MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression and play an important role in lung cancer. Profiling of miRNA expression in lung tumors has identified specific miRNAs that are upregulated or downregulated and correlate with patient outcomes. Certain miRNAs are connected to mutational status, like miRNA-155 which is increased in double negative KRAS and EGFR tumors. Integrating miRNA signatures could help with diagnostic and treatment decisions for lung cancer.

1. MOLECULAR BASIS OF LUNG
CANCER (PART 3)
PRESENTED BY DAVID TABAGARI

2. MICRO RNAS
• microRNAs(miRNAs) are small 22 nucleotide RNAs that have a
capacity to regulate gene expression through either mRNA
degradation or inhibition of translation.
• It is estimated that miRNAs may regulate up to 60% of the
human genome.
• The mechanism of change in miRNA expression in cancers are
multifactorial. First, miRNAs are encoded on a chromosomal

3. MIRNA BIOSYNTHESIS
• DGCRB- DiGeorge syndrome critical region gene 8.
• RNASEN/DROSHA- Rnase III endonuclease.
• TRBP- Transactivator Binding Protein.
• AGO- Argonaute protein.

5. MIRNA PROFILING IN LUNG CANCER
• There are investigations linking miRNA processing and lung
tumorigenesis, for instance, disruption of DICER complex
promoted lung tumorigenesis.
• Yanaihara and colleagues conducted high throughput profiling
of cases of stage I adenocarcinoma of the lung. They identified
over 40 miRNAs that distinguished lung tumors from adjacent
uninvolved lung. Of these miRNAs decreased Let-7a-2 and
increased miR-155 appeared to correlate with patient outcome.

6. MIRNAS AND MUTATIONAL STATUS IN
LUNG CANCER
• Dactic and colleagues identified several miRNAs connected with
different morphologic variants of lung cancer.
• miRNA-155 was increased in double negative(KRAS- and EGFR-)
tumors.
• miRNA-495 was increased in KRAS+ tumors.
• miRNA-25 was increased in EGFR+ tumors.
• Garafilo and colleagues demonstrated that deregulation of miRNA-
30c,30b and etc. contributed susceptibility of NSCLC to gafitinib.
• miRNA-128b,7,145 target EGFR.

7. INTEGRATING MIRNAS INTO CLINICAL
DECISION
MAKING IN LUNG CANCER
• miRNA signatures may be of value in both diagnostic and
therapeutic decision making. In particular, investigators are
exploring the potential for miRNA signatures in the settings of
indeterminate lung nodules and early detection, histologic
classification, and chemotherapeutic response, each of which
can present clinical challenges.
• miR-218, which was downregulated in smokers with SQCC.

8. NONINVASIVE MIRNA DETECTION
• miRNA detection could help with early diagnosis of the lung
cancer.
• Shen and colleagues showed that sputum levels of miR-31 and
miR-210 had a sensitivity of 65.2% and a specificity of 89.7% in
diagnosing lung cancer. Combining this with CT demonstrated
increase in specificity of diagnosis.
• An independent study identified miR-205 and 210 as
biomarkers for early stage lung cancer diagnosis.

9. MIRNAS AS INFORMATION
TRANSDUCERS
• The concept of packed miRNA as the mechanism of genetic
information transfer is exciting.
• It has been demonstrated that miRNAs might be circulating
freely or attached to several proteins(e.g. AGO) or lipids and

12. INVASION, METASTASIS, AND
ANGIOGENESIS
• The E-cadherin–catenin complex is critical for intercellular adhesiveness and
the maintenance of normal and malignant tissue architecture; its epigenetic
alteration is the basis of its decreased expression.
• Alpha3-integin is important in normal lung development, but if lost, it is
associated with poor prognosis in lung adenocarcinoma.
• Matrix metalloproteinases (MMP) degrade the extracellular matrix and
basement membrane, necessary first steps in angiogenesis. MMP2 and
MMP9 have been associated with poorer prognosis.
• Angiogenesis, the formation of new blood capillaries, is necessary for a
tumor mass to grow beyond a few millimeters in size. High microvessel
density (MVD) and VEGF overexpression are predictive of poor outcome.
• Bevacizumab- and inhibitor of VEGF is in clinical trials for NSCLC.

13. CANCER STEM CELLS
• Cancer stem cells are small fraction of tumor bulk, which are
undifferentiated, self-renewing and resistant to cytotoxic drugs. Because of
their resistance to treatment and the potential for seeding distant metastatic
disease, the study of cancer stem cells and the development of strategies
effectively to eradicate all residual stem cells is of critical importance in
cancer treatment.
• In lung tumors, CD133 and other commonly used markers of stemlike tumor
cells (Hoechst dye efflux and aldehyde dehydrogenase activity) have been
shown to identify subsets of tumor cells that display characteristics
consistent with the cancer stem cell hypothesis.
• Recent studies have defined aldehyde dehydrogenase (ALDH) activity as a
robust marker for lung adenocarcinoma stemlike cells. ALDH-positive cells
are highly tumorigenic and clonogenic as well as capable of self-renewal
compared to the ALDH subpopulation. ALDH7A1 was associated with