Abstract
We investigated the role of actin filament associated protein 1 antisense RNA1 (AFAP1-AS1) lncRNA in promoting cholangiocarcinoma (CCA). qRT-PCR analysis of patient samples showed that AFAP1-AS1 expression was higher in CCA tumors than matched adjacent non-tumor tissue. AFAP1-AS1 levels were also higher in CCA cell lines (HuCCT1 and TFK-1) than a normal biliary epithelium cell line (HIBEpic). AFAP1-AS1 knockdown in CCA cell lines using shAFAP1-AS1 reduced cell proliferation and colony formation in CCK-8 and colony formation assays, respectively. Cell cycle analysis demonstrated that AFAP1-AS1 knockdown resulted in G0/G1 cell cycle arrest and inhibition of S-G2/M transition compared to the controls. CCA cells transfected with shAFAP1-AS1 also exhibited reduced metastasis and invasiveness in Transwell and wound healing assays. This was further confirmed in xenograft experiments with nude mice using CCA cells transfected with shAFAP1-AS1 or control shRNA. AFAP1-AS1 knockdown cells produced smaller tumors, demonstrating that AFAP1-AS1 promotes tumor growth in vivo. AFAP1-AS1 knockdown also increased expression of actin filament associated protein 1 (AFAP1) and reduced cell stress filament integrity, as determined from western blot and immunofluorescence assays, respectively. These findings indicate that AFAP1-AS1 exerts oncogenic effects in CCA. We postulate that AFAP1-AS1 is a potentially useful diagnostic and prognostic biomarker and therapeutic target for CCA.
Highlights
Cholangiocarcinoma (CCA) is one of the most aggressive and lethal tumors originating from malignant transformation of cholangiocytes and epithelial cells lining the intrahepatic and extrahepatic biliary ducts [1]
We investigated the role of actin filament associated protein 1 antisense RNA1 (AFAP1-AS1) Long noncoding RNAs (lncRNAs) in promoting cholangiocarcinoma (CCA). qRT-PCR analysis of patient samples showed that AFAP1-AS1 expression was higher in CCA tumors than matched adjacent non-tumor tissue
LncRNA GAS5 has been shown to be significantly down-regulated in hepatocellular carcinoma tissues [21]. lncRNA HOTAIR has been reported to be upregulated in breast cancer, pancreatic cancer, lung cancer, and gastric cancer, and high HOTAIR
Summary
Cholangiocarcinoma (CCA) is one of the most aggressive and lethal tumors originating from malignant transformation of cholangiocytes and epithelial cells lining the intrahepatic and extrahepatic biliary ducts [1]. 80%–90% of CCAs are of extrahepatic origin that is further divided into perihilar (Klatskin tumor) and distal tumors based on their location within the extrahepatic biliary system [2]. CCA is an aggressive cancer with medial survival of less than 24 months after diagnosis. Systemic chemotherapy with gemcitabine and cisplatin is standard practice for advanced stage patients. Inspite of the combination chemotherapy, the 5-year survival rates in CCA patients remains less than 20-40% [3]. There is greater need to identify novel therapeutic targets by deciphering the critical molecular mechanisms regulating CCA in order to improve patient survival times
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