RESEARCH HIGHLIGHTS doi: 10.18282/amor.v2.i4.157 Cofactor of BRCA1: A new genetic marker for common malignant liver cancer

new study has identified a vital in the pathogenesis and progression of liver cancer hepatocellular carcinoma (HCC), according to a A team of researchers at The American University in Cairo, Egypt, in a paper published in this issue of 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 owing 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. The behavior of COBRA1 in the development and pro- gression of several cancers has previously been studied and established. Youssef observed, “For example, cell lines and tissues isolated from late-stage metastatic breast cancer tumors showed low expression levels of the COBRA1 protein, which is known to display tumor suppressor activ- ity.” In contrast, “another study reported that COBRA1 was overexpressed in upper gastrointestinal carcinoma (UGC) tissue samples,” they added.

Yet, COBRA1’s involvement in HCC tumor formation and growth has been subjected to minimal studies. “To date, the molecular mechanisms underlying HCC patho- genesis have not been fully identified, thus resulting in a lack of reliable prognostic markers for HCC,” said the re- According to data from the Surveillance Epidemiology searchers. and End Results (SEER) program, hepatocellular carcino- ma accounts for 90% of all liver cancers worldwide. In the In their study, the Egyptian team hypothesized that the United States, HCC represents the fastest growing cause of transcription factor COBRA1 is involved in HCC patho- cancer mortality overall and the second fastest growing genesis. The overexpression of COBRA1 is typically ac- cause of cancer deaths among women. Globally, the inci- companied by the decreased expression of a well-known dence of HCC in developing nations is over twice that of in tumor suppressor called trefoil factor-1 (TFF1). “COBRA1 developed countries – East Asia having highest incidence controls TFF1 expression by regulating the activator pro- of HCC with the rate of 35 male cases per 100,000, fol- tein-1 (AP-1) complex trans-activation, leading to attenu- lowed by continental Africa. ated TFF1 expression,” the researchers explained.

HCC mortality numbers in developing countries are al- AP-1 regulates the invasive response in some tumors, so more than double compared to the first world nations, hence paying a part in the mechanism of the spread of with the annual loss of 33.5 and 23.7 lives per 100,000 in cancer. According to the researchers, “AP-1…consists Asia and Africa, respectively. In addition, “HCC is usually of both Fos and Jun ’ family members, which in- diagnosed in the late stages of the tumor, where at some clude c-Fos and c-Jun. The c-Fos protein has been found point, treatment is of limited efficacy. Thus, prognoses and to be briefly up-regulated in HCC’s early stages and then, follow-ups are necessary to regularly assess the patients quickly declines in the later stages of tumor progression – and to predict any risks before the deterioration of patients’ a process for priming hepatocytes (predominant main cells condition,” said researcher Aya Youssef and her fellow of the liver) for migration and tissue invasion,” explained team members. Youssef and her team.

182 In contrast, the c-Jun protein is involved in tumor cell the AP-1 complex, and TFF1 in HCC in order to draw a survival and apoptosis by subduing cell death regulator clearer conclusion, their study nevertheless suggest poten- p53, the widely recognized and important protein known tial involvement of COBRA1 in the pathogenesis and de- as the “guardian of the genome” that plays a crucial role in velopment of HCC, as well as its function as a tumor thwarting genome mutation, and consequently preventing suppressor. cancer.Therefore, the researchers sought to investigate the expression of COBRA1, TFF1, and the AP-1 complex in The study is co-authored by Aya Youssef, Heba Shawer, tumour samples, ranging from low-grade to high-grade Alaa Afify, and Asma Amleh. Their original research HCC cell lines from patients at various stages of the dis- paper is published in this issue of AMOR (page 224–235) ease. and can be downloaded online at: http://www.adv mo- doncolres.com/ ■

“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 can- cer, while minimum levels of the three proteins were ob- served 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 ex- amined COBRA1 levels to study HCC’s growth and spread. “In order to investigate the possible associa- tion between COBRA1 levels and HCC cell migration, we carried out the scratch wound healing assay to mimic the in vivo migratory behavior of HCC cells,” they explained.

The result confirmed their theory. “The migratory abil- ity of SNU-449 (late-stage cancer cell lines) that had rela- tively 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 intricate link between COBRA1, 183