|Year : 2020 | Volume
| Issue : 2 | Page : 47-53
MicroRNA deregulation and cancer and medicinal plants as microRNA regulator
Nathan Shanmugapriya, Sreenivasan Sasidharan
Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800 Gelugor, Pulau Pinang, Malaysia
|Date of Submission||15-Apr-2019|
|Date of Decision||23-May-2019|
|Date of Acceptance||13-Dec-2019|
|Date of Web Publication||15-Jan-2020|
Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800 Gelugor, Pulau Pinang
Source of Support: This research was funded by Bridging Grant from Universiti
Sains Malaysia, Pulau Pinang, Malaysia with grant number 304.
CIPPM.6316068, Conflict of Interest: None
MircroRNAs (miRNAs) are short non-coding RNAs with a length of approximately 20-22 nucleotides, which interact with their target mRNAs at 3’-untranslated region by partial pairing. The miRNA- mRNA interaction leads to induction of mRNA degradation and eventually translational inhibition. Thus, miRNAs play an important role in virtually all cellular processes, especially differentiation, proliferation, migration, and apoptosis. The deregulation of miRNAs may lead to serious diseases including cancer. There is mounting evidence demonstrating the participation of miRNA regulation during carcinogenesis. In this review, we discuss an updated miRNA biogenesis, mechanisms involved in their deregulation, and their role in cancer development. This review also summarizes updated information on potential medicinal plants which regulate miRNA expression as a promising molecular miRNA therapeutic approach for cancers.
Keywords: MiRNA; Biogenesis; Cancer; Medicinal plants
|How to cite this article:|
Shanmugapriya N, Sasidharan S. MicroRNA deregulation and cancer and medicinal plants as microRNA regulator. Asian Pac J Trop Biomed 2020;10:47-53
|How to cite this URL:|
Shanmugapriya N, Sasidharan S. MicroRNA deregulation and cancer and medicinal plants as microRNA regulator. Asian Pac J Trop Biomed [serial online] 2020 [cited 2020 Feb 25];10:47-53. Available from: http://www.apjtb.org/text.asp?2020/10/2/47/275419
| 1. Introduction|| |
Small endogenous RNA molecules can be classified into several types, including transfer RNA (tRNA), ribosomal RNA (rRNA), small nucleolar RNA (snoRNA), small interfering RNA (siRNA) and micro RNA (miRNA). The endogenous small miRNA molecules which are approximately 20-22 nucleotides long are derived from the double stranded RNA precursor molecules. The breakthrough of miRNA was first discovered in Caenorhabditis elegans and the disclosure of small non-coding lin-4 transcript from Caenorhabditis elegans which was 22 nucleotides long found to downregulate LIN-14 protein expression via sequence complementary binding to 3’-untranslated region (UTR) of lin-14 mRNA. Since then, miRNA has attained great attention and led to detailed investigation of miRNA biogenesis and function in the advancement of molecular biology. Contemporarily, 38 589 mature miRNAs from 271 species have been identified,,,,. This arising principal class of regulatory genes have been identified by bioinformatics prediction approaches and validated through several experimental methods. The involvement of miRNA in the negative regulation of gene expression at post transcriptional level and subsequent protein translational repression clearly substantiates the major role of miRNA in diverse biological processes such as cell death, cell proliferation, cell development, cell differentiation[^], stress resistance, haematopoiesis, fat metabolism, and insulin secretion. Hence, the evolution of miRNA has exposed a novel and attractive therapeutic target and diagnostic tool for various diseases including cancer.
| 2. MiRNA biogenesis|| |
In like manner of precursor mRNA synthesis, miRNAs are also generated by RNA polymerase Π by initially producing a lengthy transcript called the primary miRNA (pri-miRNA),. The pri- miRNA transcripts have been evidently validated to possess 5’ cap and poly (A) tail at 3’ end as any other typical mRNA,. Previous studies suggest that the length of pri-miRNA transcript can be approximately 1 000 nucleotide,. Considering the length of pri-miRNA is pretty long with complementary bases within the transcript, it is legitimate to form a partially paired stemloop structure. This structure acts as substrate for RNase III class of enzymes, namely Drosha and DiGeorge Syndrome critical region gene 8 (DGCR8) which eventually recognises the hairpin- loop structure of pri-miRNA and catalyzes it into a short precursor miRNA (pre-miRNA),,. This first cleavage process is initiated by the binding of the microprocessor complex (complex of Drosha and DGCR8) to the open-ended part of the stem-looped miRNA and finally the double-stranded cleavage produces a concise hairpin shaped RNA molecule with a two nucleotide over hang at the 3’ end,. The double stranded stem-loop structure of pre-miRNA has been identified to be approximately 70-100 bp long.
