- Open Access
The MicroRNA-148/152 Family: Multi-faceted Players
Molecular Cancer volume 12, Article number: 43 (2013)
MicroRNAs(miRNA) are noncoding RNAs of about 19–23 nucleotides that are crucial for many biological processes. Members of the microRNA-148/152(miR-148/152) family, which include microRNA-148a(miR-148a), microRNA-148b(miR-148b), and microRNA-152(miR-152), are expressed differently in tumor and nontumor tissues and are involved in the genesis and development of disease. Furthermore, members of the miR-148/152 family are important in the growth and development of normal tissues. Members of the miR-148/152 family regulate target genes and are regulated by methylation of CPG islands. In this review, we report recent studies on the expression of members of the miR-148/152 family, methylation of CPG islands, and their target genes in different diseases, as well as in normal tissues.
MiRNAs are noncoding RNAs of about 19–23 nucleotides. They are transcribed by RNA polymerase II into pri-miRNAs. These are processed by RNAse III Drosha into 70 to 100-nucleotide pre-miRNAs . Pre-miRNAs, mediated by the RNAse III Dicer, generate double-stranded RNAs approximately 22 nucleotides long . These are miRNAs/miRNAs*, which are mature miRNA guides and miRNA* complementary passenger strands. One of the two strands is selected as a guide strand based on thermodynamic properties; the complementary miRNA* strand is usually degraded . Moreover, miRNAs are posttranscriptional regulators that bind by complementary base-pairing to sequences in the 3′-Untranslated Regions(3′-UTR)of target mRNAs, resulting in downregulation . Growing evidence indicates that more and more miRNAs play key roles in a wide variety of biological processes including cell fate specification, proliferation, cell death, and energy metabolism through altering the expression of targets by both downregulation  and upregulation .
Structure of the miR-148/152 family
MiR-148a, miR-148b, and miR-152 are the three members of the miR-148/152 family . The pre-miR-148/152 family members have a stem-loop structure (Figure 1) that is processed into the mature members of the miR-148/152 family by a series of intranuclear and intracytoplasmic enzymes. Mature members of the miR-148/152 family are 21–22 nucleotides in length, with the same seed sequence of approximately 6–7 nucleotides (Figure 2). The seed sequence is an important region for binding to target mRNAs. MiR-148/152 family members are involved in various biological processes through complementary binding between the seed sequence and the 3′-UTR of target mRNAs. Numerous tumors and normal tissues express the miR-148/152 family members differently during growth, development, and tumorigenesis. Therefore, miR-148/152 family members might be critical for these processes.
Functions of miR-148/152 family members in normal tissue
MiR-148/152 family members have aberrant expression in normal tissue, especially in stem cells. Merkerova et al. investigated miR-148a expression in hematopoietic stem cells (HSCs) and found that miR-148a was decreased in HSCs . MiR-148a was also downregulated in mesenchymal stem cells compared to embryonic stem cells and in osteodifferentiated multipotent mesenchymal stromal cells compared to multipotent mesenchymal stromal cells [9, 10]. Schoolmeesters et al. reported that miR-148b was upregulated in the osteogenesis of early osteogenic differentiation of human mesenchymal stem cells . Zhang et al. identified miR-148a as a novel myogenic miRNA that mediated myogenic differentiation. Expression levels of miR-148a increased during C2C12 myoblast differentiation . In a study of mouse adipogenesis, John et al. found that miR-148b expression was increased . In a study of hepatic injury and rejection after liver transplantation, Farid et al. found that miR-148a expression was significantly reduced in liver tissue with prolonged graft warm ischemia times. Conversely, serum levels were elevated in patients with liver injury and this positively correlated with aminotransferase levels. These findings might provide early, sensitive and specific biomarkers of liver injury . In a study of dendritic cells, which are important in linking the innate and adaptive immune responses, Liu et al. demonstrated that miR-148b/miR-152 family members were negative regulators of the innate response and the antigen-presenting capacity of dendritic cells by targeting CaMKIIalpha. This function might contribute to immune homeostasis and immune regulation . Manaster et al. showed that in placental tissue, both miR-148a and miR-152 were expressed at relatively low levels compared with other healthy tissues. In placental tissue, levels of human leukocyte antigen G (HLA-G), a miR-148a and miR-152 target gene, were high and therefore important for a healthy pregnancy .
Expression of miR-148/152 family members might be altered by exposure to certain physical and chemical factors. Palmieri et al. identified 16 upregulated and 2 downregulated miRNAs in osteoblast-like cells line (MG-63) cultured with Medpor, an alloplastic material used for craniofacial reconstruction. In these conditions, the expression of miR-148b and miR-152 were upregulated. These results might provide a better understanding of the molecular mechanism of bone regeneration and a model for comparing other materials with similar clinical effects . Wang et al. studied miRNA expression profiles in brains of fetal mice with prenatal ethanol exposure. MiR-152 was one of the upregulated miRNAs . Wu et al. demonstrated that miR-148b was upregulated 1.53-fold in response to radiation treatment in non-Hodgkin’s lymphoma (NHL). Further research in Raji cells indicated that miR-148b sensitized Raji cells to radiotherapy. These results demonstrated that miR-148b increased the radiosensitivity of Raji cells and suggested that miR-148b was important in the response of NHL to ionizing radiation  Wang et al. determined miRNA expression profiles in the human lung fibroblasts cell line WI-38 exposed to ionizing radiation (IR). They identified four upregulated miRNAs including miR-152. These results suggested that miRNAs are involved in the regulation of IR-induced senescence. Therefore, targeting these miRNAs might be a novel approach for modulating the cellular response to radiation exposure .
