Abstract
Cholangiocarcinoma (CCA) is a devastating disease due to resistance to traditional chemotherapies and radiotherapies. New therapeutic strategies against CCA are urgently needed. This study investigated the role of lipocalin-2 (LCN2) in human cholangiocarcinoma as a potential therapeutic target and diagnostic marker. So far, the role of LCN2 in cancer is still controversial and studies regarding the role of LCN2 in CCA are limited. LCN2 knockdown inhibited CCA cell growth in vitro and in vivo through induction of cell cycle arrest at G0/G1 phases and decreased metastatic potential due to repression of epithelial-mesenchymal transition (EMT). Overexpression of LCN2 in CCA cells increased cell metastatic potential. We showed for the first time that the N-myc downstream regulated gene 1 (NDRG1) and NDRG2, known as tumor suppressor genes, are negatively regulated by LCN2 in CCA cells. LCN2 concentration in bile was higher in patients with CCA than that in patients with gallstones, with a cutoff value of 20.08 ng/ml making this a potential diagnostic marker. Higher LCN2 expression was associated with worse survival in patients with CCA. LCN2 is a promising target for CCA treatment and bile LCN2 level is a potential diagnostic marker for CCA.
Highlights
Cholangiocarcinoma (CCA) is an epithelial malignancy arising from the bile ducts, and ranks as the second most common liver malignancy, after hepatocellular carcinoma
Since epithelial-mesenchymal transition (EMT) is a key step in cancer cell metastasis, we investigated the effect of LCN2 on EMT-related transcription factors
LCN2 is widely deemed as an oncogene in a variety of cancers despite some enduring controversy[6], but studies regarding LCN2 anti-cancer mechanisms remain limited
Summary
Cholangiocarcinoma (CCA) is an epithelial malignancy arising from the bile ducts, and ranks as the second most common liver malignancy, after hepatocellular carcinoma. Many studies have identified a pro-neoplastic role for LCN2 and related mechanisms[6,7]. Some studies have shown that LCN2 acts as a tumor suppressor gene in ovarian cancer, pancreatic cancer and colon cancer[8,9,10]. Studies investigating the role of LCN2 in CCA are still very limited. NDRG1 and NDRG2 have been widely studied and identified as tumor suppressor genes in a variety of cancers[13,14,15,16,17]. EMT is a process during which epithelial cells change towards a mesenchymal cell phenotype, playing a vital role in cancer cell metastasis. After EMT, cancer cells have increased motility and become more invasive. EMT renders cancer cells more resistant to chemotherapy and surveillance of immune cells due to increased stem cell-like characteristics[18,19,20]
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