The Mechanism Of Bif-1Regulating The Development Of HCC

BackgroundHepatocellular carcinoma (HCC) is the fifth most common cancer and the thirdleading cause of cancer mortality around the world. HCC causes thousands of deathsworldwide every year, half of which occur in China. Since the early symptoms are notobvious, the majority of clinically diagnosed liver cancer is difficult to treat with surgicalresection, and accompanied by portal vein tumor thrombus or lung metastases. More thanabout90%of deaths of HCC were attributed to tumor metastasis and recurrence. Therefore,the study of the mechanism and the treatment for inhibition of tumor metastasis are playingan important role in cancer prevention.PurposeTo research mechanisms of cell proliferation and movement in the process of tumorgrowth and metastasis,in order to provide a new target and the theoretical basis for thestudies of HCC.Methods1. Association of clinical prognosis and the expression of Bif-1in HCCThe exprsssion of Bif-1in paired HCC tissues was confirmed by detecting thecontents of Bif-1from mRNA and protein level, and the tissue microarray combine theexpression of Bif-1in different samples with clinical data to analyse the realiationshipbetween Bif-1and clinical characteristics, such as tumor size, stage, metastasis, portal veintumor thrombosis, recurrence. Furthermore, the investigation into the association betweenBif-1and prognosis (disease-free survival and overall survival) should be carried out basedon the research of differences significantly. 2. The function of Bif-1and its mechanism of infecting the liver cancer cellThe detection was carried out to conform the expression of Bif-1in differenthepatocellular carcinoma cell lines (CSQT-2, MHCCLM3, HepG2) through qRT-PCR. Thetarget gene Bif-1was knocked down to observe the change of cell line,s biologicalfunctions, which is contributed to the research of mechanism regulating the cellularsignaling networks.ResultsPart1The expression of Bif-1in cancer tissues is higher than that in normal tissues, whilethe results of Western Blot also show the same expression trend. The combination betweenthe result of tissue microarray and clinical data shows that the expression of Bif-1isassociated with four clinical indicators, including tumor size, portal vein tumor thrombus,tumor microvascular invasion and recurrence. The result of survival analysis also indicatesthat Bif-1can affect the prognosis of HCC patients, including disease-free survival (P=0.035) and overall survival (P=0.047).Part2The expression of Bif-1can promote both the proliferation of liver cancer cells andthe tumorigenicity in nude mice, which also influence the biological behaviour of cancercell such as metastasis, invasiveness and cell polarity. At the same time, with the reductionof Bif-1, the total and active forms of Cdc42protein also decreased, which shows apositive regulation. The expression of Bif-1in nuclear protein and chromatinimmunoprecipitation experiments privide the evidence to indicate that Bif-1play animportant role in the transcription of Cdc42.ConclusionsThe high expression of Bif-1in HCC, taking part in proliferation and metastasis ofcancer cell, promotes the development of HCC. Furthermore, Bif-1can be used as anindicator to determine the prognosis after surgical intervention because of its influences onpatients with liver cancer. Potential applications and noveltyThis study provides a new mechanism of the regulatory actions of Bif-1.Highexpression of Bif-1was associated with higher rates of tumor proliferation, metastasis,recurrence and poor prognosis after hepatectomy. These results strongly suggest that Bif-1may serve as a new diagnostic marker for tumour metastasis or recurrence and providingnew ideas and direction for further studies about anti-tumour therapy.