MiR-148/152 family and disease: upregulation and downregulation
Aberrant expression of MiR-148/152 family has been observed in tumor [7, 21] and nontumor  diseases. Many studies have identified that MiR-148/152 family members potentially acted as oncogenes and tumor suppressors. Moreover, the growing evidence has demonstrated that miR-148/152 family members also played important roles in some nontumor diseases, such as IgA nephropathy , type 1 diabetes , atherosclerotic lesions , chronic fatigue syndrome/myalgic encephalomyelitis .
Upregulation of miR-148/152 family
MiR-148/152 family members are upregulated in many diseases. Huang et al. reported that six miRNAs including miR-148a were significantly upregulated in the plasma of multiple myeloma (MM) and high levels of miR-148a were related to shorter relapse-free survival times . Also in plasma, Cuk et al. noted that miR-148b was significantly upregulated in breast cancer patients . Moreover, Yuan et al. reported that miR-148a was upregulated in hepatitis B cells associated with hepatocellular carcinoma (HCC) . Furthermore, Gokhale et al. found miR-148a, as one of abnormal expressed miRNAs, was overexpressed in the WNT signaling-associated medulloblastomas . Therefore, miR-148a and miR-148b might be significant biomarkers in these cancer patients and might provide an early easy detection method.
In IgA nephropathy, miR-148b, which potentially targets core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1 (C1GALT1), was upregulated . Nielsen et al. found 12 upregulated human miRNAs, including miR-152, in the serum of type 1 diabetes patients relative to age-matched healthy controls . Moreover, monocytes are critical in atherosclerotic lesion formation, and can be subdivided into classical and nonclassical subsets . Bidzhekov et al. studied miRNA expression profiles of atherosclerotic plaques and found that miR-99b and miR-152 were co-expressed in plaque tissue and classical monocytes . Taken together, these findings increase our understanding of the importance of miR-148/152 family in nontumor diseases.
Downregulation of miR-148/152 family
MiR-148/152 family members are decreased in various tumor types, indicating that they have the potential to act as tumor-suppressor miRNAs. Li et al. found miR-148b was underexpressed in liver cancer stem cells (LCSCs) . In a study of hepatic cell lines, Zhao et al. found that miR-148b was downregulated in the liver cancer cell lines HepG2, MHCC97L, and MHCC97H relative to the hepatic cell line L02 . Moreover, Huang et al. reported that miR-152 was downregulated in HBV-related HCC tissues compared with adjacent noncancerous hepatic tissues . In view of the above, we speculated that miR-148/152 family members were downregulated in hepatocellular carcinoma. Furthermore, in hepatoblastoma, the expression of miR-148a was demonstrated to be lower than that in hepatocellular carcinoma .
In gastrointestinal cancers, Chen et al. noted that miR-148a and miR-152 were downregulated in cancer tissue and cancer cell lines . Furthermore, they also found that low expression of miR-148a and miR-152 correlated with increased tumor size and advanced pT stage . Moreover, the study of Zheng et al. revealed that the low expression of miR-148a was significantly associated with lymph node metastasis in gastric cancer . They further found that Rho-associated, coiled-coil containing protein kinase 1(ROCK1), which might be a target of miR-148a, was involved in miR-148a-induced suppression of gastric cancer cell migration and invasion . Especially, the studies of Song et al. showed that miR-148b was downregulated in gastric cancer , colorectal cancer  and suppressed cell growth by targeting cholecystokinin-2 receptor(CCK2R). These results highlighted that miR-148/152 family might play important roles in gastric cancer progression and would become a potential biomarker.
In a study of cholangiocarcinoma, DNA methyltransferase 1(DNMT1) was verified as a target for miR-148a and miR-152 and the expression level of these miRNAs was decreased in cancer cells . In pancreatic ductal adenocarcinoma, Liffers et al. reported that miR-148a exhibited significant downregulation compared with normal pancreatic ductal cells and further investigation proved that miR-148a regulated cell survival through targeting cell division cycle 25B(CDC25B) . Moreover, in an animal model of oral squamous cell carcinoma, Yu et al. observed that expression of miR-148b was downregulated among 12 miRNAs .
Furthermore, the expression of miR-148/152 family members is low not only in digestive system, but also in genital system tumors. Zhou et al. observed that the expression of miR-152 was decreased in ovarian cancer tissue and ovarian cancer cell lines, but miR-148a expression was decreased only in cancer cell lines . Hiroki et al. noted that reduced miR-152 expression correlated significantly with poor overall survival and disease-free survival in endometrial serous adenocarcinomas . On the other hand, MiR-148a was also downregulated in hormone-refractory prostate cancer cells (PC3 and DU145) and overexpression of miR-148a could inhibite cell growth, cell migration, invasion by targeting Mitogen- and stress-activated kinase 1 (MSK1) . In cancer-associated fibroblasts, Aprelikova et al. showed that miR-148a was downregulated compared with matched normal tissue fibroblasts established from patients with endometrial cancer and wingless-type MMTV integration site family, member 10B (WNT10B) was a direct target of miR-148a . In some nontumor diseases, such as chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), miR-152 was significantly decreased in NK cells of CFS/ME patients compared with nonfatigued controls .