Subsequently, the transportation of pre-miRNA from nucleus to the cytoplasm is mediated by the nuclear export receptor, known as the Exportin 5,. Previous studies demonstrated that the Exportin 5 performs its role as nuclear cargo with the aid of RanGTP in which stable complexes of pre-miRNA•Exportin 5•RanGTP are productively exported to cytoplasm down the RanGTP gradient across the nuclear envelope and pre-miRNA and Exportin 5 are dissociated upon the hydrolysis of RanGTP to RanGDP in cytoplasm. The free Exportin 5 is then returned back to the nucleus to mediate new pre-miRNA exportation.
Instantaneously, the second cleavage in the biogenesis process of miRNA takes place in the cytoplasm by RNase III enzyme called the Dicer,. Dicer incorporates PAZ (Piwi, Argonaute and Zwille) domain that binds to the two nucleotide 3’ overhangs and anchors the pre-miRNA in position while placing the stem loop terminal at the positively charged catalytic domain of the Dicer,. This arrangement enables the Dicer to act as a molecular ruler, thereby assisting the cleavage to occur efficiently at approximately 65 angstrom (Å) from PAZ domain and cleaves off the loop from the pre-miRNA,,. The subsequent shorter double stranded RNA of about 20-25 nucleotides in length, with two nucleotide 3’ overhangs at both terminals is known as miRNA duplex or miRNA/ miRNA*.
miRNA duplex is then loaded into the miRNA-Induced Silencing Complex (miRISC) and releases one of the strands while selectively binds to one strand in order to generate an active complex. The strand which is integrated into the miRISC is termed as the guide strand (miRNA) while the strand which is released and degraded is termed as the passenger strand (miRNA*). The Argonaute protein, being the major component of RISC, acts as the capital for catalytic process. The Argonaute protein comprises two essential domains, namely PAZ and PIWI. The PAZ domain has been demonstrated to bind to the backbone of the guide strand, while the PIWI domain acts as the RNase H which breaks down the passenger strand,,. [Figure 1] shows an overview of the miRNA biogenesis process.
| 3. MiRNA and cancer|| |
Ever since the exploration of miRNA and its correlation with the widespread biological processes mainly including apoptosis and cell proliferation, the fundamental significance of miRNA in tumorigenesis is strongly postulated. Henceforth, the miRNA- mediated molecular mechanism in cancer biology has unfastened a novel dimension for cancer therapeutic targets as well as cancer biomarkers. The miRNA binds to its target mRNA by partial complementary binding, thus silences the gene expression and represses the post translational activity. The means of function of miRNA via alteration of gene expression and consecutive translational expression, points out that miRNAs can act as tumor suppresser genes or oncogenes depending on their target genes,. For instance, up-regulation of specific miRNA targeting the tumor suppressor genes which eventually promotes cell growth and cancer initiation acts as oncogenes. On the other hand, up-regulation of specific miRNA targeting genes responsible for oncogenic activities which ultimately lead to cancer inhibition or repression acts as tumor suppressor genes. However, the increasing investigations on miRNA have uncovered the dual role of miRNA in cancer, in which various evidence supports the concept that a same individual miRNA can act as both oncogene and tumor-suppressor gene depending on the cellular environment,,. Based on the literature, extensive studies have reported the correlation between miRNAs and cancer to date.
3.1. Mechanisms involved in miRNA deregulation in cancer
The dysregulation of miRNAs in cancer occurs through numerous overlapping mechanisms including chromosomal abnormalities, transcriptional control alterations, epigenetic modulation and disruption in the miRNA processing machinery. For instance, chromosomal alterations may occur due to amplification of a chromosome site harbouring a specific miRNA, leading to an overexpression of the particular miRNA, while deletion of the chromosome site may result in down-regulation of the specific miRNA,.
Other than that, various transcriptional factors have been evidently reported to control the expression of miRNAs such as c-Myc,,, p53,, myeloid transcription factors PU.1 and C/EBPs and transcription factors NFI-A and C/EBP α. Besides, miRNAs have also been reported to undergo epigenetic changes through CpG methylation, DNA methylation with histone acetylation inhibitors, and hypermethylation,.
Finally, dysregulation or mutation of any proteins involved in miRNA biogenesis process such as Drosha, DGCR8, Dicer,, Argonaute proteins,, TRBP and Exportin 5 leads to miRNA dysregulation.
3.2. Pathways involved in miRNA regulation in cancer
The current chemotherapy targeting miRNA is attaining great interest due to their important participation in cancer pathway. Numerous miRNAs were also evidently shown to regulate apoptosis pathway induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Based on the research conducted by Yang et al., over-expression of miR-145 was shown to down-regulate ZEB2 expression, which causes an increase in TRAIL-induced apoptosis in LX-2 cells through NF- κ B signaling pathway. The up-regulation of miR-221 and miR-222 was also demonstrated to be over-expressed, leading to the down-regulation of tumor suppressor p27kip in prostate carcinoma and melanoma.
