miRNAs are emerging as important modulators in cellular pathways and play a key role in carcinogenesis. Recent studies have identified a number of miRNAs as potential biomarkers for cancer; some of them act as oncogenes, tumor suppressors or modulators of metastasis. As different cancer therapies are effective in different subgroups of patients, there is a tremendous need for novel predictive and prognostic markers to improve the outcomea of cancer patients Citation[1].
miRNAs as molecular predictors of response to anticancer treatment & the prognostic value of miRNAs in cancer
To improve the prognosis of patients after anticancer therapy, there is a need for biomarkers to predict responses to anticancer treatment in patients, as well as to aid investigators in designing future clinical trials that better stratify patients. Microarray profiling on diagnostic small-cell lung cancer tumor samples has demonstrated that miR-92a-2*, miR-147 and miR-574-5p are significantly associated with chemoresistance. Higher expression of miR-92a-2* in tumors is also associated with decreased survival in patients with small-cell lung cancer. These miRNAs may have potential application in screening small-cell lung cancer patients at risk for de novo chemoresistance Citation[2].
In pancreatic cancer patients after surgical resection, it has been shown that gemcitabine-treated patients with high miR-142-5p expression have significantly longer survival times than those with low miR-142-5p expression. This miRNA may serve as a predictive marker for gemcitabine response in patients with resected pancreatic cancer Citation[3]. On the other hand, ovarian cancer patients without complete response to paclitaxel-based treatment have been demonstrated to have lower miR-200c levels than patients with complete response. Low tumoral miR-200 expression is shown to be significantly associated with high β-tubulin III protein content. This miRNA may represent the biomarker of response to paclitaxel-based treatments of patients with ovarian cancer Citation[4]. In estrogen receptor-positive breast cancer patients homogeneously treated with tamoxifen only, the expression of miR-210 has also been found to be associated with poor clinical outcome. Functional analyses reveal that miR-210 is involved in cell proliferation, migration and invasion Citation[5].
Aberrant miRNA expressions may have potential prognostic value in different malignancies. Measuring the miRNA expression in cancerous and noncancerous tissue pairs collected from stage I–III squamous cell carcinoma (SCC) patients without any treatment prior to surgery revealed an association between high expression of miR-31 and poor survival. The tumor suppressor DICER1 was identified as a target of miR-31 and the expression of miR-31 in human lung cancer cells can repress DICER1 activity Citation[6]. A poorer prognosis in relapse-free survival and tumor-specific survival has also been reported in esophageal SCC patients with high levels of serum miR-31. In vitro studies show that miR-31 promotes esophageal SCC colony formation, migration and invasion. Three tumor suppressor genes (EMP1, KSR2 and RGS4) have been confirmed to be targeted by miR-31 Citation[7]. This miRNA may serve as a potential prognostic biomarker for SCC.
Independent of clinical covariates in patients with resectable pancreatic ductal adenocarcinoma, high expression of miR-21 and reduced expression of miR-34a has been found to be significantly associated with poor overall survival (OS) following resection. Aberrant expression levels of these miRNAs have potential as prognostic biomarkers in pancreatic ductal adenocarcinoma Citation[8]. An important challenge in cancer research is to develop reliable predictors of tumor recurrence following standard treatment to determine whether immediate adjuvant therapy is warranted. A panel of two miRNAs and ten protein-coding genes (miR-519d, miR-647, ANXA1, BID, CCNG2, ETV1, FBP1, LETMD1, NOTCH3, RAD23B, SIM2 and TNFRSF1A) has been identified from formalin-fixed specimens that can be used to separate prostate cancer patients with and without biochemical recurrence following surgery. This panel of markers may increase the accuracy of prognostication following radical prostatectomy in patients with prostate cancer Citation[9].
In a univariate analysis of samples from diffuse large B-cell lymphoma patients treated with rituximab, cyclophosphamide, doxorubicin and vincristine, the expression of miR-18a correlated with OS, whereas the expression of miR-222 correlates with progression-free survival. Cox regression analysis including the International Prognostic Index has revealed that the expression levels of these specific miRNAs are independent predictors of survival in diffuse large B-cell lymphoma patients Citation[10]. On the other hand, the profiling of miRNA has identified miR-146b and miR-222 upregulation, as well as miR-34b and miR-130b downregulation, in aggressive compared with nonaggressive papillary thyroid carcinoma. Among BRAF-positive tumors, miR-146b shows strong association with aggressive papillary thyroid carcinoma. MET was identified as a potential target gene for miR-34b aggressive papillary thyroid carcinoma Citation[11]. Lower levels of miR-146a have also been found to be associated with lymph node metastasis, venous invasion and OS in gastric cancer. Ectopic expression of miR-146a inhibits migration and invasion, and downregulates and targets EGFR and IRAK1 expression in gastric cancer cells Citation[12].
