Roles Of CUL4B In None Small Cell Lung Cancer

Lung cancer is the primary cause of cancer related deaths in the world, which is originated from bronchial epithelial cell. Non-small cell lung cancer (NSCLC) is the most commonly diagnosed form of lung cancer, which is accounting for over80%of the cases. NSCLC is frequently diagnosed at advanced stages, resulting in an overall5-year survival rate varies from1%to25%. Conversely, the5-year survival rate of stage I NSCLC patients who received effective treatments can be as high as80%. The molecular basis of lung cancer is complex and heterogeneous. In recent years, much effort has been focused on identifying mechanism of the disease. Although several genes were shown to be associated with NSCLC tumorigenesis, noval mechanism is needed to be identified for development of novel therapeutic strategies of NSCLC.The ubiquitin-proteasome system is essential for multiple physiological processes via selective degradation of target proteins and has been shown to play a critical role in cell cycle regulation, signal transduction and DNA repair. Cullin4B is a scaffold protein that organizes CULLIN-RING ubiquitin liagse E3complexes (CRL). Recent studies showed that cullin family members were associated with tumorigenesis. Overexpression of cullin1may be an important marker for human gastric cancer lymph node metastasis and prognosis. The data generated by several groups indicated that cullin3(CUL3) was involved in the etiopathology of multiple diseases, such as lung cancer, prostate cancer. In the last years, multiple lines of evidence have suggested that the COP9signalosome (CSN)-cullin-RING ubiquitin (Ub)-ligase (CRL) pathway played a significant role in urological cancers. In addation, overexpression of CUL4A was observed in a subset of breast, lung, hepatocellular and ovarian carcinomas. As improvements in our understanding of CRL4-RING ligase’s function, many tumors associated factors that are subject to CUL4-mediated ubiquitination including TSC2, Rho GTPase activate protein, c-Jun and so on. Recent studies in our lab showed that CUL4B regulates genes expression through microRNAs pathway and regulates genes transcription by PRC2recruiting. These data suggested us that CUL4B may paly a vital role in tumorigenesis. In addition, the latest results from our and other labs showed that CUL4B could act as oncogene in esophageal cancer and colon cancer while act as tumor suppressor gene in cecum cancer. Up to now, no reports on the association between CUL4B and NSCLC tumor progession were published.Here, we explored the relationship between CUL4B expression and NSCLC by using immunohistochemical staining. Compared with those in normal controls, CUL4B was significantly over-expressed in specimens of cancer samples. Growth curve assays showed that cell growth was significantly suppressed by CUL4B knock down. Moreover, colony formation assays also showed that CUL4B knockdown result in a significant decrease in colony numbers. Using the mouse models, we found the similar result that CUL4B downexpression was associated with a marked decrease in tumor growth. At last we found that H1299cells stably transfected with CUL4B-specific shRNA were more sensitive to Adriamycin and Etoposide.Collectively, these results suggest that CUL4B may participate in the regulation of the tumorigenesis of none small cell lung cancer. Our data add new evidence to the understanding of the potential oncogenic role of CUL4B, thus supporting the pursuit of CUL4B as a target for cancer therapy.