Besides, interactions between miR-203a with ITGA4, miR- 6071 with ITGAV, and miR-375 with THBS2 were reported to be associated with the dysregulation of PI3K/Akt-signaling pathway in colorectal cancer. Recently, miRNA-146b was found to regulate the PI3K/Akt/NF- κ B signaling pathway to mediate vascular inflammation and apoptosis in myocardial infarction by phosphatase and tensin homologue (PTEN). Another example of miRNA which participates in Fas-mediated apoptotic pathway is MicroRNA- 181c which was shown to hinder apoptosis by targeting FAS receptor in Ewing’s sarcoma cells. Another cancer pathway, namely PTEN pathway, was also shown to be regulated by the expression of miRNAs. For instance, many miRNAs are reported to target and suppress the expression of PTEN which is one of the prominent tumor suppressor genes such as miR-17-5p, miR-19305p, miR-2127 and miR-221 and miR-222.
There are various miRNAs which have been reported to regulate the cell cycle regulatory pathway, in which oncogenic miRNAs tend to expedite cell cycle progression while the miRNAs with tumor suppressor effect tend to facilitate cell cycle arrest. Exemplary oncogenic miRNAs include miR-106b and miR-17-92 families which have been reported to be over-expressed in various cancers that are known to target one of the important inducer of G1 arrest, namely p21 from the Cip/Kip family of CDK inhibitors,. Other studies have also experimentally validated other miRNAs to target other genes involved in cell cycle which eventually regulate the RAS/ RAF/MAPK pathway as well as the p53 pathway. Furthermore, miRNAs are also very well known to target numerous genes involved in DNA damage response in cancer cells. For instance, miR-421 was reported to be highly over-expressed in neuroblastoma and B-cell lymphoma cell lines and was shown to target the apical damage sensor Ataxia-Telangiectasia Mutated kinase.
| 4. MiRNAs regulated by medicinal plants in human cancer cells|| |
Medicinal plants rich in bioactive phytochemicals are well utilized to treat various diseases including cancer by regulating diverse signaling pathway. Mechanistic studies revealed that plants exert their biologic effects, especially anti-cancer properties by inducing apoptosis in cancer cells through the regulation of miRNA. Plant- derived chemotherapy has recently attained vast interest as the natural secondary metabolites exert lower toxic side effects compared to that of chemically synthesised anti-cancer drugs. Based on the extensive literature, various medicinal plants have been evidently reported to regulate a diversified range of miRNAs to date.
Various medicinal plants exhibit pharmacological properties by up- regulating specific miRNAs in humans. For instance, the bioactive compound isolated from the root of Astragalus membranaceus (Fisch.) Bunge was reported to exhibit anti-cancer property on human osteosarcoma MG63 cells by inducing apoptosis through the up-regulation of miR-133a. Furthermore, Western blotting analysis revealed that the over-expression of miR-133a induced the down-regulation of proteins such as p-JNK and p-c-Jun, which eventually inactivates the c-Jun N-terminal protein kinase (JNK) pathway. Another well-known medicinal plant, Salvia miltiorrhiza (S. miltiorrhiza) was previously reported to induce caspase-dependent intrinsic apoptosis in multiple myeloma and myeloid leukemia,,. Recent study also revealed the molecular mechanism underlying the induction of apoptosis by S. miltiorrhiza, in which up-regulation of tumor suppressor gene, miR-216b was reported in S. miltiorrhiza treated U266 and U937 cells in comparison with the untreated cells. Interestingly, the target protein of miR-216b, namely c-Jun protein, was shown to be down-regulated in S. miltiorrhiza treated cells.
Saponin-rich tuber extract from Cyclamen pseudibericum was reported to inhibit cell proliferation in A549 non-small cell lung carcinoma cells through the up-regulation of miR-200c. Western blotting analysis showed that the over-expression of miR-200c inhibits its target protein, namely the zinc-finger E-box binding homeobox 1. Similarly, various studies demonstrated the anticancer properties of saponin content from American ginseng (Panax quinquefolios),. Recently, hexane fraction of Panax quinquefolius was demonstrated to exhibit anti-proliferative activity in human colon cancer cell lines by up-regulating the miR-29b expression as compared to that of vehicle control cells, and subsequent Western blotting analysis confirmed the repression of its target protein matrix metalloproteinase-2 protein.
