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Molecular Mechanisms of Cancer Chemoprevention
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Molecular Mechanisms of Cancer Chemoprevention

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 16276

Special Issue Editors

Dr. Michihiro Mutoh

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Guest Editor
1. Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
2. Epidemiology and Prevention Division, Center for Public Health Sciences, National Cancer Center, Tokyo 104-0045, Japan
Interests: cancer prevention; animal models; translational research
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Masahito Shimizu

E-Mail Website
Guest Editor
First Department of Internal Medicine, Gifu University Hospital, Gifu 501-1194, Japan
Interests: liver carcinogenesis; cancer chemoprevention; chronic hepatitis; metabolic syndrome; retinoid; phytochemicals; clinical trial
Special Issues, Collections and Topics in MDPI journals
Dr. Takuji Tanaka

E-Mail Website
Guest Editor
Department of Diagnostic Pathology and Research Center of Diagnostic Pathology, Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu 500-8513, Japan
Interests: colorectal carcinogenesis; cancer chemoprevention; inflammatory bowel disease; ulcerative colitis; Crohn’s disease; animal model
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

On the basis of the data that are now available in the GLOBOCAN series of IARC, there were 18.10 million new cases of cancer and 9.60 million cancer deaths in 2018. The number of people suffering from cancer is increasing year by year, and many types of cancer, such as pancreatic cancer, are still intractable. Thus, it is desperately desired to establish new cancer prevention methods and further develop cancer treatment methods. Given that the number of cancer survivors has also increased dramatically, the number of people at high risk for cancer that are a target for cancer prevention is assumed to increase in the future. However, dissemination and implementation of cancer prevention knowledge is not enough. One of the reasons is that the study of cancer prevention is still insufficient. Therefore, it is necessary to classify cancer preventive medicines from the viewpoint of their molecular mechanisms and to confirm their validity with evidence obtained from clinical and epidemiological studies. As shown for the development of cancer-targeting drugs, it is possible to specifically select molecules that can be effective targets for cancer prevention, sufficiently analyze the related molecular mechanisms, and establish a cancer prevention method.

Taking into consideration the various biological processes that can eliminate cancer cells, several systems can be examined to develop cancer prevention strategies, such as activation of DNA repair genes in mutated cells, induction of apoptosis in uncontrolled cells, and elimination of cancer cells by activation of the immune system. Moreover, elimination of cancer cells from a normal cell society by cell competition can also be considered.  In these processes, it is thought that many molecules interact to maintain homeostasis. Also, many molecules have already been identified as potential target molecules of cancer chemoprevention; they include adiponectin, angiotensin II receptor, carbonic anhydrase, cyclooxygenase, HMG-CoA reductase, inducible nitric oxide synthetase, NADPH oxidase, lipoprotein lipase, plasminogen activator-1.

As mentioned above, this Special Issue entitled “Molecular Mechanisms in Cancer Prevention” will cover many of the biochemical, molecular, immunological, and cellular mechanisms implicated in the development of cancer. Recent studies have shown that the biological background of diabetes and the biological background of cancer are similar. We welcome submissions both from specialists of diseases that increase the risk of cancer developement and from cancer specialists.

Dr. Michihiro Mutoh
Prof. Dr. Masahito Shimizu
Prof. Takuji Tanaka
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • chemoprevention
  • cancer
  • molecular targets
  • mechanism
  • cancer high-risk groups

Published Papers (5 papers)

