Cofactor of BRCA1: A new genetic marker for common malignant liver cancer

A new study has identified a vital gene in the pathogenesis and progression of liver cancer hepatocellular carcinoma (HCC), according to a team of biotechnology researchers at The American University in Cairo, Egypt, in a scientific paper published recently by AMOR. The study on human gene ‘Cofactor of BRCA1’ (dubbed COBRA1) and its potential role as a reliable cancer predictor for HCC is especially important due to the disease’s grim outlook. HCC is “ranked as the second most common cause of cancer-related deaths in the world in 2012,” the authors said. “Thus, it is considered as a highly aggressive cancer with poor prognosis,” they added. According to data from the Surveillance Epidemiology and End Results (SEER) program, hepatocellular carcinoma accounts for 90% of all liver cancers worldwide. In the United States, HCC represents the fastest growing cause of cancer mortality overall and the second fastest growing cause of cancer deaths among women. Globally, the incidence of HCC in developing nations is over twice that of in developed countries – East Asia having highest incidence of HCC with the rate of 35 male cases per 100,000, followed by the continent of Africa. HCC mortality statistics in the developing countries is also more than double compared to the First World nations, with the annual loss of 33.5 and 23.73 lives per 100,000 in Asia and Africa, respectively. In addition, “HCC is usually diagnosed in the late stages of the tumor where, at some point, treatment is of limited efficacy. Thus, prognoses and follow-ups are necessary to regularly assess the patients and to predict any risks before the deterioration of patients’ condition,” said researcher Aya Youssef and her fellow team members.The behaviour of COBRA1 in the development and progression of several cancers has previously been studied and established, the researchers wrote. “For example, cell lines and tissues isolated from late-stage metastatic breast cancer tumors showed low expression levels of the COBRA1 protein, which has displayed tumor suppressor activity,” they noted, adding, “another study reported that COBRA1 was overexpressed in upper gastrointestinal carcinoma (UGC) tissue samples.” Yet, COBRA1’s involvement in HCC tumor formation and growth has been subjected to minimal studies. “To date, the molecular mechanisms underlying HCC pathogenesis have not been fully identified, thus resulting in a lack of reliable prognostic markers for HCC,” said the researchers. In their study, the Egyptian team hypothesized that the transcription factor COBRA1 is involved in HCC pathogenesis. The overexpression of COBRA1 is typically accompanied by the decreased expression of a tumor suppressor called trefoil factor-1 (TFF1). “COBRA1 controls TFF1 expression by regulating the activator protein-1 (AP-1) complex trans-activation, leading to attenuated TFF1 expression,” the researchers explained. AP-1 regulates the invasive response in some tumors, hence paying a part in the mechanism of the spread of cancer. In addition, according to the researchers, “AP-1…consists of both Fos and Jun genes’ family members, which include c-Fos and c-Jun.” The c-Fos protein has been previously found to briefly up-regulated in HCC’s early stages and then quickly declines in the later stages of tumor progression – a process “for priming hepatocytes [predominant main cells of the liver] for migration and tissue invasion,” Youssef and her team explained. In contrast, the c-Jun protein is involved in tumor cell survival and apoptosis by subduing cell death regulator p53, the widely recognized and important protein known as the “guardian of the genome” that plays a crucial role in thwarting genome mutation, and consequently preventing cancer.Therefore, the researchers sought to investigate the expression of COBRA1, TFF1 and the AP-1 complex in tumour samples ranging from low-grade to high-grade HCC cell lines from patients at various stages of the disease. “To the best of our knowledge, this is the first study to evaluate the mRNA expression levels of COBRA1 and its protein in cell lines representing advanced stages of HCC,” researchers said. Their results revealed that the expressions of COBRA1, c-Fos, and c-Jun showed maximum levels in low-grade HCC cell line, i.e. tissues at early stages of cancer, while minimum levels of the three proteins were observed in high-grade HCC cell line representing late-stage tumor. “Therefore, we suggest that COBRA1 displays tumor suppressor activity and may have a potential role in HCC progression,” they said. “We propose that these molecules could be used in the characterization of HCC cell lines at the molecular level.” In addition, the researchers also examined COBRA1 levels to study HCC’s growth and spread. “In order to investigate the possible association of COBRA1 levels with HCC cell migration, we carried out the scratch wound healing assay to mimic the in vivo migratory behavior of HCC cells,” they described. The result confirmed their theory. “The migratory ability of SNU-449 [late-stage cancer cell lines] that had relatively lower COBRA1 levels was significantly higher than that of the HepG2 [early-stage] cell lines with high COBRA1 expression,” observed the researchers, “which suggests a possible correlation between the low protein level of COBRA1 and tumor cell migration and thus, poor prognosis.” While the researchers acknowledged that further studies are needed to examine the link between COBRA1, the AP-1 complex and TFF1 in HCC in order to draw a clearer conclusion, their study nevertheless suggest potential involvement of COBRA1 in the pathogenesis and development of HCC, as well as its function as tumor suppressor. The study is co-authored by Aya Youssef, Heba Shawer, Alaa Afify and Asma Amleh, and is available online on AMOR.