In summary, studies of miR-148/152 family members showed that their expression levels decreased in HCC, LCSC, gastrointestinal cancers, cholangiocarcinoma, pancreatic ductal adenocarcinoma, oral squamous cell carcinoma, ovarian cancer, endometrial serous adenocarcinoma and prostate cancer. MiR-148/152 family members might be tumor-suppressive miRNAs in these tumors.
MiR-148/152 family and methylation
DNA methylation of miR-148/152 family member genes was found in many tumors types. Interaction has been observed between DNA methylation and miR-148/152 family members through one of their target genes: DNMT1. Zhu et al. demonstrated that, in gastric cancer, miR-148a was inactivated by hypermethylation of DNA in the promoter region of its gene; this was mediated through DNMT1 overexpression. Silencing of miR-148a reduces its suppression of DNMT1 in gastric cancer, and this might result in overexpression of DNMT1, promoting DNA hypermethylation . Hanoun et al. found that hypermethylation of the DNA region encoding miR-148a was responsible for its low expression in pancreatic ductal adenocarcinoma samples and in preneoplastic pancreatic intraepithelial neoplasia lesions . Lujambio et al. used a pharmacological approach with a DNA demethylating agent to show that miR-148a, miR-34b/c, and miR-9 underwent specific hypermethylation-associated silencing in cancer cells compared with normal tissues. Most important, they found that DNA methylation-associated silencing of tumor suppressor miRNAs might contribute to the development of human cancer metastasis . Stumpel et al. identified 11 miRNAs, including miR-152, that were downregulated in t(4;11)-positive infant acute lymphoblastic leukemiaas a consequence of CpG hypermethylation. Futher study showed that both myeloid/lymphoid or mixed-lineage leukemia(MLL) and DNMT1 were potential targeted genes of miR-152 and the high degree of methylation of the miR-152 CpG island was strongly correlated with poor clinical outcome . Based on these two studies, we hypothesize that methylation of CpG islands in miR-148/152 family member genes might induce particular biological behaviors of cancer. Pavicic et al. studied inherited, familial carcinoma, including colorectal, gastric and endometrial carcinomas, and found increased DNA methylation of miR-148a and 152 in tumor tissues compared with normal tissues. In particular, hypermethylation at miR-148a and miR-152 genes was associated with microsatellite-unstable tumors. This study highlighted the importance of epigenetic DNA methylation of miRNA genes in hereditary cancers . In another breast cancer study, Xu et al. found that DNMT1 was overexpressed and this overexpression was responsible for hypermethylation of miR-148a and miR-152 promoters. As an miR-148a/152 target, DNMT1 was inversely related to the expression levels of miR-148a/152. This study revealed that a novel miR-148a/152-DNMT1 regulatory circuit might exist in breast cancer .
Therefore, methylation of miR-148/152 family member genes might occur at CpG islands, reducing expression of miR-148/152 family members. Expression of DNMT1, which is an important gene for DNA methylation and is a target gene of miR-148/152 family members, is inversely restricted to the expression level of miR-148a/152. This might result in overexpression of DNMT1, promoting DNA methylation. A novel miR-148a/152-DNMT1 regulatory circuit might exist in tumors.
MiR-148/152 family members and target genes
In different cellular contexts, one miRNA perhaps can regulate diverse pathways and cause various phenotypes depending on the availability of a certain population of mRNA targets . MiR-148/152 family members have many different targets and whether they are important to function depends on their specific target mRNAs [36, 50]. MiRNA targets are predicted mainly by three computational algorithms: TargetScan , PicTar  and miRBase targets . Moreover, microRNA arrays, real-time PCR, luciferase reporter assays and western blots are the main methods for investigating miRNA targets. To validate the targets of miR-148/152 family members, the following two criteria must be met: firstly, the expression of their target gene correlates inversely with miR-148/152 family members. Secondly, they have miR-148/152 family members binding sites with complementary sequences, which can directly bind to miR-148/152 family members. Luciferase reporter assay would be needed. The luciferase constructs with a target 3′UTR are specifically responsive to miR-148/152 family members. Inversely, deletion or mutation of the miR-148/152 family members binding sites from the 3′UTR abolishes the miR-148/152 family members regulation . The targets are summarized in Table 1.
DNMT1, which is a DNA methyltransferase enzyme, mediate the transfer of methyl groups from S-adenosylmethionine to the 5 position of cytosine bases in the dinucleotide sequence CpG . DNMT1 is important in tumorigenesis. Studies have shown that DNMT1 is abnormally expressed in many tumor types [64, 65], and their regulation by miR-148/152 family members has been reported in a number of human diseases including systemic lupus erythematosus , cholangiocarcinoma , hepatocellular carcinoma , acute lymphoblastic leukemia  and endometrial cancer . These might indicate that miR-148/152 and DNMT1 would be a significant pair in the induction and progression of human diseases. Furthermore, an interaction between DNMT1 and miR-148a/152 was found in breast cancer. This study revealed that a novel miR-148a/152-DNMT1 regulatory circuit might exist in breast cancer .
