|Researchers Discover a Unique Molecular Profile for Lung Cancer
A team of researchers has found that the expression pattern of certain microRNAs,
or miRNAs, may predict tumor aggressiveness in some patients with lung cancer.
These findings indicate that miRNAs may represent a new class of diagnostic and
prognostic tools for lung cancer. The study is a collaboration among researchers
at The Ohio State University Comprehensive Cancer Center, Columbus, Ohio; the
Jikei University School of Medicine, Tokyo, Japan; National Cancer Center Research
Institute, Tokyo, Japan; and the Center for Cancer Research at the National Cancer
Institute (NCI), which is part of the National Institutes of Health. The study
results appear in the March 13, 2006, issue of Cancer Cell*.
miRNAs are small segments of genetic material called ribonucleic acid, or RNA,
and are thought to control gene expression. Their actions could change the expression
of cancer-related genes within a cell and lead to malignancies.
The researchers identified two miRNAs — has-mir-155 and has-let-7a-2 — that
could be used as prognostic indicators in patients with adenocarcinoma, a malignancy
of the mucous glands in the lungs. High levels of has-mir-155 or low levels
of has-let-7a-2 were associated with poor prognosis. Specifically, overexpression
of has-mir-155, or the signalling of the miRNA to change the amount of
a protein produced, was the most significant indicator of this prognosis, independent
of tumor stage. Although these miRNAs have been identified in other cancers,
this is the first evidence linking has-mir-155 to lung cancer.
A tumor with an overexpression of has-mir-155 or reduced expression of has-let-7a-2 would
indicate the need for aggressive chemotherapy or radiation treatments. Other
tumors that do not show high has-mir-155 or low has-let-7a-2 levels
are less aggressive, and those patients might not require more therapy.
“This study is significant because it provides another tool for studying prognosis
that is independent of tumor stage,” said Curtis Harris, M.D., chief of the Laboratory
of Human Carcinogenesis at NCI and co-leader of this study. “Following surgery,
50 to 60 percent of patients with stage I lung cancer will develop metastatic
disease within five years. This may indicate that there are micrometastases that
have not been detected by imaging, scanning or pathology.” Harris noted that “in
the future, we can use miRNAs and other biological predictors to select patients
who may need more aggressive treatment versus those who may not. Additional studies
confirming these results are the next step before incorporating miRNA analysis
into routine clinical practice.”
Lung cancer is the leading cause of death due to cancer and is primarily caused
by exposure to tobacco smoke. Scientists seek to better understand the mechanisms
underlying this disease, and miRNAs may provide a way to examine the regulation
of cancer-related genes.
“miRNAs are going to be important biomarkers of not only diagnosis and prognosis,
but therapy, as well,” said Harris. “The next step is to identify the genes that
the miRNAs are affecting; they could be used as potential targets for developing
In the study, a total of 104 pairs of primary tumor tissues and corresponding
noncancerous lung tissues were examined. The tumor and corresponding normal tissues
were obtained from the same patient to eliminate genetic differences between
tumor and normal tissues.
Researchers focused primarily on the more common adenocarcinomas in their analysis;
adenocarcinomas and squamous cell carcinomas. Unlike adenocarcinomas, squamous
cell carcinomas form in the cells lining the internal surfaces in the lung. These
two tumor types are the most common lung cancers and are referred to as non-small
cell lung cancers (NSCLC). In the study, adenocarcinomas of the lung comprised
63 percent of the tumors studied and squamous cell carcinomas comprised 37 percent.
Patterns of miRNA expression in each tumor and normal tissue pair were studied
by microarray analysis. A microarray allows the measurement of hundreds of miRNAs
simultaneously in a single sample. Five miRNAs displayed different expression
levels in tumor tissues versus their corresponding noncancerous controls and,
thus, were selected for further study. Upon statistical analysis, data showed
that patients with high has-mir-155 or low has-let-7a-2 had poorer
survival than patients showing low has-mir-155 or high has-let-7a-2 expression.
The difference in the prognosis of these two groups was highly statistically
After examining tissue from lung cancer patients, and following each patient
to see how long they lived, researchers found that miRNA expression patterns
were independent of tumor stage. When the scientists combined all clinical and
molecular factors, they found that a high level of has-mir-155 or a low
level of has-let-7a-2 was the most significant prognostic factor for an
unfavorable patient outcome.
“This is promising research and is the first study to link these miRNAs to lung
cancer,” said Carlo Croce, M.D., chair of Molecular Virology, Immunology and
Medical Genetics at The Ohio State University and study co-leader. “We are proposing
that has-mir-155 may be acting like an oncogene in lung cancer.” Oncogenes
control cell growth and, when mutated, can contribute to abnormal cell growth. “miRNAs
control the expression of a number of genes,” noted Croce, “so if the miRNA is
altered, this could lead to the alteration of a number of genes affecting malignant
tumor growth. Although these results are encouraging, further testing is required
to demonstrate the validity of using these markers for predicting patient outcomes.”
Other types of cancers also have been shown to express specific miRNAs; however,
the exact role that miRNAs play in the development of human cancers is unknown.
A recent paper appearing in the Proceedings of the National Academy of Science supports the observation that cancer-related genes are regulated by miRNAs in
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