce an upregulation of MMP-2 and MMP-9 expression partly via the simulation of ERK1/2 signaling pathway. And further inhibition of ERK pathway significantly suppressed ICC cell viability and migration capacity. Together, our findings shed novel light on the role of CaSR as an oncogene in ICC progression and indicated that modulation of CaSR might serve as a preventive or therapeutic strategy for ICC. Copyright © 2020 Elsevier B.V. All rights reserved.

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