|Year : 2019 | Volume
| Issue : 4 | Page : 175-179
Role of microRNA profiling in oral submucous fibrosis pathogenesis and anticarcinogenic action of curcumin in microRNA dysregulation in oral carcinogenesis: A literature update
Shivesh Acharya1, Shruti Singh1, Sarabjot Kaur Bhatia2
1 Department of Dentistry, All India Institute of Medical Sciences, Raebareli, Uttar Pradesh, Chandigarh, India
2 Oral Health Sciences Centre, PGIMER, Chandigarh, India
|Date of Submission||26-Jun-2019|
|Date of Decision||09-Aug-2019|
|Date of Acceptance||09-Aug-2019|
|Date of Web Publication||1-Oct-2019|
Department of Dentistry, All India Institute of Medical Sciences, Munshiganj, Raebareli-229405, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Oral submucous fibrosis (OSF) is a potentially malignant disorder carrying the highest risk of malignant transformation among the oral premalignant lesions. A wide range of treatment modalities have been proposed for OSF, but none have proved curative or reduced the morbidity significantly. Curcumin, a hydrophobic polyphenol, derived from turmeric with its wide spectrum of biological functions has been widely accepted as a therapeutic drug in OSF. Recent studies have focused on the regulation of anticancer effect of curcumin through the regulation of microRNA (miRNA). miRNAs are small noncoding RNA molecules that play an important role in cellular growth, differentiation, apoptosis, and immune response, functioning either as tumor suppressors or as tumor promoter. The review attempts to summarize the present understanding of molecular dysregulation of miRNA in OSF pathogenesis and lay new insight on the molecular mechanism of anticarcinogenic effect of curcumin on miRNA involved in oral cancer.
Keywords: Areca nut, carcinogenesis, curcumin, microRNA, OSF
|How to cite this article:|
Acharya S, Singh S, Bhatia SK. Role of microRNA profiling in oral submucous fibrosis pathogenesis and anticarcinogenic action of curcumin in microRNA dysregulation in oral carcinogenesis: A literature update. Indian J Dent Sci 2019;11:175-9
|How to cite this URL:|
Acharya S, Singh S, Bhatia SK. Role of microRNA profiling in oral submucous fibrosis pathogenesis and anticarcinogenic action of curcumin in microRNA dysregulation in oral carcinogenesis: A literature update. Indian J Dent Sci [serial online] 2019 [cited 2019 Oct 17];11:175-9. Available from: http://www.ijds.in/text.asp?2019/11/4/175/268422
| Introduction|| |
Oral submucous fibrosis (OSF) is a chronic, progressive, premalignant condition associated with consumption of betel nut, tobacco, pan masala chewing, and smoking. It was introduced in the 1950s predominantly observed in Asian descent. The prevalence of OSF has increased over the past four decades from 0.03% to 6.42% in India. Histological feature of this disease is marked fibrosis that mainly affects the major parts of the oral cavity, pharynx, and upper third of the esophagus. Among the malignant oral lesions, it shows the highest rate of malignant transformation of 7.6% with a follow-up of 17 years.
The role of areca nut has been extensively studied and is considered the basic risk factor in the pathogenesis of OSMF. Current studies on molecular analysis have provided us vital data, unveiling the complex pathways governing the pathogenesis of oral submucous fibrosis (OSF), and studies have been conducted to establish microRNA (miRNA) dysregulation specific to OSF.
miRNAs are a broad class of small, noncoding, endogenous RNAs that play a vital role in regulating gene expression by messenger RNA (mRNA) degradation or translation repression. miRNAs, as one of the largest classes of gene regulators, are abundant in many human cell types and regulate the expression of about 60% of mammalian genes.,
Their discovery has opened a new opportunity in cancer biology. miRNA plays an important role in cellular growth, differentiation, apoptosis, and immune response, and hence, deregulation of miRNA is considered a signature of oral carcinogenesis.
The therapeutic treatment of OSF still remains a paradox, corticosteroids being standard choice in the line of treatment. Multifunctional therapeutic properties of curcumin have been extensively studied. Studies on curcumin's medicinal action on OSF include those done by Hastak et al., Chainani-Wu et al. (2008), Das et al., and Rai et al.
Due to its efficacy and regulation of multiple targets  as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and treatment of various potentially malignant disorders, malignant diseases, and inflammatory illnesses.
Latest studies have reported curcumin-induced dysregulation of miRNAs which may activate or inactivate a set of signaling pathways involved in carcinogenesis.
