Overexpression of Dicer in Precursor Lesions of Lung Adenocarcinoma

Abstract

Differential microRNA (miR) expression is described in nonsmall cell lung carcinoma. miR biogenesis requires a set of proteins collectively referred to as the miR machinery. In the proposed multistep carcinogenesis model, peripheral adenocarcinoma of the lung develops from noninvasive precursor lesions known as atypical adenomatous hyperplasia (AAH) and bronchioloalveolar carcinoma (BAC). The gene array analysis of BAC and adenocarcinoma showed a transient upregulation of Dicer (a key effector protein for small interfering RNA and miR function) and PACT along with down-regulation of most genes encoding miR machinery proteins. Immunohistochemically, Dicer was up-regulated in AAH and BAC and down-regulated in areas of invasion and in advanced adenocarcinoma. A fraction of adenocarcinomas lose Dicer as a result of deletions at the Dicer locus. Expanded immunohistochemical and Western blot analysis showed higher Dicer level in squamous cell carcinoma (SCC) of the lung when compared with adenocarcinoma. Other proteins of the RNAinduced silencing complex (RISC; SND1, PACT, and FXR1) were also present at higher levels in a SCC cell line when compared with an adenocarcinoma cell line. In conclusion, the stoichiometry of miR machinery and RISC depends on histologic subtype of lung carcinoma, varies along the AAH-BACadenocarcinoma sequence, and might explain the observed abnormal miR profile in lung cancer. The status of the endogenous miR machinery in various histologic subtypes and stages of lung cancer may help to predict the toxicity of and susceptibility to future RNA interference-based therapy.

MicroRNAs and cancer: Profile, profile, profile

“…A fraction of adenocarcinomas lose Dicer as a result of deletions at the Dicer locus. 76 The same group, 77 found by using a gene array analysis of 16 normal prostate tissue samples, 64 organ-confined, and 4 metastatic prostate adenocarcinomas, an up-regulation of major components of the miRNA machinery, including Dicer, in metastatic prostate adenocarcinoma. Immunohistochemical studies on a tissue microarray consisting of 232 prostate specimens confirmed up-regulation of Dicer in prostatic intraepithelial neoplasia and in 81% of prostate adenocarcinoma.…”

“…73 Further strengthening these findings, a large study of non-small-cell-lung cancer (NSCLC) patients, found that Dicer, but not Drosha, expression levels were reduced in a fraction of lung cancers and correlated with shortened postoperative survival and poorly differentiated status, which is a mark of bad prognosis. 74,75 Furthermore, Chiosea et al 76 by using various techniques including gene array analysis showed a transient up-regulation of Dicer along with down-regulation of most genes encoding miRNA machinery proteins in bronchioloalveolar carcinomas and in adenocarcinomas. Immunohistochemically, Dicer was upregulated in atypical adenomatous hyperplasia and bronchioloalveolar carcinoma and downregulated in areas of invasion and in advanced adenocarcinoma.…”

Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer

“…In addition, recent studies suggest that epigenetic alterations might play a critical role in regulating miRNA expression in human cancers (25). Finally, several key proteins in the miRNA biogenesis pathway may be dysfunctional (26) or deregulated in cancer (27)(28)(29)(30), which may enhance tumorigenesis (31). Therefore, DNA copy number abnormalities, epigenetic alterations, and/or defects in the miRNA biogenetic machinery might each contribute to miRNA deregulation in human cancer.…”

MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium

“…A number of miRNAs have been shown to play important roles in developmental timing, cell death, carcinogenesis, and stress responses in vitro (13)(14)(15)(16), such as hypoxia (17). Whereas miRNA expression has been examined in lung tumors (18)(19)(20)(21)(22)(23)(24), neither the expression of miRNA in bronchial epithelium nor the effect of smoking on bronchial airway miRNA expression has been characterized, and it is unclear what role miRNAs play in regulating the physiological response to environmental exposures such as tobacco smoke.…”