PTEN is a phosphatase that catalyzes the conversion of the lipid second messenger PtdIns(3,4,5)P 3 to phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P 2] . PTEN mutations occur frequently in a variety of human cancers, such as endometrial carcinoma , glioblastoma multiforme , skin  and prostate cancers . PTEN, as a target gene, has been reported to be regulated by a variety of miRNAs, such as miRNA-21 , miRNA-22  and miRNA-26a . In miR-148/152 family members, only miR-148a was reported . Further investigation would be needed.
CCKBR, also called CCK2R, has proliferative effects on various cancer, such as gastric, colorectal, pancreatic and small cell lung cancer through gastrin [74–77]. It is confirmed as a target gene of miR-148b by our research group in recent years [34, 35]. The follow-up studies are proceeding in our group.
Genes such as PXR, CAND1, HLA-C, ACVR1, IGF-IR and IRS1 represent targets of miR-148/152 family members and changes in the expression of these miRNAs are associated with cell motility or(and) cell growth. PXR is a major transcription factor regulating the inducible expression of a variety of transporters and drug-metabolizing enzymes. Takagi et al. revealed that miR-148a could recognize the miR-148a recognition sequence of PXR mRNA by reporter assay. The PXR protein level was decreased by the overexpression of miR-148a, whereas it was increased by inhibition of miR-148a in human liver . Murata et al. determined that miR-148a reduced the expression of CAND1 by binding to the 3′-UTR of CAND1 mRNA and promoted the growth of human prostate cancer . In the study of HLA-C, which associated with HIV, Kulkarni et al. confirmed HLA-C was a target gene of miR-148a. ACVR1, which was correlated with endothelial-to-mesenchymal transition in endothelial cells, was verified a target gene of miR-148a . In breast cancer, Xu et al. revealed that miR-148a and miR-152 acted as tumor suppressors by targeting IGF-IR and IRS1, which mediate key mechanisms of tumor growth and progression . Furthermore, Bcl-2 , p27 , CSF-1  and Rictor  were also demonstrated to be targets of miR-148/152 family members.
Members of the miR-148/152 family including miR-148a, miR-148b and miR-152, have been found to have different roles in various tissues such as tumor, nontumor and normal tissues. Whether upregulated or downregulated in tissues, the miR-148/152 family is involved in regulating target genes, such as genes for proliferation, differentiation and apoptosis. MiR-148/152 family members are regulated by methylation of their CpG islands. A novel miR-148a/152-DNMT1 regulatory circuit might exist. In conclusion, although great progress has been made in recent years, the molecular mechanisms of miR-148/152 family members and their function in different tissues remain unclear and should be investigated in future studies.
Hematopoietic stem cells
Human leukocyte antigen G
Core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1
Liver cancer stem cells
Rho-associated, coiled-coil containing protein kinase 1
DNA methyltransferase 1
Cell division cycle 25B
Antigen identified by monoclonal antibody AJ9
Wingless-type MMTV integration site family, member 10B
Chronic fatigue syndrome/myalgic encephalomyelitis
Myeloid/lymphoid or mixed-lineage leukemia
Pregnane X receptor
Cullin-associated and neddylation-dissociated 1
B-cell CLL/lymphoma 2
Human leukocyte antigen C
Activin A receptor, type 1
Phosphatase and tensin homolog
Cell division cycle 25B
Cholecystokinin B receptor
Insulin-like growth factor-I receptor
Insulin receptor substrate 1
Calcium/calmodulin-dependent protein kinase II alpha
Colony stimulating factor-1
RPTOR independent companion of MTOR, complex 2.
Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, Kim VN: MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 2004, 23: 4051-4060. 10.1038/sj.emboj.7600385
Yi R, Qin Y, Macara IG, Cullen BR: Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 2003, 17: 3011-3016. 10.1101/gad.1158803
Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004, 116: 281-297. 10.1016/S0092-8674(04)00045-5
Ambros V, Lee RC, Lavanway A, Williams PT, Jewell D: MicroRNAs and other tiny endogenous RNAs in C. elegans. Curr Biol. 2003, 13: 807-818. 10.1016/S0960-9822(03)00287-2
Zheng B, Liang L, Wang C, Huang S, Cao X, Zha R, Liu L, Jia D, Tian Q, Wu J, Ye Y, Wang Q, Long Z, Zhou Y, Du C, He X, Shi Y: MicroRNA-148a suppresses tumor cell invasion and metastasis by downregulating ROCK1 in gastric cancer. Clin Cancer Res. 2011, 17: 7574-7583. 10.1158/1078-0432.CCR-11-1714
Wu XJ, Li Y, Liu D, Zhao LD, Bai B, Xue MH: miR-27a as an Oncogenic microRNA of Hepatitis B Virus- related Hepatocellular Carcinoma. Asian Pac J Cancer Prev. 2013, 14: 885-889.
