Abstract
Liver cancer presents a challenge in today’s healthcare system. This study aimed at investigating the effects of Fer-1 like family member 4 (FER1L4) on chemotherapy resistance and liver cancer development by using clinically collected liver cancer tissues and commercially purchased human liver cancer cisplatin-resistant cell line HUH-7/DDP. Bioinformatics analysis, dual luciferase reporter gene assay, and RNA pull-down were applied to predict and verify the possible binding relationships. The expressions of FER1L4, E2F transcription factor 1 (E2F1), microRNA-106a-5p (miR-106a-5p), or miR-372-5p were altered in the cells, followed by flow cytometry, Cell Counting Kit-8 (CCK-8), and Transwell assays to evaluate apoptotic, proliferative, and invasive abilities in vitro and nude mice xenografts to observe tumor growth in vivo. FER1L4 was highly expressed and miR-106-5p and miR-372-5p were poorly expressed in tumor cells and tissues. FER1L4 knockdown or the overexpression of miR-106-5p and miR-372-5p inhibited the cancerous cell proliferation and invasion while promoting apoptosis. FERIL4 silencing increased the miR-106-5p/miR-372-5p expression to inhibit the E2F1-activated nuclear factor κB (NF-κB) pathway. Besides, overexpressing FER1L4 led to an increased tumor growth in nude mice, which was reversed by the NF-κB inhibitor pyrollidine dithiocarbamate (PDTC). In conclusion, the results indicated that FER1L4 could inhibit the expression of miR-106a-5p/miR-372-5p, to activate E2F1-mediated NF-κB pathway, leading to drug resistance in liver cancer.
Highlights
The incidence of liver cancer has increased by 4.6% from 2005 to 2015, the incidence of cancers in general is in the downward trend.[1]
FER1L4 expression is increased in liver cancer tissues and cell lines In this study, fluorescence in situ hybridization (FISH) and quantitative reverse transcriptase polymerase chain reaction assays were employed to explore the relationship between FER1L4 and the progression of liver cancer and the resistance of liver cancer cells
The results revealed that the expression of FER1L4 in liver cancer tissues was significantly increased compared with that of the adjacent tissues (Figure 1A)
Summary
The incidence of liver cancer has increased by 4.6% from 2005 to 2015, the incidence of cancers in general is in the downward trend.[1] This alarming news put liver cancer as the fourth most deadly cancer in the world.[2,3] In China, it was estimated that there were 370,000 new cases of liver cancer in 2015, which was approximately 17.64 per 100,000 people.[4] There are wide regional differences in the incidence of liver cancer around the world, with the majority of liver cancer cases occurring in low to medium socioeconomic societies.[5] Similar to this, rural areas appear to have a high incidence of liver cancer in China.[4] Heavy alcohol consumption, hepatitis B and C infections, and exposure to dietary toxins may be a few important risk factors for the development of liver cancer in China,[6,7] with hepatitis B and C infections accounting for 80% of all hepatocellular carcinoma cases.[8,9] Despite improvements in the early detection of liver cancer,[10] the increasing incidence may be attributed to the incomplete understanding of its pathology and drug resistance.[11,12] we investigated the pathway that was involved in the progression of liver cancer in a drug-resistant strain
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