Expression, Significance Of FHIT And P16 In HCC Tissues And Their Correlation

BackgroundPrimary hepatocellular carcinoma(HCC) is the sixth in the new cancer diagnosis and third most common cause of death in worldwide cancer. The treatment of liver cancer is far from effective and the five-year survival rate is around 10% which is depressing. Liver transplantation is considered to be the only curative therapy for HCC in the present time, but unfortunately, patients with advanced HCC and unresectable HCC accounts for the majority of HCC patients(over 80%), and these patients are not suitable for liver transplantation or surgical resection. There are some chemotherapy regimens for HCC, especially for patients with advanced cancer, which is using the conventional cytotoxic drugs, such as doxorubicin, cisplatin and fluorouracil chemotherapy. However, due to the severe toxic reaction and high rate of relapse, the survival time of advanced HCC patients treated with chemotherapy is about six months. Therefore, it is particularly necessary and urgent for us to find a new method for testing and treatment in HCC.The biological activity in the development of tumor has been the hot spot for researchers. The tumor suppressor genes and oncogenes have been confirmed to play a role in the onset of tumor along with many molecular group, molecular pathways and transcription proteins. Fragile histidine triad(FHIT) is proposed as a new concept of tumor suppressor genes by Ohta[1] and other researchers in 1996. FHIT exists in most normal tissues, cross site FRA3 B, located in chromosome 3q14.2 area, which is highly homologous with histidine triplet protein, therefore it is defined as the FHIT. It plays a role in inhibiting tumor proliferation through inducting apoptosis and blocking the cell cycle. It presents as a loss of heterozygosis, transcription errors in many malignant tumors such as bladder carcinoma, gastric cancer, lung cancer, esophageal cancer, colon cancer, etc, which results in a decrease or even lost in the expression of FHIT protein, which eventually leads to the decrease or even lost in tumor inhibition. P16 gene is a newly discovered multiple tumor suppressor(MTS1) gene. The protein molecules expressed by P16 gene is about 16 KD and named as P16 protein. The active function of cyclin- dependent kinase(CDK) is prerequisite for cells to get into growth cycle. The cyclin will combine with the CDK, and the combination of cyclin complexes can be activated. The phosphorylation of P110 Rb protein, expression products of Rb gene, relies on cyclin complex, and the activated Rb protein ensures the cell enter G 1- S stage of cell cycle. As the initiating factor in the process, P16 protein can inhibit the bioactivity of CDK[2-4]. Once the P16 protein gene fail to express P16 protein due to absence, methylation or gene mutation, the ability of competitive combination of CDK4 will decrease in cells, which leads to fail in effectively blocking the mitotic activity. With the combination of CDK4 and cyclin increases, the mitotic activity within the cell becomes active. Cell growth eventually evolves into the out of control, and leads to cancer. There are reports showing that histologic classification of malignant tumor dose not have obvious causality with the expression of P16 gene, and associated with the metastasis of lymph node and TNM staging of tumor, therefore P16 protein may be an important indicator for the prognosis of patients with liver cancer [5]. So, as targets in the process of liver cancer, FHIT and P16 are important in the diagnosis, treatment and prognosis with HCC. This experiment tested 74 cases of liver cancer specimens using immunohistochemical technique, so we can understand the expression of FHIT and P16 protein in liver cancer organizations, combined with clinical examination data, and we can explore the role of FHIT and P16 protein and their correlation, the value of clinical diagnosis and predicting the prognosis of liver cancer.ObjectlveComining clinical examination data with experimental results, we study the significance of FHIT and P16 in the development of HCC and their correlation, in order to provide new theoretical basis for early diagnosis, clinical drug treatment and the prognosis of HCC, also new thought and method for early individualized treatment and targeted therapy. MethodsWe collected 74 cases of HCC patients who received surgical treatment in the first affiliated hospital of Zhengzhou university during May 2009 to July 2011, in which 23 cases were female, age ranged from 29 to 77, mean age were 50.43±3.24 years old; while 51 male, age 26 to 73, mean age 47.18±2.36. The including criteria are as follows: 1. Had not received any kind of radiation therapy or chemotherapy before operation; 2. The pathology diagnosis results of each HCC patient was confirmed by two sub-senior medical personnel of pathology department; 3. Enough clinical data. We used streptavidin peroxdase(SP) conjugated method to detect the expression of FHIT and P16 protein in distal cancerous tissues, paracancerous tissues, and hepatoma tissues, and also adopted Biosens Digital Imaging System v1.6 to analysis the results, which turned the immunohistochemical staining to average density. We used medical statistics to analysis the expression results of FHIT and P16 protein along with their correlation. Results1. The expression of FHIT: the expression of FHIT in three groups were in order, strong positive in distal cancerous tissues, missing expression in both the paracancerous tissues, and hepatoma tissues. The order was distal cancerous tissues > paracancerous tissues > hepatoma tissues, statistically significant difference existed in each two groups(P< 0.01).2. The expression of P16: the expression of P16 in three groups were in order, strong positive in distal cancerous tissues, missing expression in both the paracancerous tissues, and hepatoma tissues. The order was distal cancerous tissues > Objectiveparacancerous tissues > hepatoma tissues, statistically significant difference existed in each two groups(Pp < 0.01).3. The correlation of the expression of P16 and FHIT in three groups:(1) in the hepatoma tissues, rs = 0.572, P = 0.004;(2) in the paracancerous tissues, rs = 0.495, P= 0.007;(3) in the distal cancerous tissues, rs = 0.309, P= 0.017. In the relativity analysis of three groups, P < 0.05, and rs positive numbers. Therefore the expression of P16 and FHIT in three groups were in positive correlation.4. The expression of FHIT has nothing to do with age, sex, size of liver cancer, TNM staging of hepatocellular carcinoma, the degree of differentiation, lymph node metastasis or formed portal venous tumor emboli. The expression of P16 has nothing to do with the gender, age, TNM stage, lymph node metastasis, or formed portal venous tumor emboli, but it is associated with the size and differentiation degree of HCC. Conclusion1.As new tumor suppressor genes, P16 and FHIT gene can inhibit the proliferation and invasive growth of HCC, and there was a positive correlation between them.2. Detections of P16 and FHIT protein can become new indexes for HCC, and they may provide new methods and bsis for the diagnosis and treatment of HCC in the future.