The Application of MicroRNAs in Cancer Diagnostics - RNA Interference from Biology to Therapeutics - page 269

recurrence in a distinct PC patient cohort [ 144 ] . As further con fi rmation of the
prognostic potential of miR-211, Martens-Uzunova et al . identi fi ed a 25-miRNA
classifier (including miR-211) for prediction of cancer-specific survival in a cohort
of 50 PC patients [ 147 ] .

13.3.5 Predictive miRNAs

Several studies have identified miRNA expression profiles associated with antican-
cer drug responsiveness, indicating that miRNAs have potential as predictive bio-
markers. Furthermore, for a growing number of miRNAs, there is experimental
evidence for direct functional roles as cellular modulators of drug resistance, sug-
gesting that some miRNAs may also have potential as new therapeutic targets in this
context [ 149, 150 ]. Multiple mechanisms are known to be involved in development
of drug resistance, including, e.g., inhibition of apoptosis, blocking of drug entry,
active efflux of the drug, and altered expression of the drug target [ 151 ] . Conceivably,
all of these cellular mechanisms may be regulated by miRNAs. Selected examples
of predictive miRNAs are described below and in Table 13.2 .
Pancreatic cancer is associated with poor prognosis and surgical treatment is often
followed by adjuvant chemotherapy. At least two independent reports found high
expression of miR-21 to be a significant predictor of poor cancer-specific survival for
pancreatic cancer patients receiving adjuvant gemcitabine-based chemotherapy [ 132,
133 ]. It was also shown that inhibition of miR-21 increased sensitivity to gemcit-
abine, while overexpression of miR-21 reduced chemosensitivity of pancreatic can-
cer cells in vitro, suggesting that miR-21 could be a new therapeutic target. High
expression of miR-21 has also been associated with drug resistance in other cancer
types. For breast cancer, it was reported that upregulation of miR-21-mediated resis-
tance to Trastuzumab, a monoclonal antibody directed against human epidermal
growth factor receptor 2 (HER2), which is commonly overexpressed and linked to
poor clinical outcome [ 134 ]. Functional studies suggested that miR-21 induced drug
resistance at least in part by targeting tumor suppressor PTEN (phosphatase and
tensin homolog) in breast and pancreatic cancer cells [ 133, 134 ] . In addition, miR-21
was included in a miRNA signature that could distinguish fludarabine-refractory and
-sensitive cases of CLL [ 135 ]. Finally, a large study including a total of 455 patients
with hepatocellular carcinoma showed that patients with low expression of miR-26
in the tumor had a favorable response to interferon alfa [ 128 ] .

13.4 Circulating miRNAs as Diagnostic Cancer Biomarkers

13.4.1 Discovery of Circulating Tumor-Speci fi c miRNAs

The recent discovery of miRNAs circulating in body fluids has initiated intense
investigation to determine if their detection may be advantageous for cancer diagnostics