Abstract
To investigate the potential oncogene promoting recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT), throughput RNA sequencing was performed in a subgroup of HCC patients. The up-regulated FAM83D in HCC tissues was found and further verified in 150 patients by real-time PCR and immunohistochemistry. FAM83D overexpression significantly correlated with high HCC recurrence rate following LT and poor HCC characteristics such as high AFP, poor differentiation. Of cancer stem cells (CSCs) markers, CD44 expression was effectively suppressed when FAM83D was knocked down by siRNA. Meanwhile, the siRNA transfected cells suppressed formation of sphere and ability of self-renew. In a xenograft tumorigenesis model, FAM83D knockdown apparently inhibited tumor growth and metastasis. Microarray assays revealed that FAM83D promotes CD44 expression via activating the MAPK, TGF-β and Hippo signaling pathways. Furthermore, CD44 knockdown presented reverse effect on above signaling pathways, which suggested that FAM83D was a key activator of loop between CD44 and above signaling pathways. In conclusion, FAM83D promotes HCC recurrence by promoting CD44 expression and CD44+ CSCs malignancy. FAM83D provides a novel therapeutic approach against HCC recurrence after LT.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the third most frequent cause of cancer deaths [1, 2], accounting for more than 70% of the total liver cancer, and epidemiologic evidence indicates that hepatocellular carcinoma (HCC) will still increase medical and economic burden during the decades [3]
Overexpression of FAM83D in HCC was significantly correlated with poor tumor characteristics, i.e. poor differentiation, portal vein tumor thrombus (PVTT), tumor number, and greatest tumor diameter (Figure 1D-1H)
To investigate the genes involving in the complicated metastasis process, we profiled the mRNA in HCC with RNA sequence
Summary
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the third most frequent cause of cancer deaths [1, 2], accounting for more than 70% of the total liver cancer, and epidemiologic evidence indicates that HCC will still increase medical and economic burden during the decades [3]. Despite recently significant advances in screening, diagnosis and treatment for HCC, the survival time of a large proportion of HCC patients is significant low and the 5-year rate remains a dismal 12%. Post-LT HCC recurrence and metastasis greatly give rise to the unsatisfactory long-term survival following LT. The number of HCC patients on the waiting line for LT and out of LT criteria is much more than liver recipients. Several target drugs are under development, only sorafenib presented a finite survival benefits for individuals with advanced HCC [4]. It is essential to find a potentially novel therapeutic target and predicting biomarker of diagnosis, treatment response and recurrence for improving HCC prognosis
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