Pterostilbene, one of the bioactive components isolated from the blueberries, was reported to promote anti-cancer activity in breast cancer cells by up-regulating the expression of miR-448, which eventually suppresses the expression of NF κ B. Another such phytochemical, namely sulforaphane which can be found in cruciferous plants, like broccoli sprouts, kale, and carrots, was shown to have anti-cancer property. Sulforaphane exhibits anticancer property in human gastric carcinoma cell lines, MGC803 and BGC823 via up-regulation of miR-124, which directly targets and suppresses the expression of interleukin-6/IL-6 receptor/signal transducer and activator of transcription 3 signalling. Oxymatrine, another bioactive compound which is found in various medicinal plants of the genus Sophora, was reported to inhibit cell proliferation and to induce apoptosis in various cancer types, including gallbladder cancer, breast cancer, melanoma and prostate cancer. Further investigation on the molecular mechanism underlying the pharmacology effect of oxymatrine revealed the up-regulation of miR-29b in oxymatrine-treated ovarian carcinoma OVCAR-3 cells, which led to reduction on the matrix metalloproteinase-2 expression, in order to inhibit proliferation and to induce apoptosis.
Moreover, medicinal plants, along with their isolated phytochemicals, have been evidently reported to exhibit anti-cancer activity via down-regulation of specific miRNAs in human cancer cells. One such medicinal plant is Cnidium officinale Makino, which has been previously reported to exert anti-cancer effect on various cancers, such as liver cancer, colorectal cancer and oral cancer. In recent study, Cnidium officinale showed its anticancerous effect through the down-regulation of miR-211 in multiple myeloma U266 cells and lymphoma U937 cells, which caused the ROS generation/CHOP activation to induce apoptosis.
One of the bioactive compounds, namely icariin, which is mainly found in the traditional Chinese medicinal plant Epimedium, has been well-documented to exhibit various pharmacological activities including anti-cancer,. In ovarian cancer A2780 cells, icariin induced caspase-dependent apoptosis through the down-regulation of miR-21 expression, which was then revealed to increase the expression levels of its target proteins, namely PTEN and RECK, in Western blotting assay. Another bioactive compound responsible for anticancer activity is mistletoe lectin-I (ML-I ) which was isolated from a medicinal plant called the mistletoe (Viscum album). The in vitro and in vivo experiments revealed the anti-cancer effect of ML-1 in colorectal cancer cells, through MTT assay and nude mouse xenograft models, respectively. Further investigation by miRNA expression array indicated the down-regulation of miR-135a&b expressions in ML-I treated colorectal cancer cells as compared to that of control cells. In addition, Western blotting analysis showed up-regulation of target proteins of miR-135a&b, namely adenomatous polyposis coli.
Interestingly, curcumin (diferuloylmethane) which is a flavonoid isolated from the rhizome of Curcuma longa has been reported to show anti-cancer activity in pancreatic cancer cell line through the regulation of miRNAs. The miRNA microarray revealed a significant up-regulation of miR-22 and down-regulation of miR- 199a* in curcumin treated BxPC-3 human pancreatic carcinoma cell line as compared to the untreated cell line. The over-expression of miR-22 was shown to significantly down-regulate the expression levels of SP1 transcription factor and estrogen receptor 1 proteins, corresponding to the prediction of target genes of miR-22 through PicTar and TargetScan bioinformatics tools.
| 5. Conclusion and future prospects|| |
Cancer which is one of the deadly diseases globally demands for more effective, cheap and less toxic therapies. Ever since miRNAs play an important role in regulating important biological processes including cell proliferation and apoptosis, gene therapy targeting miRNAs has been well established. Medicinal plants as the reservoir of various bioactive components responsible for anti-cancer properties through the regulation of miRNAs have been considered as a promising candidate for cancer chemotherapy. In this review, the possible pathways of miRNA regulation in cancer as well as the contribution of medicinal plants to regulating miRNAs are presented. To sum up, plant-derived anti-cancer drugs are highly recommended to treat cancers due to their effective miRNA targeting approach.
Conflict of interest statement
The authors declare that there is no conflict of interests.
Nathan Shanmugapriya was supported by the Graduate Assistant Scheme, Universiti Sains Malaysia, Pulau Pinang, Malaysia.
This research was funded by Bridging Grant from Universiti Sains Malaysia, Pulau Pinang, Malaysia with grant number 304. CIPPM.6316068.
