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14 pages, 2575 KiB

Open AccessArticle

CD44 Mediates Oral Squamous Cell Carcinoma-Promoting Activity of MRE11 via AKT Signaling

by Shyng-Shiou F. Yuan, Amos C. Hung, Ching-Wei Hsu, Ting-Hsun Lan, Chang-Wei Su, Tsung-Chen Chi, Yu-Chiuan Chang, Yuk-Kwan Chen and Yen-Yun Wang

J. Pers. Med. 2022, 12(5), 841; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm12050841 - 21 May 2022

Cited by 1 | Viewed by 1892

Abstract

Oral cancer is one of the highest-incidence malignancies worldwide, with the occurrence of oral squamous cell carcinoma (OSCC) being the most frequently diagnosed form. A barrier for oral cancer management may arise from tumor cells that possess properties of cancer stemness, which has [...] Read more.

Oral cancer is one of the highest-incidence malignancies worldwide, with the occurrence of oral squamous cell carcinoma (OSCC) being the most frequently diagnosed form. A barrier for oral cancer management may arise from tumor cells that possess properties of cancer stemness, which has been recognized as a crucial factor in tumor recurrence and metastasis. As such, understanding the molecular mechanisms underlying these tumor cells may provide insights for improving cancer treatment. MRE11 is the core protein of the RAD50/MRE11/NBS1 complex with a primary role in DNA damage repair, and it has been diversely associated with tumor development including OSCC. In this study, we aimed to investigate the engagement of CD44, a cancer stemness marker functioning in the control of cell growth and motility, in OSCC malignancy under the influence of MRE11. We found that overexpression of MRE11 enhanced CD44 expression and tumorsphere formation in OSCC cells, whereas knockdown of MRE11 reduced these phenomena. In addition, the MRE11-promoted tumorsphere formation or cell migration ability was compromised in OSCC cells carrying siRNA that targets CD44, as was the MRE11-promoted AKT phosphorylation. These were further supported by analyzing clinical samples, where higher CD44 expression was associated with lymph node metastasis. Additionally, a positive correlation between the expression of MRE11 and CD44, or that of CD44 and phosphorylated AKT, was observed in OSCC tumor tissues. Finally, the expression of CD44 was found to be higher in the metastatic lung nodules from mice receiving tail vein-injection with MRE11-overexpressing OSCC cells compared with control mice, and a positive correlation between CD44 and phosphorylated AKT was also observed in these metastatic lung nodules. Altogether, our current study revealed a previously unidentified mechanism linking CD44 and AKT in MRE11-promoted OSCC malignancy, which may shed light to the development of novel therapeutic strategies in consideration of this new pathway in OSCC. Full article

(This article belongs to the Special Issue Personalized Medicine in Oral Cancer)

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20 pages, 7515 KiB

Open AccessArticle

Integrated Proteomics Based on 2D Gel Electrophoresis and Mass Spectrometry with Validations: Identification of a Biomarker Compendium for Oral Submucous Fibrosis—An Indian Study

by Divyambika Catakapatri Venugopal, Soundharya Ravindran, Vidyarani Shyamsundar, Sathasivasubramanian Sankarapandian, Arvind Krishnamurthy, Ananthi Sivagnanam, Yasasve Madhavan and Vijayalakshmi Ramshankar

J. Pers. Med. 2022, 12(2), 208; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm12020208 - 03 Feb 2022

Cited by 7 | Viewed by 2593

Abstract

Oral Submucous Fibrosis (OSMF) is a chronic debilitating disease more frequently found in the South East Asian population. This disease poses a public health priority, as it is grouped under oral potentially malignant disorders, with malignant transformation rates of around 7 to 13%. [...] Read more.

