Unique microRNA molecular profiles
in lung cancer diagnosis and prognosis
MicroRNA (miRNA) expression profiles for lung cancers were examined to investigate miRNA's involvement in lung carcinogenesis. miRNA microarray analysis identified statistical unique profiles, which could discriminate lung cancers from noncancerous lung tissues as well as molecular signatures that differ in tumor histology. miRNA expression profiles correlated with survival of lung adenocarcinomas, including those classified as disease stage I. High hsa-mir-155 and low hsa-let-7a-2 expression correlated with poor survival by univariate analysis as well as multivariate analysis for hsa-mir-155. The miRNA expression signature on outcome was confirmed by real-time RT-PCR analysis of precursor miRNAs and crossvalidated with an independent set of adenocarcinomas. These results indicate that miRNA expression profiles are diagnostic and prognostic markers of lung cancer.
miRNAs are a class of small noncoding RNA genes found to be abnormally expressed in several types of cancer, suggesting that miRNAs play a substantial role in the pathogenesis of human cancers. Lung cancer is the leading cause of cancer deaths in the world, reflecting the need for a better understanding of the mechanisms that underlie lung carcinogenesis. Although focusing on known genes and proteins has already yielded new information, unknown markers may also lend insight into the biology of lung cancer. Researchers showed that lung cancer has extensive alterations of miRNA expression that may deregulate cancer-related genes. Furthermore, the miRNA molecular signature of lung adenocarcinomas, including those without evidence of metastasis, also correlates with patient survival.
Little is known about the expression levels or function of miRNAs in normal and neoplastic cells, although it is becoming clear that miRNAs play major roles in the regulation of gene expression during development (Ambros, 2003, McManus, 2003). They reported here that the genome-wide expression profiling of miRNAs was significantly different among primary lung cancers and corresponding noncancerous lung tissues. The microarray data were validated by both solution hybridization detection method for mature miRNAs and real-time RT-PCR analysis for precursor miRNAs. Several of the miRNAs identified as differentially expressed are located inside FRAs and/or in the chromosomal regions where genomic imbalance in lung cancers has been observed previously with high frequency. As FRAs are preferential sites of translocation, deletion, amplification, or integration of exogenous genome, it is possible that miRNAs located near FRAs could be possible targets of such genomic alteration. Even though there is the possibility that the differences in miRNA expression may simply be a surrogate for cytogenetic changes in lung cancers, the fact that >50% of miRNAs are located at cancer-related chromosomal regions supported the idea that miRNAs may play a role as oncogenes or tumor suppressor genes. Moreover, these miRNAs are suggested to be involved in cancer.
Precise molecular mechanisms for the altered expression of miRNAs in lung cancers are unclear. Abnormal expression of miRNAs in lung cancers could be caused by somatic genetic alterations. Alternatively, the reduced expression of miRNAs in lung cancer could be caused by epigenetic change such as DNA methylation and alterations of chromatin structure, which are important processes of transcriptional silencing in many genes, including tumor suppressor genes, and as an alternative to genetic defects in human carcinogenesis (Jones and Baylin, 2002, Eberharter and Becker, 2002).
In conclusion, human lung cancer has extensive alterations of miRNA expression that may deregulate cancer-related genes. The miRNA molecular profiles of lung adenocarcinoma also correlate with patient survival.
Altered miRNA expression in primary lung cancers and identification of miRNAs associated with clinicopathological features of lung cancer
Researchers analyzed the miRNA expression in 104 pairs of primary lung cancers and corresponding noncancerous lung tissues. They compared miRNA expression of several group pairs. Expression profiles were generated by comparing lung cancers, except when comparing lung cancer tissues with corresponding noncancerous lung tissues. They identified miRNAs, which were expressed differently in phenotypical and histological classifications. When they compared miRNA expression among lung cancer tissues versus corresponding noncancerous lung tissues, 43 miRNAs had statistical differences in expression between groups.
specific molecular signatures for subsets of lung cancer that differ in clinical behavior. For this analysis,they examined the relationship of five types of clinical and pathological information. Among them, they identified six miRNAs (hsa-mir-205, hsa-mir-99b, hsa-mir-203, hsa-mir-202, hsa-mir-102, and hsa-mir-204-prec) that were expressed differently in the two most common histological types of NSCLC, adenocarcinoma and squamous cell carcinoma. The expression levels of hsa-mir-99b and hsa-mir-102 were higher in adenocarcinoma. No miRNAs were identified as differently expressed when classified by age, gender, or race in their data set.