SS conceived the original idea and supervised the project. NS and SS wrote the manuscript.
| References|| |
Svobodova E, Kubikova J, Svoboda P. Production of small RNAs by mammalian Dicer. Pflugers Arch
Lee RC, Feinbaum RL, Ambros V. The C. elegans
heterochronic gene Lin-4
encodes small RNAs with antisense complementarity to Lin-14. Cell
Kozomara A, Griffiths-Jones S. MiRBase: Annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res
Kozomara A, Griffiths-Jones S. MiRBase: Integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res
Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. MiRBase: Tools for microRNA genomics. Nucleic Acids Res
Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ. MiRBase: MicroRNA sequences, targets and gene nomenclature. Nucleic Acids Res
Griffiths-Jones S. The microRNA registry. Nucleic Acids Res
Oliveto S, Mancino M, Manfrini N, Biffo S. Role of microRNAs in translation regulation and cancer. World J Biol Chem
Xu PZ, Guo M, Hay BA. MicroRNAs and the regulation of cell death. Trends Genet
Cheng AM, Byrom MW, Shelton J, Ford LP. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res
Koenecke C, Krueger A. MicroRNA in T-cell development and T-cell mediated acute graft-versus-host disease. Front Immunol
Li N, Long B, Han W, Yuan SM, Wang K. MicroRNAs: Important regulators of stem cells. Stem Cell Res Ther
Sanz-Carbonell A, Marques MC, Bustamante A, Fares MA, Rodrigo G, Gomez G. Inferring the regulatory network of the miRNA-mediated response to biotic and abiotic stress in melon. BMC Plant Biol
Kotaki R, Koyama-Nasu R, Yamakawa N, Kotani A. MiRNAs in normal and malignant hematopoiesis. Int J Mol Sci
Aryal B, Singh AK, Rotllan N, Price N, Fernández-Hernando C. MicroRNAs and lipid metabolism. Curr Opin Lipidol
Zhang MY, Sun WL, Zhou MH, Tang Y. MicroRNA-27a regulates hepatic lipid metabolism and alleviates NAFLD via
repressing FAS and SCD1. Sci Rep
Chen L, Qian HY, Xue JL, Zhang J, Chen H. MicroRNA-152 regulates insulin secretion and pancreatic β cell proliferation by targeting PI3K α. Mol Med Rep
O’Brien J, Hayder H, Zayed Y, Peng C. Overview of MicroRNA biogenesis, mechanisms of actions, and circulation. Front Endocrinol (Lausanne)
Cai XZ, Hagedorn CH, Cullen BR. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA
Lee Y, Kim M, Han JJ, Yeom KH, Lee S, Baek SH, et al. MicroRNA genes are transcribed by RNA polymerase Π . EMBO J
Lee Y, Ahn C, Han JJ, Choi H, Kim J, Yim J, et al. The nuclear RNase Π drosha initiates microRNA processing. Nature
Kooshapur H, Choudhury NR, Simon B, Mühlbauer M, Jussupow A, Fernandez N, et al. Structural basis for terminal loop recognition and stimulation of pri-miRNA-18a processing by hnRNP A1. Nat Commun
Piedade D, Azevedo-Pereira JM. MicroRNAs as important players in host-adenovirus interactions. Front Microbiol
Martinez I, Hayes KE, Barr JA, Harold AD, Xie MY, Bukhari SIA, et al. An Exportin-1-dependent microRNA biogenesis pathway during human cell quiescence. Proc Natl Acad Sci USA
Pong SK, Gullerova M. Noncanonical functions of microRNA pathway enzymes - Drosha, DGCR8, Dicer and Ago proteins. FEBS Lett
Han JJ, Lee Y, Yeom KH, Nam JW, Heo I, Rhee JK, et al. Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell
Masliah G, Maris C, König SL, Yulikov M, Aeschimann F, Malinowska AL, et al. Structural basis of siRNA recognition by TRBP double- stranded RNA binding domains. EMBO J
Yi R, Qin Y, Macara IG, Cullen BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev
Lund E, Güttinger S, Calado A, Dahlberg JE, Kutay U. Nuclear export of microRNA precursors. Science
Bohnsack MT, Czaplinski K, Gorlich D. Exportin 5 is a RanGTP- dependent dsRNA-binding protein that mediates nuclear export of pre- miRNAs. RNA
Grishok A, Pasquinelli AE, Conte D, Li N, Parrish S, Ha I, et al. Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans
developmental timing. Cell
Ketting RF, Fischer SE, Bernstein E, Sijen T, Hannon GJ, Plasterk RH. Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev
MacRae IJ, Zhou KH, Doudna JA. Structural determinants of RNA recognition and cleavage by Dicer. Nat Struct Mol Biol
MacRae IJ, Zhou KH, Li F, Repic A, Brooks AN, Cande WZ, et al. Structural basis for double-stranded RNA processing by Dicer. Science