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Research

13 pages, 2330 KiB  
Article
The Radical Scavenger NZ-419 Suppresses Intestinal Polyp Development in Apc-Mutant Mice
by Yurie Kurokawa, Gen Fujii, Susumu Tomono, Shingo Miyamoto, Takahiro Hamoya, Maiko Takahashi, Takumi Narita, Masami Komiya, Masaki Kobayashi, Yoshikazu Higami and Michihiro Mutoh
J. Clin. Med. 2020, 9(1), 270; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9010270 - 18 Jan 2020
Cited by 1 | Viewed by 2640
Abstract
Colorectal cancer is the fourth leading cause of cancer death worldwide, and it is important to establish effective methods for preventing colorectal cancer. One effective prevention strategy could be the use of antioxidants. However, the role of the direct antioxidative function of antioxidants [...] Read more.
Colorectal cancer is the fourth leading cause of cancer death worldwide, and it is important to establish effective methods for preventing colorectal cancer. One effective prevention strategy could be the use of antioxidants. However, the role of the direct antioxidative function of antioxidants against carcinogenesis has not been clarified. Thus, we aimed to determine whether the direct removal of reactive oxygen species by a hydroxyl radical scavenger, NZ-419, could inhibit colorectal carcinogenesis. NZ-419 is a creatinine metabolite that has been shown to be safe and to inhibit the progression of chronic kidney disease in rats, and it is now under clinical development. In the present study, we demonstrated that NZ-419 eliminated reactive oxygen species production in HCT116 cells after H2O2 stimulation and suppressed H2O2-induced Nrf2 promoter transcriptional activity. The administration of 500 ppm NZ-419 to Apc-mutant Min mice for 8 weeks resulted in a decrease in the number of polyps in the middle segment of the small intestine to 62.4% of the value in the untreated control (p < 0.05 vs. control group). As expected, NZ-419 treatment affected the levels of reactive carbonyl species, which are oxidative stress markers in the serum of Min mice. Suppression of the mRNA levels of the proliferation-associated factor c-Myc was observed in intestinal polyps of Min mice after NZ-419 treatment, with a weak suppression of epithelial cell proliferation assessed by proliferation cell nuclear antigen (PCNA) staining in the intestinal polyps. This study demonstrated that NZ-419 suppress the development of intestinal polyps in Min mice, suggesting the utility of radical scavenger/antioxidants as a cancer chemopreventive agent. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Chemoprevention)
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15 pages, 4186 KiB  
Article
Dietary Fucoxanthin Induces Anoikis in Colorectal Adenocarcinoma by Suppressing Integrin Signaling in a Murine Colorectal Cancer Model
by Masaru Terasaki, Mimori Ikuta, Hiroyuki Kojima, Takuji Tanaka, Hayato Maeda, Kazuo Miyashita and Michihiro Mutoh
J. Clin. Med. 2020, 9(1), 90; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9010090 - 29 Dec 2019
Cited by 35 | Viewed by 3464
Abstract
Fucoxanthin (Fx), abundantly contained in edible brown algae, is a carotenoid with strong anti-cancer potential. Anoikis is an anchor-dependent apoptosis particularly related to integrin signaling, and a target for cancer preventive strategies. We recently demonstrated that Fx prevented colon cancer in azoxymethane-dextrane sodium [...] Read more.
Fucoxanthin (Fx), abundantly contained in edible brown algae, is a carotenoid with strong anti-cancer potential. Anoikis is an anchor-dependent apoptosis particularly related to integrin signaling, and a target for cancer preventive strategies. We recently demonstrated that Fx prevented colon cancer in azoxymethane-dextrane sodium sulfate (AOM/DSS) carcinogenic model mice, and that it increased anoikis-like integrin β1low/-/cleaved caspase-3high cells in colonic mucosal crypts. However, an induction mechanism of anoikis by Fx in adenocarcinoma tissue remains unresolved. Thus, we investigated anoikis in colonic adenocarcinoma in AOM/DSS mice. Fx administration (30 mg/kg body weight) significantly suppressed the incidence and multiplicity of colonic adenocarcinoma in AOM/DSS mice. A number of anoikis-like integrin β1low/-/cleaved caspase-3high cells in colonic adenocarcinoma and mucosal crypts were significantly increased, 8.3- and 3.5-fold in the Fx group compared with those of the control group, respectively. The results indicated the increase of anoikis-like cells occurred more strongly in colonic adenocarcinoma than in colonic mucosal crypts. In addition, integrin β1 expression, and pFAK (Tyr397) and pPaxillin (Tyr31) activation in mucosal tissue decreased 0.7-, 0.5- and 0.6-fold by Fx administration, respectively. The results suggest that Fx induces anoikis in colonic adenocarcinoma developed by AOM/DSS treatment through attenuation of integrin signaling. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Chemoprevention)
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24 pages, 3677 KiB  
Article
Molecular Insights into miRNA-Driven Resistance to 5-Fluorouracil and Oxaliplatin Chemotherapy: miR-23b Modulates the Epithelial–Mesenchymal Transition of Colorectal Cancer Cells
by Stasė Gasiulė, Nadezda Dreize, Algirdas Kaupinis, Raimundas Ražanskas, Laurynas Čiupas, Vaidotas Stankevičius, Žana Kapustina, Arvydas Laurinavičius, Mindaugas Valius and Giedrius Vilkaitis
J. Clin. Med. 2019, 8(12), 2115; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8122115 - 02 Dec 2019
Cited by 24 | Viewed by 4223
Abstract
Although treatment of colorectal cancer with 5-florouracil and oxaliplatin is widely used, it is frequently followed by a relapse. Therefore, there is an urgent need for profound understanding of chemotherapy resistance mechanisms as well as the profiling of predictive markers for individualized treatment. [...] Read more.
