Chromosome region maintenance 1 in lung cancer



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Lung cancer continues to be the leading cause of cancer-related death in the United States. Non-small cell lung cancer (NSCLC) is the predominant form of lung cancer. About 80-90% of lung cancers are directly or indirectly traceable to tobacco use. More than 60 known carcinogens have been identified in cigarette smoke. NNK is an example nitrosamine with highly carcinogenic activities and consistent presence in relatively considerable amounts in cigarette smoke. NNK has been shown to have lung-selective toxicity and selectively induce lung adenocarcinoma in a variety of laboratory animals.

The development of lung cancer has been extensively investigated and key molecular alterations including mutations in several proto-oncogenes and tumor suppressor genes, like p53 gene, and such alterations have been associated with the initiation and progression of lung cancer. In about 50% of tumors and 60% of lung cancer, p53 is mutated and lost its function in promoting genomic stability, cell cycle arrest, apoptosis, and DNA repair. Besides mutations, p53 can be inactivated by nucleo-cytoplasmic transport, which is critical in mediating biological functions like transcription and cell cycle regulation.

CRM1, a well-characterized nuclear export receptor, has been found to play an essential role in nuclear export signal (NES)-dependent nuclear export of various cancer-associated ‘cargo’ proteins, including p53. Elevated CRM1 protein expression has been identified in various human tumors. The role of CRM1 in association with p53 during the development of lung cancer is still not clear and requires further investigation to better understand the etiology of lung cancer. Here, we observed that CRM1 is over expressed in NNK induced in vitro and in vivo models and tobacco smoking patients. In addition, we demonstrated that gene expression changes after modulation of CRM1 expression level is strongly associated with normal cell proliferation and lung carcinogenesis. Our study suggested that CRM1 plays an important role in lung cancer development.

Although surgical techniques and combined therapies have improved in the past 40 years, the relative survival rate for lung cancer remains as low as 15% in the United States. Cancer chemotherapy has been used successfully in a variety of circumstances involving malignancies. However, its effectiveness is still limited due to drug resistance and side effects. Therapies focusing on specific molecule(s)/pathway(s) have the potential to overcome these limitations. Our study of combination use of Leptomycin B (LMB), CRM1 specific inhibitor, with other drugs by inducing severe DNA damage and p53 activation, like Doxorubicin (DOX), significantly increased the efficacy of LMB in the inhibition of lung cancer cell proliferation, indicating the potential use of LMB by targeting CRM1 in lung cancer treatment.



Lung cancer, Chromosome region maintenance 1 (CRM1)