As there are limited data available on miRNA profile in relation to OSF, this review article focuses on analyzing the miRNA signature of OSF and emphasizes on understanding the curcumin-induced dysregulation of miRNAs involved in oral carcinogenesis which may provide a potential therapeutic target for oral malignant lesions.
| Micrornas|| |
miRNAs are small (19–25 nucleotides long) noncoding, single-stranded RNAs that control gene expression by targeting mRNA transcripts and leading to their translational repression or degradation, according to the level of complementarity with them.,, It can be roughly estimated that ~10%–40% of the mRNA sequences are targeted by miRNAs in human. Various miRNA signatures can accurately distinguish tumor from normal tissue, as well as various cancerous subtypes among them. It is well established that miRNAs can serve as candidate biomarkers for diagnostic and prognostic purposes. miRNA genes are usually intronic and clustered and are transcribed by RNA polymerase II producing a primary miRNAs (pri-miRNAs). PrimiRNAs are cleaved at specific sites in the nucleus forming premiRNAs by the RNase Drosha. These Pre-miRNAs form mature miRNAs in the cytoplasm by Dicer. Mature miRNAs are then activated by binding to the argonaute-2 in the miRNA-induced silencing complex.,
Mature miRNAs are critically involved in the pathogenesis, evolution, and progression of cancers. According to their role on the development of tumor, miRNAs could be classified into two groups: onco-miRNAs and tumor suppressor miRNAs  [Figure 1].
|Figure 1: Representation of microRNA biogenesis and regulation through various enzymes|
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Several miRNAs have been identified to regulate epithelial–mesenchymal transition (EMT). Dysregulated miRNAs play vital roles in tumor biology through regulating expression of target genes and then influencing multiple cancer-related signaling pathways.
| Microrna And Oral Submucous Fibrosis|| |
The important event in the pathogenesis of OSF includes collagen accumulation and malignant transformation which are attributed to arecoline, a major component of areca nut. The accumulation of collagen follows two major pathways: increased production of collagen due to overexpression of cytokines such as transforming growth factor-beta (TGF-β) and decreased degradation of collagen due to increased secretion of tissue inhibitors of matrix metalloproteinases (MMPs) and reduced secretion of MMPs. Recent studies have focused on gene expression profiles (TGF-β2, SMAD-3, MMP-1, MMP-2, and MMP-9) involved in immune response, inflammatory response, and TGF-β-induced EMT. It can be assumed that direct effects on epithelial cells with TGF-β activation can suppress antifibrogenetic cytokines, including bone morphogenetic protein-7 and stimulated fibroblast activity  [Figure 2].
|Figure 2: Transforming growth factor-beta-induced epithelial–mesenchymal transition pathway of OSF pathogenesis|
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Studies correlating the role of miRNA in the initiation and progression of fibrosis in visceral organs , have raised the possibility of miRNA's role in the pathogenesis of OSF. miRNA modulates the expression of multiple genes by posttransitional regulation. It plays a major role in fibrosis by controlling the differentiation of fibrotic cells and regulating the translation of extracellular matrix (ECM) components.
miRNAs regulate both the transcriptional and posttranscriptional regulatory mechanisms of EMT and thus may serve as biomarkers and therapeutic targets for EMT-based pathological conditions, including OSF. EMT marker miR21 was studied for OSF.
Limited studies have been done in miRNA markers in relation to OSF in specific though persistent research is being done in upregulation and downregulation of miRNA in oral squamous cell carcinoma (OSCC). Repressed expression of miRNA-133 in OSF was reported in a study by Singh et al.
TGF is considered to be a major mediator of fibrosis in OSF. It enhances the expression of connective tissue growth factor (CTGF), which in turn enhances the signaling of TGF and multiple profibrotic factors, such as vascular endothelial growth factor, insulin-like growth factor-1, integrins, Wnts, and endothelin-1.,
Studies have shown that at least ten miRNAs play a major role in signal regulation of TGF-β/CTGF. Upregulation of profibrotic miRNA or downregulation of antifibrotic miRNA may lead to fibrosis. According to the current literature, forty miRNAs have been linked to fibrosis in various organs and disease settings. Most of these miRNAs directly induce or protect from fibrosis by targeting TGF canonical and noncanonical pathways, CTGF,, ECM structural proteins, or enzymes involved in ECM remodeling. Another set of miRNAs indirectly regulates fibrogenesis by affecting EMT  or by inducing proliferation and resistance to apoptosis in myofibroblasts. Thus, identifying the miRNA signature of OSF patients will be of diagnostic and therapeutic significance. Liu et al. demonstrated the changes in miRNA signature in normal mucosa before and after treatment with arecoline. The study also showed that the miRNA expression was reversed after treating the OSF tissue with saliva combined with low doses of prednisolone.,
In the most recent review of biomarker done by Maheswari et al. on saliva miRNA in oral premalignant diseases compiling the statistical data of the studies done, the upregulated salivary miRNA-184 and miRNA-21 and downregulated salivary miRNA-145 were concluded to be used as potential biomarkers to predict malignancy.
