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Non-Coding RNAs as Molecular Targets of Resveratrol Underlying Its Anticancer Effects Man Wang, Shuai Jiang, Fei Yu, Li Zhou, and Kun Wang J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.9b01667 • Publication Date (Web): 16 Apr 2019 Downloaded from http://pubs.acs.org on April 16, 2019
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Journal of Agricultural and Food Chemistry
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Non-Coding
RNAs
as
Molecular
Targets
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Resveratrol Underlying Its Anticancer Effects
of
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Man Wang1*, Shuai Jiang2, Fei Yu1, Li Zhou3, Kun Wang1*
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1
7
Dengzhou Road 38, Qingdao 266021, China
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2
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Academy of Sciences, Qingdao 266071, China
Institute for Translational Medicine, Medical College of Qingdao University,
Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese
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3
11
University School of Medicine, Wuhan 430071, China
Animal Biosafety Level III Laboratory at the Center for Animal Experiment, Wuhan
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* Corresponding authors: Man Wang, Kun Wang
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Mailing address: Institute for Translational Medicine, Medical College of Qingdao
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University, Dengzhou Road 38, Qingdao 266021, China
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Tel.: +86-532-82991791
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E-mail:
[email protected] (M.W.);
[email protected] (K.W.)
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Abstract
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Cancer is a significant disease burden worldwide. Chemotherapy is the mainstay
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of cancer treatment. Clinically used chemotherapeutic agents may elicit severe
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side-effects. Remarkably, most of cancer cells develop chemoresistance after a period
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of treatment. Therefore, it is imperative to seek more effective agents without
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side-effects. In recent years, increasing research efforts have attempted to identify
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natural agents that may be used alone or in combination with traditional therapeutics
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for cancer management. Resveratrol is a natural polyphenolic phytoalexin that can be
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found in various foods including blueberries, peanuts and red wine. As a natural food
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ingredient, resveratrol possesses antioxidant, anti-inflammatory and cardioprotective
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properties. Moreover, resveratrol exhibited promising effects in suppressing the
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initiation and progression of cancers. Non-coding RNAs (ncRNAs) have been
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universally accepted as vital regulators in cancer pathogenesis. The modulation of
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miRNAs and lncRNAs by resveratrol has been described. Thus, the mechanism
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involving the domination of ncRNA function is one of the keys to understand the
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anticancer effects of resveratrol. In this review, we focus on the antagonistic effects of
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resveratrol on cancer progression through regulation of miRNAs and lncRNAs. We
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also discuss the potential application of resveratrol in cancer management.
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Keywords:
Resveratrol;
cancer;
miRNA;
lncRNA;
anticancer
effect
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Introduction
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Cancers are a large family of diseases that are characterized by uncontrolled cell
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growth with tremendous potential to invade other parts of the body 1. There were
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approximately 1,600,000 new cancer diagnoses and over 600,000 cancer-related
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deaths in 2017 throughout the world 2. Therefore, cancer has become a predominant
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public health problem worldwide that dramatically undermines human life span and
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quality 3. Surgery, radiotherapy and chemotherapy are commonly used therapeutic
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approaches for cancer treatment 4. Chemotherapy is the most frequently used regimen
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for inhibiting cancer cell growth and metastasis. However, tumor chemoresistance is a
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challenging issue that dramatically affects the efficiency of anticancer agents. It is
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urgent to discover novel, effective therapeutic agents for improved cancer therapy.
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In the past decade, more and more natural products have been found to possess 5-7.
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anticancer activity
Resveratrol (chemically: 3,5,4’-trihydroxystilbene) is one such
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agent that has been a focus of intensive study. Resveratrol, a natural polyphenolic
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phytoalexin, is found in many foods, including grapes, blueberries, peanuts and red
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wine 8-11. However, the amounts of resveratrol are very low in grapes (0.16-3.54 μg/g),
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blueberries (dry sample, ~4 μg/g) and peanuts (0.02-1.79 μg/g) 12. The concentrations
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of this compound vary from 0.1 to 14.3 mg/L in commercially available red wines 13.
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The stilbene-based structure of resveratrol consists of two phenolic rings connected by
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a styrene double bond to generate 3,5,4’-trihydroxystilbene, which occurs in both the
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cis- and trans-isoforms 14. The trans-isoform is the major isoform and also represents
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the most extensively studied chemical form. Multiple studies have documented its
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antioxidant and anti-inflammatory properties
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attention owing to its anticancer property 18-19. Resveratrol plays multifaceted roles in
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the biological behaviors of cancer cells including proliferation, apoptosis,
15-17.
Resveratrol has gained increasing
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epithelial-mesenchymal transition (EMT), invasion and metastasis
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resveratrol may represent a promising anticancer agent.
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20.
Therefore,
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Recent systematic molecular profiling in various types of cancers has disclosed
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the dysregulation of both protein-coding genes and non-coding RNAs (ncRNAs) 21-23.
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According to their length, ncRNAs can be classified into small ncRNAs (sncRNAs)
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and long ncRNAs (lncRNAs)
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members of ncRNAs, and they function as critical gene regulators
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miRNAs and lncRNAs have been identified as oncogenic drivers and tumor
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suppressors in multiple types of cancers
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represent a promising field for novel anti-cancer therapies. The complicated
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relationship between miRNAs/lncRNAs and cancer pathogenesis has attracted
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considerable attention. Resveratrol can regulate the expression of miRNAs and
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lncRNAs
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anti-carcinogenic property. At present, our understanding of the effects of resveratrol
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on cancer-associated miRNAs/lncRNAs is still in its infancy. Many reviews have
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summarized different aspects related to the anticancer mechanisms of resveratrol 1-2, 27.
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Most of these reviews focus on cellular signaling pathways and critical genes/proteins
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that account for the anticancer effects of resveratrol. The functional role of lncRNAs
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in resveratrol-mediated inhibition of cancer progression has yet to be elaborately
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discussed. In this review, we highlight the impact of resveratrol on the expression of
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miRNAs and lncRNAs involved in cancer progression, and also discuss its potential
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application for clinical cancer therapy.
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Bioavailability, Absorption and Pharmacokinetics of Resveratrol
19.
24.
miRNAs and lncRNAs are the most significant
26.
25.
Notably,
Therefore, miRNAs and lncRNAs
The targeting of ncRNAs by resveratrol contributes to its
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Although a large number of in vitro studies verified the beneficial effects of
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resveratrol, however, the in vivo effects of resveratrol have not been validated 28. This
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may be due to the low bioavailability of resveratrol, which is regarded as a major
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obstacle in translating its effects in clinical cancer management. Comprehensive
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characterization of the bioavailability and pharmacokinetics of resveratrol would be
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fundamental to employ this compound in the clinical setting. The chemical structure
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of resveratrol results in its low water solubility (