Chen Y, Song Y, Wang Z, Yue Z, Xu H, Xing C, Liu Z: Altered expression of MiR-148a and MiR-152 in gastrointestinal cancers and its clinical significance. J Gastrointest Surg. 2010, 14: 1170-1179. 10.1007/s11605-010-1202-2
Merkerova M, Vasikova A, Belickova M, Bruchova H: MicroRNA expression profiles in umbilical cord blood cell lineages. Stem Cells Dev. 2010, 19: 17-26. 10.1089/scd.2009.0071
Giraud-Triboult K, Rochon-Beaucourt C, Nissan X, Champon B, Aubert S, Pietu G: Combined mRNA and microRNA profiling reveals that miR-148a and miR-20b control human mesenchymal stem cell phenotype via EPAS1. Physiol Genomics. 2011, 43: 77-86. 10.1152/physiolgenomics.00077.2010
Gao J, Yang T, Han J, Yan K, Qiu X, Zhou Y, Fan Q, Ma B: MicroRNA expression during osteogenic differentiation of human multipotent mesenchymal stromal cells from bone marrow. J Cell Biochem. 2011, 112: 1844-1856. 10.1002/jcb.23106
Schoolmeesters A, Eklund T, Leake D, Vermeulen A, Smith Q, Force AS, Fedorov Y: Functional profiling reveals critical role for miRNA in differentiation of human mesenchymal stem cells. PLoS One. 2009, 4: e5605- 10.1371/journal.pone.0005605
Zhang J, Ying ZZ, Tang ZL, Long LQ, Li K: MicroRNA-148a promotes myogenic differentiation by targeting the ROCK1 gene. J Biol Chem. 2012, 287: 21093-21101. 10.1074/jbc.M111.330381
John E, Wienecke-Baldacchino A, Liivrand M, Heinaniemi M, Carlberg C, Sinkkonen L: Dataset integration identifies transcriptional regulation of microRNA genes by PPARgamma in differentiating mouse 3T3-L1 adipocytes. Nucleic Acids Res. 2012, 40: 4446-4460. 10.1093/nar/gks025
Farid WR, Pan Q, der Meer AJ, de Ruiter PE, Ramakrishnaiah V, de Jonge J, Kwekkeboom J, Janssen HL, Metselaar HJ, Tilanus HW, Kazemier G, der Laan LJ: Hepatocyte-derived microRNAs as serum biomarkers of hepatic injury and rejection after liver transplantation. Liver Transpl. 2012, 18: 290-297. 10.1002/lt.22438
Liu X, Zhan Z, Xu L, Ma F, Li D, Guo Z, Li N, Cao X: MicroRNA-148/152 impair innate response and antigen presentation of TLR-triggered dendritic cells by targeting CaMKIIalpha. J Immunol. 2010, 185: 7244-7251. 10.4049/jimmunol.1001573
Manaster I, Goldman-Wohl D, Greenfield C, Nachmani D, Tsukerman P, Hamani Y, Yagel S, Mandelboim O: MiRNA-mediated control of HLA-G expression and function. PLoS One. 2012, 7: e33395- 10.1371/journal.pone.0033395
Palmieri A, Pezzetti F, Brunelli G, Martinelli M, Scapoli L, Arlotti M, Masiero E, Carinci F: Medpor regulates osteoblast’s microRNAs. Biomed Mater Eng. 2008, 18: 91-97.
Wang LL, Zhang Z, Li Q, Yang R, Pei X, Xu Y, Wang J, Zhou SF, Li Y: Ethanol exposure induces differential microRNA and target gene expression and teratogenic effects which can be suppressed by folic acid supplementation. Hum Reprod. 2009, 24: 562-579.
Wu Y, Liu GL, Liu SH, Wang CX, Xu YL, Ying Y, Mao P: MicroRNA-148b enhances the radiosensitivity of non-Hodgkin’s Lymphoma cells by promoting radiation-induced apoptosis. J Radiat Res. 2012, 53: 516-525. 10.1093/jrr/rrs002
Wang Y, Scheiber MN, Neumann C, Calin GA, Zhou D: MicroRNA regulation of ionizing radiation-induced premature senescence. Int J Radiat Oncol Biol Phys. 2011, 81: 839-848. 10.1016/j.ijrobp.2010.09.048
Huang JJ, Yu J, Li JY, Liu YT, Zhong RQ: Circulating microRNA expression is associated with genetic subtype and survival of multiple myeloma. Med Oncol. 2012, 29: 2402-2408. 10.1007/s12032-012-0210-3
Serino G, Sallustio F, Cox SN, Pesce F, Schena FP: Abnormal miR-148b expression promotes aberrant glycosylation of IgA1 in IgA nephropathy. J Am Soc Nephrol. 2012, 23: 814-824. 10.1681/ASN.2011060567
Nielsen LB, Wang C, Sorensen K, Bang-Berthelsen CH, Hansen L, Andersen ML, Hougaard P, Juul A, Zhang CY, Pociot F, Mortensen HB: Circulating levels of microRNA from children with newly diagnosed type 1 diabetes and healthy controls: evidence that miR-25 associates to residual beta-cell function and glycaemic control during disease progression. Exp Diabetes Res. 2012, 2012: 896362-
Bidzhekov K, Gan L, Denecke B, Rostalsky A, Hristov M, Koeppel TA, Zernecke A, Weber C: microRNA expression signatures and parallels between monocyte subsets and atherosclerotic plaque in humans. Thromb Haemost. 2012, 107: 619-625. 10.1160/TH11-09-0607
Brenu EW, Ashton KJ, van DM, Staines DR, Peterson D, Atkinson GM, Marshall-Gradisnik SM: Cytotoxic lymphocyte microRNAs as prospective biomarkers for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. J Affect Disord. 2012, 141: 261-269. 10.1016/j.jad.2012.03.037
Cuk K, Zucknick M, Heil J, Madhavan D, Schott S, Turchinovich A, Arlt D, Rath M, Sohn C, Benner A, Junkermann H, Schneeweiss A, Burwinkel B: Circulating microRNAs in plasma as early detection markers for breast cancer. LID. Int J Cancer. 2012, 10.1002/ijc.27799.