In the study done by Chattopadhyay et al., deregulation of 7 miRNAs (mir204, mir31, mir133a, mir7, mir206, and mir1293) associated with oral precancerous condition was studied, and as a result, it was concluded that in OSF samples, expression of hsa-miR-31 was upregulated and hsa-miR-204 was downregulated. Expression of hsa-miR-7, and hsa-miR-1293 was significantly upregulated in cancer, leukoplakia, and lichen planus samples and that of hsa-miR-204 was significantly downregulated in OSF samples.
| Mode Of Action Of Curcumin In Relation To Osf Pathogenesis|| |
Oral submucous fibrosis (OSF) as defined by Pindborg et al. “an insidious chronic disease affecting oral mucosa or any part of the oral cavity and occasionally extending into pharynx and esophagus occasionally preceded by and/or associated with vesicle formation, it is always associated with juxtaepithelial inflammatory reaction followed by fibroelastic change in the lamina propria with epithelial atrophy leading to stiffness of oral mucosa causing trismus and inability to eat.
As the definition signifies the progressive events involved in the disease, there are multiple factors involved in its pathogenesis, areca nut chewing being the most significant risk factor.
Numerous biological pathways have been involved which are either downregulated or upregulated in various stages of the disease  [Figure 3].
Curcumin (diferuloylmethane) is a polyphenol compound isolated from ground rhizomes of the plant Curcuma longa L. (Zingiberaceae) found in South Asia. It is naturally occurring yellow pigment of turmeric. Curcumin suppresses acute and chronic inflammation by lowering histamine levels and by possibly increasing the production of natural cortisone by the adrenal glands. Anti-inflammatory action on human vascular cells of curcumin is by attenuating inflammatory response of tumor necrosis factor-α-stimulated human endothelial cells by interfering with nuclear factor-kappa B. It also affects other growth factors such as platelet-derived growth factor and epidermal growth factors (EGFs). Antioxidant property of curcumin is by scavenging superoxide radicals, hydrogen peroxide, and nitric oxide from activated macrophages, reducing iron complex inhibiting lipid peroxidation.
Thereby correlating the action of curcumin to the pathogenesis of OSF which involves multiple pathways, various studies by Agarwal et al., Deepa et al., Yadav et al., and Rai et al. have been conducted to prove the efficacy of curcumin on treatment of OSMF. Zhang et al. studied that curcumin inhibits proliferation, disrupts the cell cycle, induces apoptosis, and decreases the expression levels of type I and III collagen, confirming its potential therapeutic value in OSF patients.
| Curcumin Dysregulation Mechanism of Microrna in Oral Cancer|| |
Curcumin multifactorial actions on various diseases have been well proven and accepted. In recent years, the most important field of interest has been its potential anticancer property.
In adjunct to its conventional mode of action, recent studies have focused on its effect on the regulation of epigenetic changes such as histone modification, inhibition of DNA methyltransferases, and regulation of miRNA expressions. Studies showed that curcumin could regulate the expression of miRNAs in various cancers through which it exerts anticancer effect.,,
In OSCC, EGF was reported to upregulate the expression of miR-31 (an oncogenic miRNA) through the activation of Akt. Curcumin exhibited anticancer potential through attenuating Akt activation which then resulted in the downregulation of miR-31.
Curcumin inhibits cancer cell proliferation and promotes apoptosis through upregulating a set of tumor suppressor miRNAs, which include miR-15a, miR-34a, miR-181b, miR-186, miR-192-5p, and miR-215, or downregulating numerous onco-miRNAs, such as miR-19, miR-21, and miR-208. The dysregulated miRNAs mediate the inhibitory effect of curcumin on cancer cell proliferation by activating or inactivating multiple signaling pathways, including Akt, p53, PTEN, and Bcl-2 pathways. The expression of p53 is associated with cancer aggressiveness. Bcl-2 is a regulator of apoptosis; evidence also show that Bcl-2 could also promote cancer cell migration and invasion. P53 and Bcl-2 are downstream targets of PI3K/AKT pathway which can also be regulated by curcumin by upregulating miR-22.