Oral Submucous Fibrosis (OSMF) is a chronic debilitating disease more frequently found in the South East Asian population. This disease poses a public health priority, as it is grouped under oral potentially malignant disorders, with malignant transformation rates of around 7 to 13%. Hence, early identification of high-risk OSMF patients is of the utmost importance to prevent malignant transformation. Proteomic expression profiling is a promising method for identifying differentially expressed proteins for disease prognosis and risk stratification in OSMF. In this study, overexpressed proteins in OSMF, OSMF transformed into oral squamous cell carcinoma (OSCC) and normal tissues were evaluated by proteomic analysis using two-dimensional electrophoresis (2DE) and mass spectrometry, which revealed 23 upregulated proteins. Validation was done using immunohistochemistry for three secretory proteins, namely 14-3-3ε (n = 130), carbonic anhydrase 1 (CA 1) (n = 125) and heat shock protein 70 (HSP 70) (n = 117), which showed significant overexpression in OSMF, OSCC compared to normal. The present study is the first of its kind in India to the best of our knowledge, assessing the altered expression of proteins in OSMF and OSMF which has undergone malignant transformation, obtaining a better knowledge of the molecular pathways involved in the disease progression. The current study shows that the biomarkers studied can be potentially useful for risk stratification of OSMF to OSCC serving as novel targets for therapeutic intervention. Clinical validation of the targets can further pave way for precision medicine to improve the quality of life in OSMF patients. Full article

(This article belongs to the Special Issue Personalized Medicine in Oral Cancer)

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18 pages, 4527 KiB

Open AccessArticle

Enrichment of SOX2-Positive Cells in BRAF V600E Mutated and Recurrent Ameloblastoma

by Chih-Huang Tseng, Pei-Hsuan Lu, Yi-Ping Wang and Julia Yu Fong Chang

J. Pers. Med. 2022, 12(1), 77; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm12010077 - 08 Jan 2022

Cited by 4 | Viewed by 2579

Abstract

Ameloblastoma is the most common benign odontogenic neoplasm, but with an aggressive behavior and a high recurrence rate. Nowadays wide surgical resection is the current recommended treatment, which can cause further loss of function and esthetics. Recent studies point to the stem/progenitor cells [...] Read more.

Ameloblastoma is the most common benign odontogenic neoplasm, but with an aggressive behavior and a high recurrence rate. Nowadays wide surgical resection is the current recommended treatment, which can cause further loss of function and esthetics. Recent studies point to the stem/progenitor cells as both initiators and propagators of the tumors. Elucidation of the cellular and molecular mechanisms underlying the tumor stem cells is of broad interest for understanding tumorigenesis and for developing effective targeted therapies. SRY related HMG box gene 2 (SOX2) is a transcription factor that plays important roles in development, stem cell renewal, and cancer formation. Few studies have revealed increased SOX2 expression in atypical ameloblastoma and ameloblastic carcinoma. For the development of personalized medicine for ameloblastoma, biomarkers that provide prognostic or predictive information regarding a tumor’s nature or its response to treatment are essential. Thus, in this study, we aimed to study if SOX2-positive cells exist in ameloblastomas and their correlation with the clinicopathologic parameters. Our data suggested BRAF(V600E) mutation might contribute to the expansion of SOX2-positive cells. The identification of BRAF(V600E) mutation and the amplification of SOX2-positive cells in ameloblastomas imply the possible benefit of applying BRAF and SOX2 inhibitors in recurrent and un-resectable ameloblastomas. Full article

(This article belongs to the Special Issue Personalized Medicine in Oral Cancer)

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9 pages, 876 KiB

Open AccessArticle

Decreased Circulating Melatonin with Loss of Age-Related Biphasic Change in Patients with Oral Squamous Cell Carcinoma

by Yu-Fen Tsai, Yen-Yun Wang, Wan-Chi Tsai, Chang-Wei Su, Ching-Wei Hsu and Shyng-Shiou F. Yuan

J. Pers. Med. 2021, 11(12), 1357; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11121357 - 13 Dec 2021

Cited by 2 | Viewed by 1968

Abstract

Background: Melatonin, produced by the pineal gland, is known for its antioxidant, oncostatic, and anti-inflammatory properties. However, studies on serum melatonin levels in different cancer types have yielded conflicting results, and little is known about the clinical significance of serum melatonin in oral [...] Read more.