Yuan K, Lian Z, Sun B, Clayton MM, Ng IO, Feitelson MA: Role of miR-148a in hepatitis B associated hepatocellular carcinoma. PLoS One. 2012, 7: e35331- 10.1371/journal.pone.0035331
Gokhale A, Kunder R, Goel A, Sarin R, Moiyadi A, Shenoy A, Mamidipally C, Noronha S, Kannan S, Shirsat NV: Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway. J Cancer Res Ther. 2010, 6: 521-529. 10.4103/0973-1482.77072
Woollard KJ, Geissmann F: Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol. 2010, 7: 77-86. 10.1038/nrcardio.2009.228
Li R, Qian N, Tao K, You N, Wang X, Dou K: MicroRNAs involved in neoplastic transformation of liver cancer stem cells. J Exp Clin Cancer Res. 2010, 29: 169- 10.1186/1756-9966-29-169
Zhao Y, Jia HL, Zhou HJ, Dong QZ, Fu LY, Yan ZW, Sun J, Ren N, Ye QH, Qin LX: [Identification of metastasis-related microRNAs of hepatocellular carcinoma in hepatocellular carcinoma cell lines by quantitative real time PCR]. Zhonghua Gan Zang Bing Za Zhi. 2009, 17: 526-530.
Huang J, Wang Y, Guo Y, Sun S: Down-regulated microRNA-152 induces aberrant DNA methylation in hepatitis B virus-related hepatocellular carcinoma by targeting DNA methyltransferase 1. Hepatology. 2010, 52: 60-70. 10.1002/hep.23660
Magrelli A, Azzalin G, Salvatore M, Viganotti M, Tosto F, Colombo T, Devito R, Di MA, Antoccia A, Lorenzetti S, Maranghi F, Mantovani A, Tanzarella C, Macino G, Taruscio D: Altered microRNA expression patterns in hepatoblastoma patients. Transl Oncol. 2009, 2: 157-163.
Song YX, Yue ZY, Wang ZN, Xu YY, Luo Y, Xu HM, Zhang X, Jiang L, Xing CZ, Zhang Y: MicroRNA-148b is frequently down-regulated in gastric cancer and acts as a tumor suppressor by inhibiting cell proliferation. Mol Cancer. 2011, 10: 1- 10.1186/1476-4598-10-1
Song Y, Xu Y, Wang Z, Chen Y, Yue Z, Gao P, Xing C, Xu H: MicroRNA-148b suppresses cell growth by targeting cholecystokinin-2 receptor in colorectal cancer. Int J Cancer. 2012, 131: 1042-1051. 10.1002/ijc.26485
Braconi C, Huang N, Patel T: MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes. Hepatology. 2010, 51: 881-890.
Liffers ST, Munding JB, Vogt M, Kuhlmann JD, Verdoodt B, Nambiar S, Maghnouj A, Mirmohammadsadegh A, Hahn SA, Tannapfel A: MicroRNA-148a is down-regulated in human pancreatic ductal adenocarcinomas and regulates cell survival by targeting CDC25B. Lab Invest. 2011, 91: 1472-1479. 10.1038/labinvest.2011.99
Yu T, Wang XY, Gong RG, Li A, Yang S, Cao YT, Wen YM, Wang CM, Yi XZ: The expression profile of microRNAs in a model of 7, 12-dimethyl-benz[a]anthrance-induced oral carcinogenesis in Syrian hamster. J Exp Clin Cancer Res. 2009, 28: 64- 10.1186/1756-9966-28-64
Zhou X, Zhao F, Wang ZN, Song YX, Chang H, Chiang Y, Xu HM: Altered expression of miR-152 and miR-148a in ovarian cancer is related to cell proliferation. Oncol Rep. 2012, 27: 447-454.