Curcumin exerts anticancer effects on tumor progression through modulating the expression of tumor suppressor miRNAs and onco-miRNAs in different cancer cells both in vitro and in vivo. There are multiple signaling pathways regulating the transformation and progression of cancers. Curcumin could target numerous signaling pathways through regulating multiple miRNAs, as compared to the monomodal therapy that targets only a single gene in a signaling pathway; hence, its use has been more promising cancer therapy.
Studies have also reported that curcumin increases chemotherapy sensitivity through miRNAs in various cancers though information is not available in case of oral cancers.
Despite its huge array of action in carcinogenesis, its poor solubility and limited bioavailability  restrict its clinical application. Its analogs, such as difluorinated curcumin, 3,5-bis (2-flurobenzylidene) piperidin-4-one, as well as curcumin nanoparticle formulation, have greater bioavailability and are more effective in delivering curcumin into tumors. As most of the researches done in its therapeutic action are in vitro than in vivo, it still has a very long way to be utilized, which has a concrete drug therapy in cancer strategy.
| Conclusion|| |
The review focuses on analyzing the miRNA profiles specific to OSF and also compiles data available on curcumin-mediated inhibition or enhancement of miRNAs specific to oral premalignant conditions and OSCC. In spite of its acceptance has a therapeutic agent in OSF, its role in oral carcinogenesis through miRNA needs further research. Alterations in function and regulation of miRNA have evolved as important factors in cancer pathogenesis. In comparison to mRNA-based studies, miRNA expression analysis is more effective in cancer classification. However, the current need of the hour is to formulate well-designed studies with a larger sample size to ascertain the diagnostic role of miRNAs in OSF and in oral cancer. As curcumin has been studied for its anticancer properties through inhibiting miRNA, its mechanism pertaining to oral cancer needs further detailing.
| Clinical Significance|| |
Creating multiple miRNA profiles using large-scale samples in OSF cases will provide us with a template for monitoring the disease progression and treatment response. Further, understanding the molecular action of curcumin through miRNA can prove a very useful treatment option in oral cancers.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Singh P, Srivastava AN, Sharma R, Mateen S, Shukla B, Singh A, et al.
Circulating microRNA-21 expression as a novel serum biomarker for oral sub-mucous fibrosis and oral squamous cell carcinoma Asian Pac J Cancer Prev 2018;19:1053-7.
Singh P, Srivastava AN, Sharma R, Jain A, Anwar M. Down-regulated MicroRNA-133a in oral squamous cell carcinoma and oral sub-mucous fibrosis: Non-invasive biomarker. Int J Biol Pharm Allied Sci 2018;7:497-506.
Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: Review on aetiology and pathogenesis. Oral Oncol 2006;42:561-8.
Bansal SK, Leekha S, Puri D. Biochemical changes in OSMF. J Adv Med Dent Sci 2013;1:101-5.
Patil S, Raj Thirumal A, Rao R. MicroRNA – A critical regulator in the pathogenesis and malignant transformation of oral submucous fibrosis. World J Dent 2015;6:5-6.
Wollina U, Verma SB, Ali FM, Patil K. Oral submucous fibrosis: An update. Clin Cosmet Investig Dermatol 2015;8:193-204.
Zhou S, Zhang S, Shen H, Chen W, Xu H, Chen X, et al.
Curcumin inhibits cancer progression through regulating expression of microRNAs. Tumour Biol 2017;39:1-11.
Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009;19:92-105.
Maheswari TN, Venugopal A, Sureshbabu NM, Ramani P. Salivary micro RNA as a potential biomarker in oral potentially malignant disorders: A systematic review. Ci Ji Yi Xue Za Zhi 2018;30:55-60.
Hazarey VK, Sakrikar AR, Ganvir SM. Efficacy of curcumin in the treatment for oral submucous fibrosis – A randomized clinical trial. J Oral Maxillofac Pathol 2015;19:145-52.
] [Full text]
Kohli K, Ali J, Ansari MJ, Raheman Z. Curcumin: A natural antiinflammatory agent. Indian J Pharmacol 2005;37:141.
Hastak K, Jakhi SD, More C, John A, Ghaisas SD, Bhide SV. Therapeutic response to turmeric oil and turmeric oleoresin in oral submucous fibrosis patient. Amala Res Bull 1998;18:23-8.