Park JE, Heo I, Tian Y, Simanshu DK, Chang H, Jee D, et al. Dicer recognizes the 5’ end of RNA for efficient and accurate processing. Nature
Sheng PK, Fields C, Aadland K, Wei TQ, Kolaczkowski O, Gu TJ, et al. Dicer cleaves 5’-extended microRNA precursors originating from RNA polymerase Π transcription start sites. Nucleic Acids Res
Bhandare V, Ramaswamy A. Structural dynamics of human argonaute2 and its interaction with siRNAs designed to target mutant tdp43. Adv Bioinformatics
Ma JB, Ye KQ, Patel DJ. Structural basis for overhang-specific small interfering RNA recognition by the PAZ domain. Nature
Ma JB, Yuan YR, Meister G, Pei Y, Tuschl T, Patel DJ. Structural basis for 5’-end-specific recognition of Guide RNA by the A. fulgidus
Piwi protein. Nature
Song JJ, Smith SK, Hannon GJ, Joshua-Tor L. Crystal structure of argonaute and its implications for RISC slicer activity. Science
Martinez J, Tuschl T. RISC is a 5’ phosphomonoester-producing RNA endonuclease. Genes Dev
Svoronos AA, Engelman DM, Slack FJ. OncomiR or tumor suppressor? the duplicity of MicroRNAs in cancer. Cancer Res
Zhou KC, Liu MX, Cao Y. New insight into microRNA functions in cancer: Oncogene-microRNA-tumor suppressor gene network. Front Mol Biosci
Flores CP, García-Vázquez R, Rincón DG, Ruiz-García E, de la Vega HA, Marchat LA, et al. MicroRNAs driving invasion and metastasis in ovarian cancer: Opportunities for translational medicine (Review). Int J Oncol
Ding L, Lan ZW, Xiong XH, Ao HS, Feng YT, Gu H, et al. The dual role of MicroRNAs in colorectal cancer progression. Int J Mol Sci
Wang B, Li DP, Filkowski J, Rodriguez-Juarez R, Storozynsky Q, Malach M, et al. A dual role of miR-22 modulated by RelA/p65 in resensitizing fulvestrant-resistant breast cancer cells to fulvestrant by targeting FOXP1 and HDAC4 and constitutive acetylation of p53 at Lys382. Oncogenesis
Yang C, Tabatabaei SN, Ruan XY, Hardy P. The dual regulatory role of MiR-181a in breast cancer. Cell Physiol Biochem
Peng Y, Croce CM. The role of MicroRNAs in human cancer. Signal Transduct Target Ther
Wang TZ, Wang GY, Zhang XX, Wu D, Yang L, Wang GY, et al. The expression of miRNAs is associated with tumour genome instability and predicts the outcome of ovarian cancer patients treated with platinum agents. Sci Rep
Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res
Misiewicz-Krzeminska I, Krzeminski P, Corchete L, Quwaider D, Rojas E, Herrero A, et al. Factors regulating microRNA expression and function in multiple myeloma. ncRNA
Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA
Han H, Sun D, Li WJ, Shen HX, Zhu YH, Li C, et al. A c-Myc- MicroRNA functional feedback loop affects hepatocarcinogenesis. Hepatology
Chang TC, Yu DN, Lee YS, Wentzel EA, Arking DE, West KM, et al. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet
Hermeking H. The miR-34 family in cancer and apoptosis. Cell Death Differ
He L, He XY, Lim LP, de Stanchina E, Xuan ZY, Liang Y, et al. A microRNA component of the p53 tumour suppressor network. Nature
Fukao T, Fukuda Y, Kiga K, Sharif J, Hino K, Enomoto Y, et al. An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling. Cell
Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis ML, Nervi C, et al. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Cell
Fazi F, Racanicchi S, Zardo G, Starnes LM, Mancini M, Travaglini L, et al. Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell
Saito Y, Liang GN, Egger G, Friedman JM, Chuang JC, Coetzee GA, et al. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell
Lujambio A, Calin GA, Villanueva A, Ropero S, Sánchez-Céspedes M, Blanco D, et al. A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci USA
Lehmann U, Hasemeier B, Christgen M, Müller M, Römermann D, Länger F, et al. Epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer. J Pathol
Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev
Walz AL, Ooms A, Gadd S, Gerhard DS, Smith MA, Guidry Auvil JM, et al. Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors. Cancer Cell
Iliou MS, da Silva-Diz V, Carmona FJ, Ramalho-Carvalho J, Heyn H, Villanueva A, et al. Impaired DICER1 function promotes stemness and metastasis in colon cancer. Oncogene
Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet
Zhang J, Fan XS, Wang CX, Liu B, Li Q, Zhou XJ. Up-regulation of Ago2 expression in gastric carcinoma. Med Oncol
