miR-185 and miR-133b deregulation is associated with overall survival and metastasis in colorectal cancer

Abstract

Abstract. Colorectal cancer (CRC) is one of the most common and deadly forms of cancer. Despite improved treatment modalities, post-operative recurrence and metastasis remain the major problems for extending patient survival after surgery. This highlights the need to search for biomarkers for prognostication and treatment stratification of colorectal cancer patients. In this study, we applied the SYBR-green quantitative PCR-based array approach to screen for differentially expressed miRNAs between patients with short (<50 months, range 10-33 months) and long survival (≥50 months, range 50-152 months). The selected candidate prognostic miRNAs were validated in a cohort of 50 CRC patients by TaqMan quantitative PCR. We found that high expression of miR-185 and low expression of miR-133b were correlated with poor survival (p=0.001 and 0.028, respectively) and metastasis (p=0.007 and 0.036, respectively) in colorectal cancer. Our findings suggest the potential prognostic values of these miRNAs for predicting clinical outcome after surgery. IntroductionColorectal cancer (CRC) is the second most common cancer in women and the third in men worldwide (1). It ranks the second most common cause of cancer death in the Western world (2). Currently, there are several treatment modalities for CRC, including surgery, radiotherapy, chemotherapy and targeted therapy (e.g., cetuximab). However, the long-term survival remains low in metastatic disease (3).Given that CRC usually follows a stepwise progression from benign to malignant lesion and distant metastasis, there is a possibility for early diagnosis in order to reduce morbidity and mortality. The commonly used method to characterize CRC tumor in clinic is T1-T3 staging system. However, the staging system reflects only morphological characteristics of the tumor and does not consider tumor molecular biology, thus, it is inaccurate in predicting the future outcome for each particular case. Therefore, the development of screening tools and new biomarkers to facilitate early diagnosis is particularly warranted. Further investigations in the search for new prognostic biomarkers may help to improve post-operative treatment approaches for CRC patients.Several studies have documented a link between the aberrant expression of a class of small non-coding RNAs, termed microRNAs (miRNAs), and the pathogenesis/prognosis of several cancer types, including colorectal cancer (4,5). These molecules provide a potentially valuable diagnostic/prognostic tool for CRC pathology, because mature miRNA species are relatively more stable than mRNAs and well preserved in formalin-fixed, paraffin-embedded samples which are commonly used in clinical routine (6). Furthermore, only a small number of miRNAs are required to distinguish cancerous tissues from non-cancerous tissues compared with mRNA profiles (7), which makes them more feasible candidate biomarkers.miRNAs are endogenous single-stranded non-coding RNAs of ~22-nucleotides in length, which are generated by an RNase III enzyme Dicer from endogenou...

Fascin-1 overexpression and miR-133b downregulation in the progression of gastrointestinal stromal tumor

“…15 Recent studies have reported that miR-133b, mapped on chromosome 6p12.2, was downregulated in carcinomas in the urinary bladder, colon, lung and esophagus. [18][19][20][21] Downregulation of miR-133b in cancer cells seems to result in upregulation of target mRNA and thus, overexpression or activation of oncoprotein. In lung cancer, downregulation of miR-133b is correlated with upregulation of MCL-1 and BCL2L2, suggesting an anti-apoptotic role.…”

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

“…Increased expression of miR-1/-133a is associated with t(14;16) translocation multiple myeloma [152] , whilst reduced expression is associated with prostate cancer [102] and RCC [138] , respectively. Reduced expression of other myomiR combinations is also associated with TSCC [111] , ESCC [132] , HNSCC [114,143] , GIST [281] , bladder cancer (TCC) [93] , lung cancer [85,99] , colorectal cancer [86,87] and rhabdomyosarcoma [88] . downregulated and upregulated myomiRs respectively, and Table 6 lists validated myomiR targets related to enhanced cancer progression.…”

“…downregulated and upregulated myomiRs respectively, and Table 6 lists validated myomiR targets related to enhanced cancer progression. An excellent review by Nohata et al [84] (2012) reported changes in the expression of the miR1/ 133a and miR206/133b cistron clusters in numerous cancers, typically finding reduced expression of different combinations of myomiRs, such as in lung cancer [85] , colorectal cancer [86,87] , rhabdomyosarcoma [88,89] , chordoma [90] osteosarcoma [91] , muscleinvasive bladder cancer [92] , bladder cancer (transitional cell carcinoma) (TCC) [93] , ESCC [94] , breast cancer [95] and prostate cancer [9597] . In different cancers (Figure 3) deregulation typically involves downregulation of one or more myomiR isomers, indicating they normally function as tumor suppressors in the tissues, limiting Metastatic CRC [301] Notch3, Hes1, Bcl-2 and MMP-9; Exogenous upregulation of miR-206 expression;…”

“…Reduced expression of myomiRs was associated with numerous cancers, such as with PDAC [103] colorectal cancer [86,104] , NSCLC [105] , HCC [98] , prostate Circulating microRNA Tumor-derived exosomes Human non-small-cell lung cancer [320] AKT1: V-akt murine thymoma viral oncogene homolog 1; CN-AML: Cytogenetically normal acute myeloid leukemia.…”

Downregulation of miR‐133b predict progression and poor prognosis in patients with urothelial carcinoma of bladder

“…Akçakaya et al. 11 found that combination of upregulation of miR‐185 and downregulation of miR‐133b could predict poor survival and higher metastatic probability. Recent study by Nofech‐Mozes et al.…”