Circulating miRNAs are potential noninvasive prognostic biomarkers for cancer. In the study of paired plasma and serum samples from patients with early stage non-small-cell lung cancer and matched controls, reduced plasma expression of let-7b has been shown to be modestly associated with worse cancer-specific mortality in all patients and reduced serum expression of miR-223 is modestly associated with cancer-specific mortality in stage IA/B patients Citation[13]. On the other hand, the plasma levels of let-7a and miR-16 have been observed to be bimodal in myelodysplastic syndrome patients. Their expression levels are significantly associated with OS and progression-free survival. Multivariate analysis reveals that let-7a is a strong independent predictor for OS in this patient cohort Citation[14]. Another recent study has identified a five-miRNA signature (miR-142-3p, miR-29c, miR-26a, miR-30e and miR-93) significantly associated with disease-free survival in nasopharyngeal carcinoma patients. This biomarker panel may add prognostic value to the TNM staging system and inform treatment decisions for patients at high risk of progression Citation[15].
A prognostic signature of expression levels of five miRNAs (let-7a, miR-21, miR-135a, miR-206 and miR-335) in colorectal cancer for detecting the presence of metastases has also been identified. Among them, let-7a shows elevated expression in metastatic disease in KRAS mutation-positive tumors. The five-miRNA signature may be a potential prognostic tool in colorectal cancer Citation[16]. Similarly, evaluating the expression of miRNAs in ependymomas and normal brain tissue found miR-203 to be an independent marker for relapse, and three miRNAs (let-7d, miR-367 and miR-596) that strongly correlated with OS have also been identified Citation[17]. Screening of the let-7 family by in situ hybridization has revealed that the diminished expression of let-7g can also serve as a prognostic biomarker of lymph node metastasis and poor survival in breast cancer patients. Abrogation of let-7g expression in nonmetastatic mammary carcinoma cells elicits rapid metastasis from the orthotopic location through GAB2 and FN1, as well as consequent activation of p44/42 MAPK and specific matrix metalloproteinases Citation[18].
Integrated miRNA and mRNA global expression profiling has identified nine miRNAs (miR-27b, miR-29c, miR-30c, miR-30e-3p, miR-128a, miR-150, miR-210, miR-342 and miR-548d) that are independently associated with distant relapse-free survival in breast cancer cases. Among them, miR-27b, miR-150 and miR-342 are prognostic in triple receptor-negative tumors Citation[19]. MLLT11 is a poor prognostic biomarker for pediatric acute myeloid leukaemia. Transfection experiments have demonstrated that miR-29b directly regulates MLLT11 expression in vitro. Acute myeloid leukemia patients with low miR-29b and elevated MLLT11 expression have poor OS, suggesting miR-29b to be a potential prognostic biomarker for acute myeloid leukemia patients Citation[20]. On the other hand, the miRNA profile of medullary thyroid cancer has indicated that overexpression of miR-183 and miR-375 in medullary thyroid cancer predicts lateral lymph node metastases. They are found to be associated with residual disease, distant metastases and mortality. Knockdown of miR-183 expression in human medullary thyroid cancer cells induces a significant decrease in the viable cell count and upregulation of the autophagy-associated protein LC3B Citation[21].
Discussion & perspectives
Finding informative biomarkers has been one of the major focuses of cancer research in the past decade. Blood is regarded as an ideal type of sample for cancer biomarker discovery as it can be collected easily in a minimally invasive manner Citation[22]. Some studies have also attempted to use miRNAs from feces as markers for gastrointestinal cancer Citation[23,24]. The use of different sample types enables the discovery of novel markers under various constraints. On the other hand, there is a trend towards combining several miRNAs as a panel of markers, which will normally contribute to improving sensitivity and specificity. Similarly, the combination of miRNA markers with other molecular signatures (such as protein markers, SNPs and DNA methylation signatures) may also help to better predict the treatment outcomes of individual patients. However, even though statistically significant differences have been reported in a number of predictive and prognostic markers, the application of these exciting results in clinical practice still requires proper validation Citation[25]. In order to improve the reliability, quality assurance and validity of biomarkers, setting up standard preparation processes for various types of samples and designing better methods to assess the quality of miRNA markers is also needed. A robust and reliable miRNA marker should be well validated by a multicenter endeavor. Cancer is such a complex genetic disease that deciphering the role of miRNAs in the signaling pathways responsible for recurrence and metastasis would allow better utilization of miRNAs for the prediction and prognosis of cancer treatments. Although a number of challenges remain to be addressed, recent encouraging results demonstrate that miRNAs have the potential to become useful predictive and prognostic markers for human cancers.
Financial & competing interests disclosure
The author has no relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Related Research Data
References
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