Völler D, Reinders J, Meister G, Bosserhoff AK. Strong reduction of AGO2 expression in melanoma and cellular consequences. Br J Cancer
Melo SA, Ropero S, Moutinho C, Aaltonen LA, Yamamoto H, Calin GA, et al. A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function. Nat Genet
Melo SA, Moutinho C, Ropero S, Calin GA, Rossi S, Spizzo R, et al. A genetic defect in exportin-5 traps precursor microRNAs in the nucleus of cancer cells. Cancer Cell
Yang JF, Liu QX, Cao SY, Xu T, Li XF, Zhou DD, et al. MicroRNA- 145 increases the apoptosis of activated hepatic stellate cells induced by TRAIL through NF- κ b signaling pathway. Front Pharmacol
Galardi S, Mercatelli N, Giorda E, Massalini S, Frajese GV, Ciafrè SA, et al. MiR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J Biol Chem
Felicetti F, Errico MC, Bottero L, Segnalini P, Stoppacciaro A, Biffoni M, et al. The promyelocytic leukemia zinc finger-microRNA-221/-222 pathway controls melanoma progression through multiple oncogenic mechanisms. Cancer Res
Slattery ML, Mullany LE, Sakoda LC, Wolff RK, Stevens JR, Samowitz WS, et al. The PI3K/AKT signaling pathway: Associations of miRNAs with dysregulated gene expression in colorectal cancer. Mol Carcinog
Zhao L, Yang XR, Han X. MicroRNA-146b induces the PI3K/Akt/NF- κ
B signaling pathway to reduce vascular inflammation and apoptosis in myocardial infarction by targeting PTEN. Exp Ther Med
Kawano M, Tanaka K, Itonaga I, Iwasaki T, Tsumura H. MicroRNA- 181c prevents apoptosis by targeting of FAS receptor in Ewing’s sarcoma cells. Cancer Cell Int
Xiao CC, Srinivasan L, Calado DP, Patterson HC, Zhang BC, Wang J, et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol
Zhang CZ, Han L, Zhang AL, Fu YC, Yue X, Wang GX, et al. MicroRNA-221 and microRNA-222 regulate gastric carcinoma cell proliferation and radioresistance by targeting PTEN. BMC Cancer
Ivanovska I, Ball AS, Diaz RL, Magnus JF, Kibukawa M, Schelter JM, et al. MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression. Mol Cell Biol
Kim YK, Yu J, Han TS, Park SY, Namkoong B, Kim DH, et al. Functional links between clustered microRNAs: Suppression of cell- cycle inhibitors by microRNA clusters in gastric cancer. Nucleic Acids Res
Masliah-Planchon J, Garinet S, Pasmant E. RAS-MAPK pathway epigenetic activation in cancer: MiRNAs in action. Oncotarget
Hu HL, Du LT, Nagabayashi G, Seeger RC, Gatti RA. ATM is down- regulated by N-Myc-regulated microRNA-421. Proc Natl Acad Sci USA
Chu YC, Fang Y, Chi JW, Li J, Zhang DY, Zou YW, et al. Astragalus polysaccharides decrease proliferation, migration, and invasion but increase apoptosis of human osteosarcoma cells by up-regulation of microRNA-133a. Braz J Med Biol Res
(12): e7665. Doi: 10.1590/1414-431X20187665.
Yun SM, Jung JH, Jeong SJ, Sohn EJ, Kim B, Kim SH. Tanshinone IIA induces autophagic cell death via
activation of AMPK and ERK and inhibition of mTOR and p70 S6K in KBM-5 leukemia cells. Phytother Res
Liu P, Xu S, Zhang M, Wang WW, Zhang YF, Rehman K, et al. Anticancer activity in human multiple myeloma U266 cells: Synergy between cryptotanshinone and arsenic trioxide. Metallomics
Liu JJ, Liu WD, Yang HZ, Zhang Y, Fang ZG, Liu PQ, et al. Inactivation of PI3k/Akt signaling pathway and activation of caspase-3 are involved in tanshinone I -induced apoptosis in myeloid leukemia cells in vitro. Ann Hematol
Kim C, Song HS, Park H, Kim B. Activation of ER stress-dependent mir-216b has a critical role in Salvia miltiorrhiza
ethanol-extract-induced apoptosis in U266 and U937 cells. Int J Mol Sci
Karagur ER, Ozay C, Mammadov R, Akca H. Anti-invasive effect of Cyclamen pseudibericum
extract on A549 non-small cell lung carcinoma cells via
inhibition of ZEB1 mediated by miR-200c. J Nat Med
Wang CZ, Aung HH, Ni M, Wu J, Tong R, Wicks S, et al. Red American ginseng: Ginsenoside constituents and antiproliferative activities of heatprocessed Panax quinquefolius
roots. Planta Med
Liu WK, Xu SX, Che CT. Anti-proliferative effect of ginseng saponins on human prostate cancer cell line. Life Sci
Poudyal D, Cui XL, Le PM, Hofseth AB, Windust A, Nagarkatti M, et al. A key role of microRNA-29b for the suppression of colon cancer cell migration by American ginseng. PLoS One
(10): e75034. Doi: 10.1371/journal.pone.0075034.
