MICRORNA AND LUNG CANCER

MicroRNA and Lung Cancer

MicroRNA and Lung Cancer

Introduction

Lung cancer is the leading cause of death from cancer in the world. Its pathogenesis is closely associated with tobacco smoking. Lung cancer is divided into two main histological groups including non- small cell lung cancer (NSCLC, 85%) and small cell lung cancer (SCLC, 15%). NSCLC can be further subclassified into adenocarcinomas, squamous cell, large cell and bronchoalveolar carcinomas (BAC). It is well known that genetic alterations could occur at the chromosomal level (e.g. large gains and deletions), at the nucleotide level (e.g. nucleotide mutation), or at epigenetic level (e.g. DNA methylation). Such a change could result in the activation of oncogenes (e.g. Ras, Myc) and other growth promoting genes (e.g. ERBB1, IGF-IR), and the inactivation of tumor suppressor genes (e.g. p53, p16INK4A, Rb, FHIT). Ten or more genetic or epigenetic abnormalities are generally needed before lung tumor becomes clinically evident. The molecular network of lung carcinogenesis has been partly known at the levels of genes and proteins in the last decade. However, since 1970 the high mortality rate (80-85% within 5 years) has not been markedly improved. The lack of effective tools to diagnose at an early stage and the deficiency of therapeutic treatments to the late stage of the disease are the two major reasons.

Currently available diagnostics for lung cancer, including chest imaging (X-ray or low-dose CT) and sputum cytology, often lack the sensitivity and specificity that are necessary to identify early stage disease. Only 16% of lung cancer is discovered prior to spread of the disease so far. Previous reports have shown that two blinded expert observers, when asked to give an independent histological classification of NSCLC, both agreed that the specificity of the disease was only 74.7 percent of the time, whereas sensitivity for squamous cell carcinoma is only 70.9 percent. And even 40 percent of samples diagnosed as SCLC at regional labs were later reclassified as other lung cancer at central labs. Surgery only partly cured lung cancer patients at early stages . Experimental treatment approaches, including small molecule targeted therapeutics, gene modified tumor vaccines, and viral-based gene therapy induced tumor regression, are still only used in a small proportion of patients. Currently, lung-cancer staging rests on histopathological and clinical criteria have only limited power to predict relapse and survival. A major effort to improve the control of lung cancer entails the use of molecular profiling to characterize tumors and to provide accurate predictions of the outcome after standard or novel treatments.

Mechanism Relationships Between miRNAs AND siRNA

The phenomenon of RNAi was discovered in 1998. And now, both biochemical and genetic approaches have led to the current models of RNAi. RNAi is first initiated by dsRNAs, which are cleaved by the ribonuclease III-type enzyme DCR into siRNAs-short 21-23 nt duplexes with a symmetric 2 nt overhang at the 3'-end and a 5'-phosphate and 3'-hydroxy group. This siRNA molecule is incorporated into a nuclease-containing multi-protein complex called RNA-induced silencing complex ...