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Microrna-155-3P Promotes Hepatocellular Carcinoma Formation

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Microrna-155-3P Promotes Hepatocellular Carcinoma Formation Tang et al. Journal of Experimental & Clinical Cancer Research (2016) 35:93 DOI 10.1186/s13046-016-0371-6 RESEARCH Open Access MicroRNA-155-3p promotes hepatocellular carcinoma formation by suppressing FBXW7 expression Bo Tang1,2†, Biao Lei1,2†, Guangying Qi3†, Xingsi Liang1,2, Fang Tang1,2, Shengguang Yuan1,2, Zhenran Wang1,2, Shuiping Yu1,2 and Songqing He1,2* Abstract Background: MicroRNAs (miRNAs) are small non-coding RNAs frequently dysregulated in human malignant tumors. In the present study, we analyzed the role miR-155-3p plays in Hepatocellular carcinoma (HCC), which has been reported participation in some other types of cancer. Methods: qRT-PCR was used to measure the levels of miR-155-3p in HCC specimens and HCC cell lines. Overexpression of miR-155-3p and miR-155-3p inhibitor were transfected into HCC cell lines to investigate its role in HCC. Colony formation assay and 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assays were used to analyses cell proliferation in vitro. In vivo tumor formation assays were performed in BALB/c nude mice. Luciferase reporter assay was carried out to measure the translation of F-Box and WD repeat romain containing 7 (FBXW7). Results: We found that miR-155-3p was remarkably upregulated both in HCC tissue and cell lines. Overexpression of miR-155-3p enhanced HCC cell proliferation in vitro and tumorigenesis in vivo. In addition, overexpression of miR-155-3p is correlated with decreased levels FBXW7 mainly through inhibiting the expression of FBXW7. Conclusions: Our studies suggest that miR-155-3p plays an important role in the pathogenesis of HCC and implicates its potential applications in the treatment of HCC cancer. Keywords: FBXW7, Hepatocellular carcinoma, miR-155-3p Background Previous studies found that the occurrence of liver can- Hepatocellular carcinoma (HCC) is one of most com- cer is a slow process with gradual changes that develop mon malignant tumor worldwide and ranks third of mainly as a result of chronic hepatitis and hepatic fibro- mortality rate, with about 500,000 new cases annually sis. Those pathological processes suggest gene and [1]. The major risk factors for HCC includes the pres- protein expression alterations [4]. ence of cirrhosis, Hepatitis B virus/hepatitis C virus MicroRNAs (MIRs) are endogenous non-coding RNAs (HBV/HCV) infection, and other factors, such as nonal- which contain 18 to 25 nucleotides and play important coholic steatohepatitis, are common in certain areas of roles in regulating gene expression [5]. The mature the world [2]. HCC is the second most common mortal- forms of MIRs silence the gene expression is binding to ity factor of cancer and is characterized with late diagno- the 3’-untranslated region (UTR) of target mRNAs and sis, poor prognosis, as well as metastatic tendency and initiate the translational repression or cleavage of cog- insensitivity to chemotherapy and radiotherapy [3]. nate mRNAs [6, 7]. miRNAs have frequently been impli- cated in carcinogenesis [8–11]. In the setting of HCC, * Correspondence: [email protected] miR-222 [12], miR-21 [13], miR-106b [14] and miR-331- †Equal contributors 3p [15] have been reported to be tumor oncogene. 1 Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Among the known oncomirs, miR-155 stands out as Hospital, Guilin 541001, Guangxi, People’s Republic of China 2Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical an important entity. It is one of the most commonly up- University, Guilin 541001, Guangxi, People’s Republic of China regulated miRNAs in tumors [16]. Furthermore, miR- Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Tang et al. Journal of Experimental & Clinical Cancer Research (2016) 35:93 Page 2 of 12 155 has been reported as an oncomir in various human of Guilin Medical University. All tissues were collected cancers, including colorectal [17], glioma [18], esopha- immediately upon resection of the tumors in the oper- geal [19], liver [20], oral squamous [21] and lymphatic ation theater, transported in liquid nitrogen, and then system [22]. miR-155-5p and miR-155-3p, two different stored at -80 °C.We set the samples on the slide glass miRNA strands, produced from the miR-155 host gene and microscopically recognized the malignantly trans- produces,. The miR-155-5p has been considered as the formed epithelial lesion by H&E staining, then cored out only functional miR-155 form [23]. Previous studies the epithelial lesion. Study protocols were approved by found that miR-155-3p is also strongly upregulated in T the Hospital Ethics Committee of