Although treatment of colorectal cancer with 5-florouracil and oxaliplatin is widely used, it is frequently followed by a relapse. Therefore, there is an urgent need for profound understanding of chemotherapy resistance mechanisms as well as the profiling of predictive markers for individualized treatment. In this study, we identified the changes in 14 miRNAs in 5-fluouracil and 40 miRNAs in oxaliplatin-resistant cell lines by miRNA sequencing. The decrease in miR-224-5p expression in the 5-fluorouracil-resistant cells correlated with drug insensitivity due to its overexpression-induced drug-dependent apoptosis. On the other hand, the miR-23b/27b/24-1 cluster was overexpressed in oxaliplatin-resistant cells. The knockout of miR-23b led to the partial restoration of oxaliplatin susceptibility, showing the essential role of miR-23b in the development of drug resistance by this cluster. Proteomic analysis identified target genes of miR-23b and showed that endothelial–mesenchymal transition (EMT) was implicated in oxaliplatin insensibility. Data revealed that EMT markers, such as vimentin and SNAI2, were expressed moderately higher in the oxaliplatin-resistant cells and their expression increased further in the less drug-resistant cells, which had miR-23b knockout. This establishes that the balance of EMT contributes to the drug resistance, showing the importance of the miR-23b-mediated fine-tuning of EMT in oxaliplatin-resistant cancer cells. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Chemoprevention)
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15 pages, 873 KiB  
Article
Genetic Variants of lncRNA MALAT1 Exert Diverse Impacts on the Risk and Clinicopathologic Characteristics of Patients with Hepatocellular Carcinoma
by Lan-Ting Yuan, Jer-Hwa Chang, Hsiang-Lin Lee, Yi-Chieh Yang, Shih-Chi Su, Chien-Liang Lin, Shun-Fa Yang and Ming-Hsien Chien
J. Clin. Med. 2019, 8(9), 1406; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8091406 - 06 Sep 2019
Cited by 23 | Viewed by 2541
Abstract
The long noncoding (lnc)RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), plays a crucial role in the development of hepatocellular carcinoma (HCC). However, potential genetic variants (single nucleotide polymorphisms, SNPs) in MALAT1 that affect the susceptibility and progression of HCC have rarely [...] Read more.
The long noncoding (lnc)RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), plays a crucial role in the development of hepatocellular carcinoma (HCC). However, potential genetic variants (single nucleotide polymorphisms, SNPs) in MALAT1 that affect the susceptibility and progression of HCC have rarely been explored. Three tagging SNPs, viz., rs3200401 C > T, rs619586 A > G, and rs1194338 C > A, in MALAT1 were genotyped by a TaqMan allelic discrimination assay in 394 HCC patients and 1199 healthy controls. A stratified analysis showed that younger patients (<55 years) with the MALAT1 rs619586 G allele had a decreased risk of HCC under a codominant model (AOR = 0.289, 95% CI: 0.108–0.773, p = 0.013) and dominant model (AOR = 0.286, 95% CI: 0.107–0.765, p = 0.013). Female patients and patients with a smoking habit who carried the CA + AA genotype of rs1194338 had a lower risk of developing vascular invasion (p = 0.049) and a high Child–Pugh grade (B or C) (p = 0.036), respectively. Under the dominant model, smokers with the MALAT1 rs3200401 CT + TT genotype had a higher frequency of hepatitis B virus (HBV) infection (p = 0.034). Moreover, the aspartate aminotransferase was higher in patients with the rs3200401 CT + TT genotype. Furthermore, analyses of clinical datasets revealed that MALAT1 expression level was gradually unregulated during HCC development from normal liver, cirrhotic liver, dysplastic liver to HCC and correlated with poor survival rates in HCC patients, especially in the hepatitis virus-infected population. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Chemoprevention)
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16 pages, 533 KiB  
Article
Non-CYP2D6 Variants Selected by a GWAS Improve the Prediction of Impaired Tamoxifen Metabolism in Patients with Breast Cancer
by Ewa E. Hennig, Magdalena Piątkowska, Krzysztof Goryca, Ewelina Pośpiech, Agnieszka Paziewska, Jakub Karczmarski, Anna Kluska, Elżbieta Brewczyńska and Jerzy Ostrowski
J. Clin. Med. 2019, 8(8), 1087; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8081087 - 24 Jul 2019
Cited by 6 | Viewed by 2747
Abstract
A certain minimum plasma concentration of (Z)-endoxifen is presumably required for breast cancer patients to benefit from tamoxifen therapy. In this study, we searched for DNA variants that could aid in the prediction of risk for insufficient (Z)-endoxifen exposure. [...] Read more.
A certain minimum plasma concentration of (Z)-endoxifen is presumably required for breast cancer patients to benefit from tamoxifen therapy. In this study, we searched for DNA variants that could aid in the prediction of risk for insufficient (Z)-endoxifen exposure. A metabolic ratio (MR) corresponding to the (Z)-endoxifen efficacy threshold level was adopted as a cutoff value for a genome-wide association study comprised of 287 breast cancer patients. Multivariate regression was used to preselect variables exhibiting an independent impact on the MR and develop models to predict below-threshold MR values. In total, 15 single-nucleotide polymorphisms (SNPs) were significantly associated with below-threshold MR values. The strongest association was with rs8138080 (WBP2NL). Two alternative models for MR prediction were developed. The predictive accuracy of Model 1, including rs7245, rs6950784, rs1320308, and the CYP2D6 genotype, was considerably higher than that of the CYP2D6 genotype alone (AUC 0.879 vs 0.758). Model 2, which was developed using the same three SNPs as for Model 1 plus rs8138080, appeared as an interesting alternative to the full CYP2D6 genotype testing. In conclusion, the four novel SNPs, tested alone or in combination with the CYP2D6 genotype, improved the prediction of impaired tamoxifen-to-endoxifen metabolism, potentially allowing for treatment optimization. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cancer Chemoprevention)
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