Asian Pacifc Journal of Cancer Prevention, Vol 13, 2012 65 DOI:http://dx.doi.org/10.7314/APJCP.2012.13.KKSuppl.65 Expression Profles of miR-21 and let-7a in Opisthorchis-Associated Cholangiocarcinoma Asian Pacifc J Cancer Prev, 13, 65-69 Introduction Cholangiocarcinoma (CCA) is an aggressive type of cancer that originates from the bile duct epithelium. Cases of CCA are increasing worldwide (McLean and Patel, 2006). In Thailand, the highest incidence is in the northeast region and is primarily associated with chronic infection with the liver fuke, Opisthorchis viverrini (Ov) (Haswell-Elkins et al., 1994; Sripa et al., 2007). At present, only surgical resection of all detectable tumors leads to an improvement of the fve-year survival. Surgical resection is often incomplete and typically results in subsequent local recurrence and metastasis. In order to prevent post-surgical recurrence, chemotherapy is a preferred adjunctive treatment. Accordingly, molecular mechanisms of CCA genesis and progression need to be studied to identify the targets for chemoprevention and treatment. MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate the expression of target genes by interacting with the 3’UTR and promoting translational repression or degradation of mRNAs (Peek and Blaser, 2002; Pillai, 2005). In recent years, abnormalities in miRNA expression have been identifed in the progression of various cancers and consequently have been proposed as potential targets for anticancer therapies (Croce, 2008). miRNAs have been shown to function as both tumor suppressors or oncogenes in various cancers 1 Department of Biochemistry, 2 Department of Pathology, 3 Department of Surgery, Faculty of Medicine, Khon Kean University, 4 Liver Fluke and Cholangiocarcinoma Research Center, 5 Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand, & Equal contribution *For correspondence: puangrat@kku.ac.th Abstract Altered miRNA expression could be a determinant of cancer development and/or progression. We aimed to study the role of oncomir miR-21 and tumor suppressor let-7a in the genesis of Opisthorchiasis-associated cholangiocarcinoma (CCA). The results showed that miR-21 was up-regulated while let-7a was down-regulated during cholangiocarcinogenesis in the hamster model and also in human CCA samples. The expression level of miR-21 had an inverse correlation with the mRNA level of its target RECK, a metastasis suppressor, in human CCA. Knockdown of miR-21 of KKU100 CCA cells signifcantly increased the mRNA level of RECK and suppressed the wound-induced migration of CCA cells. Our data suggest that miR-21 is one key molecule playing crucial roles in the CCA growth and metastasis. Manipulation of miRNA expression offers a potential avenue of CCA therapy. Keywords: miR-21 - let-7a - RECK - Opisthorchis viverrini - cholangiocarcinoma RESEARCH ARTICLE Expression Profles of Oncomir miR-21 and Tumor Suppressor let-7a in the Progression of Opisthorchiasis -Associated Cholangiocarcinoma N Namwat 1,4& , P Chusorn 1,4& , W Loilome 1,4 , A Techasen 1,4,5 , J Puetkasichonpasutha 1,4 , C Pairojkul 2,4 , N Khuntikeo 3,4 , P Yongvanit 1,4 * (Kent and Mendell, 2006; He et al., 2007). Among these oncogenic miRNAs, miR-21 has been identifed as the top-rank upregulated miRNA in various types of cancers as reviewed by Krichevsky and Gabriely (2009). miR- 21 has been linked with infammation-related cancers by activating its expression via infammatory mediators such as interleukin 6 (IL6) (Schetter et al., 2010) through a signal transducers and activators of transcription 3 (STAT3)-dependent mechanism (Loffer et al., 2007) and stimulating maturation via transforming growth factor β (TGFβ) through the Smads signaling cascade (Hata and Davis, 2009). miR-21 emerges as a principal regulator targeting to mRNAs of several tumor suppressor genes. One of well-characterized miR-21 targets that has recently been reported is the metastasis suppressor RECK (Reversion-inducing cysteine rich protein with Kazal motifs) (Gabriely et al., 2008; Reis et al., 2012; Zhang et al., 2008). RECK functions as the inhibitor of metalloproteinases (MMPs) that play roles in regulation of extracellular matrix and basement membrane degradation, which is the key step of cancer metastasis (Oh et al., 2001). Recently, we demonstrated that RECK was downregulated in CCA tissues and cell cultures and the RECK level was inversely correlated with MMP-2 and MMP-9 expressions. Low level of RECK protein was associated with poor survival of CCA patients (Namwat et al., 2011). Knockdown of RECK using siRNA resulted