Guilin Medical Uni- cells. Functional manipulation of miR-155-3p expression versity, and written informed consent was obtained from revealed its important role in regulating Th17 develop- patients based on the Declaration of Helsinki. ment. The search for miRNA-155-3p target genes highlighted transcripts of two heat shock protein 40 genes, Dnaja2 and Dnajb1 [24]. Such exploration is likely qRT-PCR to provide important information regarding the miR- Total RNA was extracted using TRIzol Reagent (Invitro- 155-3p signature and their target genes at a very early gen, Carlsbad, CA, USA). The miR-155-3p and U6 levels stage of liver tumorigenesis and their relationship to the were quantified using qRT-PCR with the TaqMan® miRNA signature of primary human HCC that can be Micro-RNA Reverse Transcription Kit (Applied Biosys- used in the diagnosis and prognosis of liver cancer. tems, Foster City, CA, USA) and TaqMan® MicroRNA F-box and WD repeat domain containing 7 (FBXW7) Assays (Applied Biosystems) according to the manufac- turer’s instructions. We assessed the RNA expression ac- protein encodes a substrate adaptor for an E3 SCF ubi- -ΔΔCt quitin ligase complex and negatively regulates the abun- cording to relative quantification using the 2 dance of different oncoproteins [25]. Many observations method to determine the fold change in the expression. indicate that FBXW7 lies at the nexus of many pathways The primers used for the expression analysis were as fol- ′ include controlling cell growth, cell differentiation, and lows: GAPDH-forward, 5 -C TCATGACCACAGTCCA ′ ′ tumor genesis. FBXW7 gene is further supported as a TGC-3 : GAPDH-reverse, 5 - TTACTCCTTGGAGGC ′ ′ human tumor suppressor by the discovery of FBXW7 CATGT-3 : U6-forward, 5 - CTCGCTTCGGCAGCAC ′ ′ gene mutations in cancers from a wide spectrum of hu- A-3: U6 - reverse, 5 - AACGCTTCACGAATTTGCGT ′ ′ man tissues [26]. A recent study showed that colorectal 3 . FBXW7 - forward, 5 - GGG AGCACTTTGCTGA ′ ′ cancer patients with low FBXW7 levels had poorer prog- AATC-3 : FBXW7 - reverse, 5 -CAGCAGCCACTTC ′ noses [27]. TTGAAAC -3 . In this study, we aimed to investigate whether miR- 155-3p is an oncomir in human HCC and identify the miR-155-3p measurement direct target correlated with the malignant phenotype of miR-155-3p levels were determined by two-step real HCC. We demonstrated that miR-155-3p upregulating time-PCR. Reverse transcription reaction was performed was a frequent event in HCC tissues and could be a po- with specific microRNA primers. Real time PCR amplifi- tential targets for HCC patients. Furthermore, our find- cation was carried out with a Rotorgene 3000 machine ings also showed that ectopic expression of miR-155-3p (Corbett). Relative microRNA concentrations are given could accelerate clone formation and proliferation ability as the ratios between the amount of the target gene and of HCC cells. In addition, we further identified FBXW7 the endogenous control U6. as a functional target of miR-155-3p and demonstrated FBXW7 involve in the effects of increased miR-155-3p on promoting clone formation and proliferation. Our Cell lines data suggest a fundamental role for miR-155-3p in clone The human HCC cell lines THLE-3, HepG2, Hep3B and formation and HCC cells proliferation, and implicate the SUN475 were obtained from RIKEN BioResource Center potential application of miR-155-3p in prognosis predic- (Tsukuba, Japan) and maintained in Dulbecco’s Modified tion therapy of liver cancer. Eagle’s Medium (DMEM) with 10 % FBS, 2 mM L-glu- tamine and 100 U/ml of penicillin and streptomycin in a Methods 6-cm dish. BEL-7405, BEL-7404 and BEL-7402 were ob- Patients and specimens tained from the ATCC (Manassas, VA, USA) and main- Hepatocellular carcinoma tumor tissues and normal liver tained in Mc-Coy’s 5a Medium with 10 % FBS, 2 mM L- tissues (para-cancerous tissues) were randomly collected glutamine and 100 U/ml of penicillin and streptomycin from HCC patients who underwent curative resection and in Roswell Park Memorial Institute medium 1640 with informed consent between 2012 and 2014 at the with 10 % FBS, 2 mM L-glutamine and 100 U/ml of Department of Hepatobiliary Surgery, Affiliated Hospital penicillin and streptomycin. Tang et al. Journal of Experimental & Clinical Cancer Research (2016) 35:93 Page 3 of 12 Fig. 1 The expression of miR-155-3p is elevated in Hepatocellular carcinoma tissues. a miR-155-3p expression in Hepatocellular carcinoma in comparison to normal tissues was measured by qRT-PCR. b miR-155-3p expression levels are significantly elevated in Hepatocellular carcinoma in comparison to normal tissues. c miR-155-3p expression levels are significantly increased in patients of stage III-IV in comparison to the stage I-II.
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