Hiroki E, Akahira J, Suzuki F, Nagase S, Ito K, Suzuki T, Sasano H, Yaegashi N: Changes in microRNA expression levels correlate with clinicopathological features and prognoses in endometrial serous adenocarcinomas. Cancer Sci. 2010, 101: 241-249. 10.1111/j.1349-7006.2009.01385.x
Fujita Y, Kojima K, Ohhashi R, Hamada N, Nozawa Y, Kitamoto A, Sato A, Kondo S, Kojima T, Deguchi T, Ito M: MiR-148a attenuates paclitaxel resistance of hormone-refractory, drug-resistant prostate cancer PC3 cells by regulating MSK1 expression. J Biol Chem. 2010, 285: 19076-19084. 10.1074/jbc.M109.079525
Aprelikova O, Palla J, Hibler B, Yu X, Greer YE, Yi M, Stephens R, Maxwell GL, Jazaeri A, Risinger JI, Rubin JS, Niederhuber J: Silencing of miR-148a in cancer-associated fibroblasts results in WNT10B-mediated stimulation of tumor cell motility. LID. Oncogene. 2012, 10.1038/onc.2012.351.
Zhu A, Xia J, Zuo J, Jin S, Zhou H, Yao L, Huang H, Han Z: MicroRNA-148a is silenced by hypermethylation and interacts with DNA methyltransferase 1 in gastric cancer. Med Oncol. 2012, 29: 2701-2709. 10.1007/s12032-011-0134-3
Hanoun N, Delpu Y, Suriawinata AA, Bournet B, Bureau C, Selves J, Tsongalis GJ, Dufresne M, Buscail L, Cordelier P, Torrisani J: The silencing of microRNA 148a production by DNA hypermethylation is an early event in pancreatic carcinogenesis. Clin Chem. 2010, 56: 1107-1118. 10.1373/clinchem.2010.144709
Lujambio A, Calin GA, Villanueva A, Ropero S, Sanchez-Cespedes M, Blanco D, Montuenga LM, Rossi S, Nicoloso MS, Faller WJ, Gallagher WM, Eccles SA, Croce CM, Esteller M: A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci USA. 2008, 105: 13556-13561. 10.1073/pnas.0803055105
Stumpel DJ, Schotte D, Lange-Turenhout EA, Schneider P, Seslija L, de Menezes RX, Marquez VE, Pieters R, den Boer ML, Stam RW: Hypermethylation of specific microRNA genes in MLL-rearranged infant acute lymphoblastic leukemia: major matters at a micro scale. Leukemia. 2011, 25: 429-439. 10.1038/leu.2010.282
Pavicic W, Perkio E, Kaur S, Peltomaki P: Altered methylation at microRNA-associated CpG islands in hereditary and sporadic carcinomas: a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA)-based approach. Mol Med. 2011, 17: 726-735.
Xu Q, Jiang Y, Yin Y, Li Q, He J, Jing Y, Qi YT, Xu Q, Li W, Lu B, Peiper SS, Jiang BH, Liu LZ: A regulatory circuit of miR-148a/152 and DNMT1 in modulating cell transformation and tumor angiogenesis through IGF-IR and IRS1. J Mol Cell Biol. 2013, 5: 3-13. 10.1093/jmcb/mjs049
Krichevsky AM, Gabriely G: miR-21: a small multi-faceted RNA. J Cell Mol Med. 2009, 13: 39-53.
Murata T, Takayama K, Katayama S, Urano T, Horie-Inoue K, Ikeda K, Takahashi S, Kawazu C, Hasegawa A, Ouchi Y, Homma Y, Hayashizaki Y, Inoue S: miR-148a is an androgen-responsive microRNA that promotes LNCaP prostate cell growth by repressing its target CAND1 expression. Prostate Cancer Prostatic Dis. 2010, 13: 356-361. 10.1038/pcan.2010.32
Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB: Prediction of mammalian microRNA targets. Cell. 2003, 115: 787-798. 10.1016/S0092-8674(03)01018-3
Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, MacMenamin P, da PI, Gunsalus KC, Stoffel M, Rajewsky N: Combinatorial microRNA target predictions. Nat Genet. 2005, 37: 495-500. 10.1038/ng1536
Griffiths-Jones S, Grocock RJ, van DS, Bateman A, Enright AJ: miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 2006, 34: D140-D144. 10.1093/nar/gkj112
Takagi S, Nakajima M, Mohri T, Yokoi T: Post-transcriptional regulation of human pregnane X receptor by micro-RNA affects the expression of cytochrome P450 3A4. J Biol Chem. 2008, 283: 9674-9680. 10.1074/jbc.M709382200
Pan W, Zhu S, Yuan M, Cui H, Wang L, Luo X, Li J, Zhou H, Tang Y, Shen N: MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1. J Immunol. 2010, 184: 6773-6781. 10.4049/jimmunol.0904060
Zhang H, Li Y, Huang Q, Ren X, Hu H, Sheng H, Lai M: MiR-148a promotes apoptosis by targeting Bcl-2 in colorectal cancer. Cell Death Differ. 2011, 18: 1702-1710. 10.1038/cdd.2011.28
Guo SL, Peng Z, Yang X, Fan KJ, Ye H, Li ZH, Wang Y, Xu XL, Li J, Wang YL, Teng Y, Yang X: miR-148a promoted cell proliferation by targeting p27 in gastric cancer cells. Int J Biol Sci. 2011, 7: 567-574.