Mak KK, Wu AT, Lee WH, Chang TC, Chiou JF, Wang LS, et al. Pterostilbene, a bioactive component of blueberries, suppresses the generation of breast cancer stem cells within tumor microenvironment and metastasis via
modulating NF- κ B/microRNA 448 circuit. Mol Nutr Food Res
Zhang YS, Tang L. Discovery and development of sulforaphane as a cancer chemopreventive phytochemical. Acta Pharmacol Sin
Wang XX, Li Y, Dai Y, Liu QQ, Ning SL, Liu J, et al. Sulforaphane improves chemotherapy efficacy by targeting cancer stem cell-like properties via
the miR-124/IL-6R/STAT3 axis. Sci Rep
Wu XS, Yang T, Gu J, Li ML, Wu WG, Weng H, et al. Effects of oxymatrine on the apoptosis and proliferation of gallbladder cancer cells. Anticancer Drugs
Wu J, Cai Y, Li M, Zhang Y, Li H, Tan Z. Oxymatrine promotes S-Phase arrest and cell proliferation of human breast cancer cells in vitro
through mitochondria-mediated apoptosis. Biol Pharm Bull
Zhang YF, Liu HH, Jin JY, Zhu XH, Lu LX, Jiang H. The role of endogenous reactive oxygen species in oxymatrine-induced caspase-3- dependent apoptosis in human melanoma A375 cells. Anticancer Drugs
Wu CZ, Huang WP, Guo Y, Xia P, Sun XB, Pan XD, et al. Oxymatrine inhibits the proliferation of prostate cancer cells in vitro
and in vivo. Mol Med Rep
Li JW, Jiang KL, Zhao FJ. Oxymatrine suppresses proliferation and facilitates apoptosis of human ovarian cancer cells through upregulating microRNA-29b and downregulating matrix metalloproteinase-2 expression. Mol Med Rep
Hong H, An JC, de La Cruz JF, Hwang SG. Cnidium officinale
Makino extract induces apoptosis through activation of caspase-3 and p53 in human liver cancer HepG2 cells. Exp Ther Med
de la Cruz J, Kim DH, Hwang SG. Anti cancer effects of Cnidium officinale
Makino extract mediated through apoptosis and cell cycle arrest in the HT-29 human colorectal cancer cell line. Asian Pac J Cancer Prev
Lee KE, Shin JA, Hong IS, Cho NP, Cho SD. Effect of methanol extracts of Cnidium officinale
Makino and Capsella bursa-pastoris
on the apoptosis of HSC-2 human oral cancer cells. Exp Ther Med
Cha J, Song HS, Kang B, Park M, Park K, Kim SH, et al. Mir-211 plays a critical role in Cnidium officinale
Makino extract-induced, ROS/ER stress-mediated apoptosis in U937 and U266 cells. Int J Mol Sci
Yang LJ, Wang YX, Guo H, Guo ML. Synergistic anti-cancer effects of icariin and temozolomide in glioblastoma. Cell Biochem Biophys
Zhou JM, Wu JF, Chen XH, Fortenbery N, Eksioglu E, Kodumudi KN, et al. Icariin and its derivative, ICT, exert anti-inflammatory, anti-tumor effects, and modulate myeloid derived suppressive cells (MDSCs) functions. Int Immunopharmacol
Wang Q, Hao J, Pu J, Zhao LN, Lü ZL, Hu JG, et al. Icariin induces apoptosis in mouse MLTC-10 Leydig tumor cells through activation of the mitochondrial pathway and down-regulation of the expression of piwil4. Int J Oncol
Li JW, Jiang KL, Zhao FJ. Icariin regulates the proliferation and apoptosis of human ovarian cancer cells through microRNA-21 by targeting PTEN, RECK and Bcl-2. Oncol Rep
Hajto T, Hostanska K, Gabius HJ. Modulatory potency of the beta- galactoside-specific lectin from mistletoe extract (Iscador) on the host defense system in vivo
in rabbits and patients. Cancer Res
Li LN, Zhang HD, Zhi R, Yuan SJ. Down-regulation of some miRNAs by degrading their precursors contributes to anti-cancer effect of mistletoe lectin- I . Br J Pharmacol
Sun M, Estrov Z, Ji Y, Coombes KR, Harris DH, Kurzrock R. Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells. Mol Cancer Ther