Background: Melatonin, produced by the pineal gland, is known for its antioxidant, oncostatic, and anti-inflammatory properties. However, studies on serum melatonin levels in different cancer types have yielded conflicting results, and little is known about the clinical significance of serum melatonin in oral squamous cell carcinoma (OSCC) in the Southern Asian population. Therefore, we explored its role in OSCC in this study. Methods: A total of 67 male OSCC patients and 78 healthy controls were enrolled in this case–control study. The serum levels of melatonin were determined by enzyme-linked immunosorbent assay (ELISA) and compared between the two groups. Results: The serum melatonin levels were significantly lower in OSCC patients compared with healthy controls (mean ± standard deviation, 15.0 ± 4.6 vs. 18.5 ± 11.8 pg/mL, p = 0.02). In the subgroup of age less than 55 years (mean age of OSCC), OSCC patients had a significantly decreased melatonin level than healthy controls (mean melatonin, 15.7 ± 12.6 vs. 20.8 ± 3.9 pg/mL, p = 0.02). Decreased serum melatonin (odds ratio (OR): 0.95, 95%CI: 0.91–0.99), alcohol consumption (OR: 29.02, 95%CI: 11.68–72.16), betel quid chewing (OR:136.44, 95%CI: 39.17–475.27), and cigarette smoking (OR:29.48, 95%CI: 11.06–78.60) all increased the risk of OSCC under univariate analyses of logistic regression. Betel quid chewing (OR: 45.98, 95%CI: 10.34–204.49) and cigarette smoking (OR:6.94, 95%CI: 1.60–30.16) were the independent risk factors for OSCC in Taiwan. In addition, a negative correlation between age and melatonin level was observed in healthy controls (Pearson r = −0.24, p = 0.03). However, the negative correlation was lost in patients with OSCC. Melatonin concentration had no association with the severity of OSCC. Conclusion: Overall, our study provides evidence that serum melatonin levels decreased in OSCC patients in Taiwan and the decreased level is much significant in young populations and suggests that the decreased melatonin was associated with OSCC, especially in young populations. Further studies are warranted to investigate whether melatonin can be a useful non-invasive screening tool for OSCC. Full article

(This article belongs to the Special Issue Personalized Medicine in Oral Cancer)

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16 pages, 4306 KiB

Open AccessArticle

Nepenthes Extract Induces Selective Killing, Necrosis, and Apoptosis in Oral Cancer Cells

by Kun-Han Yang, Jen-Yang Tang, Yan-Ning Chen, Ya-Ting Chuang, I-Hsuan Tsai, Chien-Chih Chiu, Li-Jie Li, Tsu-Ming Chien, Yuan-Bin Cheng, Fang-Rong Chang, Ching-Yu Yen and Hsueh-Wei Chang

J. Pers. Med. 2021, 11(9), 871; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11090871 - 31 Aug 2021

Cited by 4 | Viewed by 2247

Abstract

Ethyl acetate Nepenthes extract (EANT) from Nepenthes thorellii × (ventricosa × maxima) shows antiproliferation and apoptosis but not necrosis in breast cancer cells, but this has not been investigated in oral cancer cells. In the present study, EANT shows no cytotoxicity to normal [...] Read more.

Ethyl acetate Nepenthes extract (EANT) from Nepenthes thorellii × (ventricosa × maxima) shows antiproliferation and apoptosis but not necrosis in breast cancer cells, but this has not been investigated in oral cancer cells. In the present study, EANT shows no cytotoxicity to normal oral cells but exhibits selective killing to six oral cancer cell lines. They were suppressed by pretreatment of the antioxidant inhibitor N-acetylcysteine (NAC), demonstrating that EANT-induced cell death was mediated by oxidative stress. Concerning high sensitivity to EANT, Ca9-22 and CAL 27 oral cancer cells were chosen for exploring detailed selective killing mechanisms. EANT triggers a mixture of necrosis and apoptosis as determined by annexin V/7-aminoactinmycin D analysis. Still, they show differential switches from necrosis at a low (10 μg/mL) concentration to apoptosis at high (25 μg/mL) concentration of EANT in oral cancer cells. NAC induces necrosis but suppresses annexin V-detected apoptosis in oral cancer cells. Necrostatin 1 (NEC1), a necroptosis inhibitor, moderately suppresses necrosis but induces apoptosis at 10 μg/mL EANT. In contrast, Z-VAD-FMK, a pancaspase inhibitor, slightly causes necrosis but suppresses apoptosis at 10 μg/mL EANT. Furthermore, the flow cytometry-detected pancaspase activity is dose-responsively increased but is suppressed by NAC and ZVAD, although not for NEC1 in oral cancer cells. EANT causes several oxidative stress events such as reactive oxygen species, mitochondrial superoxide, and mitochondrial membrane depolarization. In response to oxidative stresses, the mRNA for antioxidant signaling, such as nuclear factor erythroid 2-like 2 (NFE2L2), catalase (CAT), heme oxygenase 1 (HMOX1), and thioredoxin (TXN), are overexpressed in oral cancer cells. Moreover, EANT also triggers DNA damage, as detected by γH2AX and 8-oxo-2′-deoxyguanosine adducts. The dependence of oxidative stress is validated by the evidence that NAC pretreatment reverts the changes of cellular and mitochondrial stress and DNA damage. Therefore, EANT exhibits antiproliferation involving an oxidative stress-dependent necrosis/apoptosis switch and DNA damage in oral cancer cells. Full article