Kulkarni S, Savan R, Qi Y, Gao X, Yuki Y, Bass SE, Martin MP, Hunt P, Deeks SG, Telenti A, Pereyra F, Goldstein D, Wolinsky S, Walker B, Young HA, Carrington M: Differential microRNA regulation of HLA-C expression and its association with HIV control. Nature. 2011, 472: 495-498. 10.1038/nature09914
Song H, Wang Q, Wen J, Liu S, Gao X, Cheng J, Zhang D: ACVR1, a Therapeutic Target of Fibrodysplasia Ossificans Progressiva, Is Negatively Regulated by miR-148a. Int J Mol Sci. 2012, 13: 2063-2077. 10.3390/ijms13022063
Zhu XM, Han T, Wang XH, Li YH, Yang HG, Luo YN, Yin GW, Yao YQ: Overexpression of miR-152 leads to reduced expression of human leukocyte antigen-G and increased natural killer cell mediated cytolysis in JEG-3 cells. Am J Obstet Gynecol. 2010, 202: 592-e1-7.
Woo HH, Laszlo CF, Greco S, Chambers SK: Regulation of colony stimulating factor-1 expression and ovarian cancer cell behavior in vitro by miR-128 and miR-152. Mol Cancer. 2012, 11: 58- 10.1186/1476-4598-11-58
Tsuruta T, Kozaki K, Uesugi A, Furuta M, Hirasawa A, Imoto I, Susumu N, Aoki D, Inazawa J: miR-152 is a tumor suppressor microRNA that is silenced by DNA hypermethylation in endometrial cancer. Cancer Res. 2011, 71: 6450-6462. 10.1158/0008-5472.CAN-11-0364
Herman JG, Baylin SB: Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003, 349: 2042-2054. 10.1056/NEJMra023075
Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA: The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res. 1999, 27: 2291-2298. 10.1093/nar/27.11.2291
Tennis MA, Vanscoyk MM, Wilson LA, Kelley N, Winn RA: Methylation of Wnt7a is modulated by DNMT1 and cigarette smoke condensate in non-small cell lung cancer. PLoS One. 2012, 7: e32921- 10.1371/journal.pone.0032921
Maehama T, Dixon JE: The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3, 4, 5-trisphosphate. J Biol Chem. 1998, 273: 13375-13378. 10.1074/jbc.273.22.13375
Risinger JI, Hayes AK, Berchuck A, Barrett JC: PTEN/MMAC1 mutations in endometrial cancers. Cancer Res. 1997, 57: 4736-4738.
Wang SI, Puc J, Li J, Bruce JN, Cairns P, Sidransky D, Parsons R: Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 1997, 57: 4183-4186.
Kubo Y, Urano Y, Hida Y, Arase S: Lack of somatic mutation in the PTEN gene in squamous cell carcinomas of human skin. J Dermatol Sci. 1999, 19: 199-201. 10.1016/S0923-1811(98)00058-9
Cairns P, Okami K, Halachmi S, Halachmi N, Esteller M, Herman JG, Jen J, Isaacs WB, Bova GS, Sidransky D: Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res. 1997, 57: 4997-5000.
Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T: MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007, 133: 647-658. 10.1053/j.gastro.2007.05.022
Bar N, Dikstein R: miR-22 forms a regulatory loop in PTEN/AKT pathway and modulates signaling kinetics. PLoS One. 2010, 5: e10859- 10.1371/journal.pone.0010859
Huse JT, Brennan C, Hambardzumyan D, Wee B, Pena J, Rouhanifard SH, Sohn-Lee C, le SC, Agami R, Tuschl T, Holland EC: The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev. 2009, 23: 1327-1337. 10.1101/gad.1777409
Pagliocca A, Wroblewski LE, Ashcroft FJ, Noble PJ, Dockray GJ, Varro A: Stimulation of the gastrin-cholecystokinin(B) receptor promotes branching morphogenesis in gastric AGS cells. Am J Physiol Gastrointest Liver Physiol. 2002, 283: G292-G299.
Xie B, He SW, Wang XD: Effect of gastrin on protein kinase C and its subtype in human colon cancer cell line SW480. World J Gastroenterol. 2000, 6: 304-306.
Yen TW, Sandgren EP, Liggitt HD, Palmiter RD, Zhou W, Hinds TR, Grippo PJ, McDonald JM, Robinson LM, Bell RH: The gastrin receptor promotes pancreatic growth in transgenic mice. Pancreas. 2002, 24: 121-129. 10.1097/00006676-200203000-00002
Moody TW, Jensen RT: CI-988 inhibits growth of small cell lung cancer cells. J Pharmacol Exp Ther. 2001, 299: 1154-1160.
This work was supported by National Science Foundation of China (No. 81201888 and No. 81172370),the Project of Science and Technology of Shenyang (F12-193-9-08) and the Program of Education Department of Liaoning Province (L2011137).
The authors declare that they have no competing interests.
YC collected and read the related paper and drafted the manuscript. YXS cooperated and helped to draft the manuscript. ZNW participated in the design of the review and helped to draft the manuscript. All authors read and approved the final manuscript.
Yue Chen, Yong-Xi Song contributed equally to this work.
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Chen, Y., Song, YX. & Wang, ZN. The MicroRNA-148/152 Family: Multi-faceted Players. Mol Cancer 12, 43 (2013). https://doi.org/10.1186/1476-4598-12-43
- miR-148/152 family
- Normal tissue