Das DA, Balan A, Sreelatha KT. Comparative study of the efficacy of curcumin and turmeric oil as chemopreventive agents in oral submucous fibrosis: A clinical and histopathological evaluation. J Indian Acad Oral Med Radiol 2010;22:88. [Full text]
Rai B, Kaur J, Jacobs R, Singh J. Possible action mechanism for curcumin in pre-cancerous lesions based on serum and salivary markers of oxidative stress. J Oral Sci 2010;52:251-6.
Ara SA, Mudda J, Lingappa A, Rao P, Zakaullah S. Efficacy of curcumin in oral submucous fibrosis – A randomized controlled clinical trial. Int J Pharm Sci Res 2018;9:5277-86.
Manasa VG, Kannan S. Impact of microRNA dynamics on cancer hallmarks: An oral cancer scenario. Tumour Biol 2017;39. Doi: doi.org/10.1177/1010428317695920.
Kozomara A, Griffiths-Jones S. MiRBase: Integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res 2011;39:D152-7.
Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 2010;11:597-610.
Dalmay T. Mechanism of miRNA-mediated repression of mRNA translation. Essays Biochem 2013;54:29-38.
Zaravinos A, Lambrou GI, Mourmouras N, Katafygiotis P, Papagregoriou G, Giannikou K, et al.
New miRNA profiles accurately distinguish renal cell carcinomas and upper tract urothelial carcinomas from the normal kidney. PLoS One 2014;9:e91646.
Rana TM. Illuminating the silence: Understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 2007;8:23-36.
Zhang B, Wang Q, Pan X. MicroRNAs and their regulatory roles in animals and plants. J Cell Physiol 2007;210:279-89.
Zaravinos A. The regulatory role of microRNAs in EMT and cancer. J Oncol 2015;2015:865816.
Babalola O, Mamalis A, Lev-Tov H, Jagdeo J. The role of microRNAs in skin fibrosis. Arch Dermatol Res 2013;305:763-76.
Vettori S, Gay S, Distler O. Role of microRNAs in fibrosis. Open Rheumatol J 2012;6:130-9.
Mann J, Chu DC, Maxwell A, Oakley F, Zhu NL, Tsukamoto H, et al.
MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 2010;138:705-14, 714.e1-4.
Liu B, Chen J, Jian X. Changes of miRNA after oral submucous fibrosis co-cultured with salvia and low-dose prednisolone. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2014;39:471-6.
Chattopadhyay E, Singh R, Ray A, Roy R, De Sarkar N, Paul RR, et al.
Expression deregulation of mir31 and CXCL12 in two types of oral precancers and cancer: Importance in progression of precancer and cancer. Sci Rep 2016;6:32735.
Kandasamy M, Anisa N, Rahman A, Rajan MA, Prakash A, Lal J. Etiopathogenesis of oral submucous fibrosis-review of literature. J Adv Med Dent Sci Res 2015;3:53.
Alok A, Singh ID, Singh S, Kishore M, Jha PC. Curcumin-pharmacological actions and its role in oral submucous fibrosis: A review. J Clin Diagn Res 2015;9:ZE01-3.
Agarwal N, Singh D, Sinha A, Srivastava S, Prasad RK, Singh G. Evaluation of efficacy of turmeric in management of oral submucous fibrosis. Journal of Indian Academy of Oral Medicine and Radiology 2014;26:260.
Deepa DA, Balan A, Sreelatha KT. Comparative study of the efficacy of curcumin and turmeric oil as chemopreventive agents in oral submucous fibrosis: A clinical and histopathological evaluation. J Indian Acad Oral Med Radiol 2010;22:88-92.
Yadav M, Aravinda K, Saxena VS, Srinivas K, Ratnakar P, Gupta J, et al.
Comparison of curcumin with intralesional steroid injections in oral submucous fibrosis – A randomized, open-label interventional study. J Oral Biol Craniofac Res 2014;4:169-73.
Zhang SS, Gong ZJ, Li WH, Wang X, Ling TY. Antifibrotic effect of curcumin in TGF-β 1-induced myofibroblasts from human oral mucosa. Asian Pac J Cancer Prev 2012;13:289-94.
Saini S, Arora S, Majid S, Shahryari V, Chen Y, Deng G, et al.
Curcumin modulates microRNA-203-mediated regulation of the Src-Akt axis in bladder cancer. Cancer Prev Res (Phila) 2011;4:1698-709.
Sreenivasan S, Thirumalai K, Danda R, Krishnakumar S. Effect of curcumin on miRNA expression in human Y79 retinoblastoma cells. Curr Eye Res 2012;37:421-8.
Deguchi A. Curcumin targets in inflammation and cancer. Endocr Metab Immune Disord Drug Targets 2015;15:88-96.
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