(This article belongs to the Special Issue Personalized Medicine in Oral Cancer)

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11 pages, 1185 KiB

Open AccessArticle

Reduction in and Preventive Effects for Oral-Cancer Risk with Antidepressant Treatment

by Chia-Min Chung, Tzer-Min Kuo, Kun-Tu Yeh, Chien-Hung Lee and Ying-Chin Ko

J. Pers. Med. 2021, 11(7), 591; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11070591 - 23 Jun 2021

Cited by 5 | Viewed by 1946

Abstract

Areca nut (AN) was identified as carcinogenic to humans. Around 600 million people globally use AN in some form, yet no effective therapeutic drug is available to overcome AN addiction. This preclinical study examines the effects of antidepressants on AN use with animal [...] Read more.

Areca nut (AN) was identified as carcinogenic to humans. Around 600 million people globally use AN in some form, yet no effective therapeutic drug is available to overcome AN addiction. This preclinical study examines the effects of antidepressants on AN use with animal models. We produced AN powder and dissolved it into drinking water, training 55 C57BL/6 mice in free self-selection to drink AN water or normal water. Then, the mice were randomly divided into four groups. Selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs) were given as three treatment groups and one placebo group for four weeks. In the follow-up period, the preference and amount of free selection of AN and normal water, and oral pathological change were evaluated. There was a significant decrease in preference for AN drinking during the first four weeks, and the 36th week after drug withdrawal in the MAOI and SSRI groups (all p < 0.05). The drug-reducing effect of AN water in the 1–4-week period was significant in the MAOI group (p < 0.0001) and was also significant in the 3–4-week period in the SSRI group (p = 0.03). The TCA group did not show a decrease effect. At the endpoint (60 weeks), oral mucosal fibrosis (OSF) levels and risk in the SSRI (p = 0.0081) and MAOI (p = 0.01) groups were significantly lower than those in the control group. Antidepressant drugs MAOIs and SSRIs could reduce the amount of AN use and decrease the early stage of oral fibrosis in mice, but SSRIs may need to be boosted again. Full article

(This article belongs to the Special Issue Personalized Medicine in Oral Cancer)

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11 pages, 962 KiB

Open AccessArticle

Polygenic Panels Predicting the Susceptibility of Multiple Upper Aerodigestive Tract Cancer in Oral Cancer Patients

by Huei-Tzu Chien, Chi-Chin Yeh, Chi-Kuang Young, Tzu-Ping Chen, Chun-Ta Liao, Hung-Ming Wang, Kai-Lun Cho and Shiang-Fu Huang

J. Pers. Med. 2021, 11(5), 425; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11050425 - 18 May 2021

Cited by 1 | Viewed by 1791

Abstract

Head and neck cancer was closely related with habitual use of cigarette and alcohol. Those cancer patients are susceptible to develop multiple primary tumors (MPTs). In this study, we utilized the single nucleotide polymorphisms (SNPs) array (Affymetrix Axion Genome-Wide TWB 2.0 Array Plate) [...] Read more.

