Review Article
Involvement of microRNAs in lung cancer biology and therapy

https://doi.org/10.1016/j.trsl.2011.01.001Get rights and content

MicroRNAs (miRNAs) are a class of small RNAs that regulate gene expression. Expression profiles of specific miRNAs have improved cancer diagnosis and classification as well as provided prognostic information in many human cancers, including lung cancer. Tumor-suppressive and oncogenic miRNAs were uncovered in lung carcinogenesis. The biological functions of these miRNAs in lung cancer were validated recently in well-characterized cellular, murine transgenic as well as transplantable lung cancer models, and in human paired normal-malignant lung tissue banks and tissue arrays. Tumor-suppressive and oncogenic miRNAs that were identified in lung cancer will be reviewed here. Emphasis is placed on highlighting those functionally validated miRNAs that are not only biomarkers of lung carcinogenesis but also candidate pharmacologic targets. How these miRNA findings advance an understanding of lung cancer biology and how they could improve lung cancer therapy are discussed in this article.

Section snippets

miRNAs and Lung Cancer

Lung cancer is the leading cause of cancer mortality for men and women in the United States.18 Two major types of lung cancer exist—small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).18 NSCLC is much more prevalent than SCLC, and is the focus of this review. Despite advances made in surgery, radiation therapy, and chemotherapy, the 5-year survival for lung cancer remains at only about 16%.18 This finding underscores the need for an improved understanding of lung cancer biology

Oncomirs in Lung Cancer

Oncomirs have a higher basal expression in malignant as compared with adjacent normal lung tissues. Some are potential prognostic biomarkers as in miR-92a-2∗ in SCLC31 or in the examples of miR-155, miR-130a, let-7f, and miR-30e-3p in NSCLC.29, 32, 33 To date, few candidate oncomirs have had mechanistic validation or identification of the target genes that would exert their oncogenic effects.

One of these oncomirs is miR-21, which plays a key functional role in several cancers34, 35, 36, 37

Tumor-Suppressive miRNAs in Lung Cancer

In contrast to oncomirs, the expression profiles of candidate tumor-suppressive miRNAs are repressed in cancers versus adjacent normal lung tissues. For example, reduced expression of the miRNA let-7 was reported to occur in bronchioloalveolar carcinoma43 as well as in lung adenocarcinoma.29, 44 The miR-146b expression patterns in squamous cell lung cancer predicted a poor clinical outcome, and miR-34a expression was identified as a biomarker for clinical relapse in surgically resected NSCLC.45

miRNAs as Lung Cancer Targets

Specific miRNAs play critical roles in regulating tumorigenicity. It is therefore appealing to consider pharmacologic strategies to target specific miRNAs in lung carcinogenesis. These approaches can use miRNA derivatives as anticancer agents. The inhibition of specific oncomirs is achieved by using optimized antisense derivatives. For example, locked nucleic acid (LNA) miRNA derivatives represent a class of chemically modified nucleic acids that inhibit specific miRNAs in mouse models69 and in

Future Directions

Expression profiles of miRNAs are useful to improve diagnosis and classification as well as to provide clinical prognostic information in lung cancer. It is necessary to assess the miRNA signatures for each histopathologic subtype of lung cancer and to compare any changes relative to the normal lung in addition to the clinical features present at diagnosis such as stage, smoking history, age, and gender. Likewise, miRNA profiles might prove informative in predicting the response to

Conclusions

Lung cancer is the most common cause of cancer mortality for both women and men in the United States.18 Given this, it is essential to develop new ways of combating this cancer. One way to begin to address this is by taking advantage of what already has been learned about miRNAs. The miRNAs play a key role in regulating gene expression in normal and neoplastic cells or tissues. Expression profiles uncovered miRNAs that either are repressed or are increased in lung cancers relative to the

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    Supported by National Institutes of Health (NIH) and National Cancer Institute (NCI) Grants R01-CA087546, R01-CA111422, R03-CA130102, RO3-CA141564, a Samuel Waxman Cancer Research Foundation award, a grant from the American Lung Association, an American Cancer Society Institutional grant, a grant from The Mary Jo’s Fund to Fight Cancer/Uniting Against Lung Cancer, and an AACR-Pancreatic Cancer Action Network Cancer Development Award.

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