Head and neck cancer was closely related with habitual use of cigarette and alcohol. Those cancer patients are susceptible to develop multiple primary tumors (MPTs). In this study, we utilized the single nucleotide polymorphisms (SNPs) array (Affymetrix Axion Genome-Wide TWB 2.0 Array Plate) to investigate patients’ risks of developing multiple primary cancers. We recruited 712 male head and neck cancer patients between Mar 1996 and Feb 2017. Two hundred and eighty-six patients (40.2%) had MPTs and 426 (59.8%) had single cancer. Four hundred and twelve normal controls were also recruited. A list of seventeen factors was extracted and ten factors were demonstrated to increase the risks of multiple primary cancers (alcohol drinking, rs118169127, rs149089400, rs76367287, rs61401220, rs141057871, rs7129229, older age, rs3760265, rs9554264; all were p value < 0.05). Polygenic scoring model was built and the area under curve to predict the risk developing MPTs is 0.906. Alcohol drinking, among the seventeen factors, was the most important risk factor to develop MPT in upper aerodigestive tract (OR: 7.071, 95% C.I.: 2.134–23.434). For those with high score in polygenic model, routine screening of upper digestive tract including laryngoscope and esophagoscope is suggested to detect new primaries early. Full article

(This article belongs to the Special Issue Personalized Medicine in Oral Cancer)

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16 pages, 21163 KiB

Open AccessArticle

Downregulation of ATM and BRCA1 Predicts Poor Outcome in Head and Neck Cancer: Implications for ATM-Targeted Therapy

by Yu-Chu Wang, Ka-Wo Lee, Yi-Shan Tsai, Hsing-Han Lu, Si-Yun Chen, Hsin-Ying Hsieh and Chang-Shen Lin

J. Pers. Med. 2021, 11(5), 389; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11050389 - 10 May 2021

Cited by 5 | Viewed by 1813

Abstract

ATM and BRCA1 are DNA repair genes that play a central role in homologous recombination repair. Alterations of ATM and BRCA1 gene expression are found in cancers, some of which are correlated with treatment response and patient outcome. However, the role of ATM [...] Read more.

ATM and BRCA1 are DNA repair genes that play a central role in homologous recombination repair. Alterations of ATM and BRCA1 gene expression are found in cancers, some of which are correlated with treatment response and patient outcome. However, the role of ATM and BRCA1 gene expression in head and neck cancer (HNC) is not well characterized. Here, we examined the prognostic role of ATM and BRCA1 expression in two HNC cohorts with and without betel quid (BQ) exposure. The results showed that the expression of ATM and BRCA1 was downregulated in BQ-associated HNC, as the BQ ingredient arecoline could suppress the expression of both genes. Low expression of either ATM or BRCA1 was correlated with poor overall survival (OS) and was an independent prognostic factor in multivariate analysis (ATM HR: 1.895, p = 0.041; BRCA1 HR: 2.163, p = 0.040). The combination of ATM and BRCA1 expression states further improved on the prediction of OS (HR: 4.195, p = 0.001, both low vs. both high expression). Transcriptomic analysis showed that inhibition of ATM kinase by KU55933 induced apoptosis signaling and potentiated cisplatin-induced cytotoxicity. These data unveil poor prognosis in the HNC patient subgroup with low expression of ATM and BRCA1 and support the notion of ATM-targeted therapy. Full article

(This article belongs to the Special Issue Personalized Medicine in Oral Cancer)

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Review

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15 pages, 2529 KiB

Open AccessReview

Contemporary Molecular Analyses of Malignant Tumors for Precision Treatment and the Implication in Oral Squamous Cell Carcinoma

by Julia Yu Fong Chang, Chih-Huang Tseng, Pei Hsuan Lu and Yi-Ping Wang

J. Pers. Med. 2022, 12(1), 12; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm12010012 - 28 Dec 2021

Cited by 6 | Viewed by 2401

Abstract

New molecular tests and methods, in addition to morphology-based diagnosis, are widely used as a new standard of care in many tumors. “One-size-fits-all medicine” is now shifting to precision medicine. This review is intended to discuss the key steps toward to development of [...] Read more.

New molecular tests and methods, in addition to morphology-based diagnosis, are widely used as a new standard of care in many tumors. “One-size-fits-all medicine” is now shifting to precision medicine. This review is intended to discuss the key steps toward to development of precision medicine and its implication in oral squamous cell carcinoma. The challenges and opportunities of precision medicine in oral cancer will be sequentially discussed based on the four steps of precision medicine: identification/detection, diagnosis, treatment and monitoring. Full article

(This article belongs to the Special Issue Personalized Medicine in Oral Cancer)

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