Impact of VEGF-C Gene Polymorphisms and Environmental Factors on Oral Cancer Susceptibility in Taiwan

Background

Oral cancer, which is the fourth most common male cancer, is associated with environmental carcinogens in Taiwan. Vascular endothelial growth factor (VEGF)-C, an angiogenic/lymphangiogenic factor with high expression levels in tumor tissues, plays important roles in the development of several malignancies. This study was designed to examine associations of five VEGF-C gene polymorphisms with the susceptibility to and clinicopathological characteristics of oral squamous cell carcinoma.

Methodology/Principal Findings

Five single-nucleotide polymorphisms (SNPs) of VEGF-C were analyzed by a real-time polymerase chain reaction (PCR) in 470 male patients with oral cancer and 426 cancer-free controls. In this study, we found that the VEGF-C rs7664413 and rs2046463 polymorphisms were associated with oral-cancer susceptibility but not with any clinicopathological parameters. The GGACA or GACTG haplotype of five VEGF-C SNPs (rs3775194, rs11947611, rs1485766, rs7664413, and rs2046463) combined was also related to the risk of oral cancer. Among 611 male smokers, VEGF-C polymorphism carriers who also chewed betel quid were found to have a 14.5–24.2-fold risk of having oral cancer compared to the VEGF-C wild-type carrier who did not chew betel quid. Among 461 male betel-quid chewers, VEGF-C polymorphism carriers who also smoked had a 2.7–18.1-fold risk of having oral cancer compared to those who carried the wild type but did not smoke.

Conclusions

Our results suggest that the two SNPs of VEGF-C (rs7664413 and rs2046463) and either of two haplotypes of five SNPs combined have potential predictive significance in oral carcinogenesis. Gene-environmental interactions among VEGF-C polymorphisms, smoking, and betel-quid chewing might alter one''s susceptibility to oral cancer.     

Risk Stratification of Oral Potentially Malignant Disorders in Fanconi Anemia Patients Using Autofluorescence Imaging and Cytology-On-A Chip Assay

Fanconi anemia (FA) is a hereditary genomic instability disorder with a predisposition to leukemia and oral squamous cell carcinomas (OSCCs). Hematopoietic stem cell transplantation (HSCT) facilitates cure of bone marrow failure and leukemia and thus extends life expectancy in FA patients; however, survival of hematologic malignancies increases the risk of OSCC in these patients. We developed a “cytology-on-a-chip” (COC)–based brush biopsy assay for monitoring patients with oral potentially malignant disorders (OPMDs). Using this COC assay, we measured and correlated the cellular morphometry and Minichromosome Maintenance Complex Component 2 (MCM2) expression levels in brush biopsy samples of FA patients’ OPMD with clinical risk indicators such as loss of autofluorescence (LOF), HSCT status, and mutational profiles identified by next-generation sequencing. Statistically significant differences were found in several cytology measurements based on high-risk indicators such as LOF-positive and HSCT-positive status, including greater variation in cell area and chromatin distribution, higher MCM2 expression levels, and greater numbers of white blood cells and cells with enlarged nuclei. Higher OPMD risk scores were associated with differences in the frequency of nuclear aberrations and differed based on LOF and HSCT statuses. We identified mutation of FAT1 gene in five and NOTCH-2 and TP53 genes in two cases of FA patients’ OPMD. The high-risk OPMD of a non-FA patient harbored FAT1, CASP8, and TP63 mutations. Use of COC assay in combination with visualization of LOF holds promise for the early diagnosis of high-risk OPMD. These minimally invasive diagnostic tools are valuable for long-term surveillance of OSCC in FA patients and avoidance of unwarranted scalpel biopsies.     

Genomic DNA Copy Number Aberrations,Histological Diagnosis,Oral Subsite and Aneuploidy in OPMDs/OSCCs

Oral potentially malignant disorders (OPMDs) characterized by the presence of dysplasia and DNA copy number aberrations (CNAs), may reflect chromosomal instability (CIN) and predispose to oral squamous cell carcinoma (OSCC). Early detection of OPMDs with such characteristics may play a crucial role in OSCC prevention. The aim of this study was to explore the relationship between CNAs, histological diagnosis, oral subsite and aneuploidy in OPMDs/OSCCs. Samples from OPMDs and OSCCs were processed by high-resolution DNA flow cytometry (hr DNA-FCM) to determine the relative nuclear DNA content. Additionally, CNAs were obtained for a subset of these samples by genome-wide array comparative genomic hybridization (aCGH) using DNA extracted from either diploid or aneuploid nuclei suspension sorted by FCM. Our study shows that: i) aneuploidy, global genomic imbalance (measured as the total number of CNAs) and specific focal CNAs occur early in the development of oral cancer and become more frequent at later stages; ii) OPMDs limited to tongue (TNG) mucosa display a higher frequency of aneuploidy compared to OPMDs confined to buccal mucosa (BM) as measured by DNA-FCM; iii) TNG OPMDs/OSCCs show peculiar features of CIN compared to BM OPMDs/OSCCs given the preferential association with total broad and specific focal CNA gains. Follow-up studies are warranted to establish whether the presence of DNA aneuploidy and specific focal or broad CNAs may predict cancer development in non-dysplastic OPMDs.     

Impacts of CA9 Gene Polymorphisms and Environmental Factors on Oral-Cancer Susceptibility and Clinicopathologic Characteristics in Taiwan

Background

In Taiwan, oral cancer has causally been associated with environmental carcinogens. Carbonic anhydrase 9 (CA9) is reportedly overexpressed in several types of carcinomas and is generally considered a marker of malignancy. The current study explored the combined effect of CA9 gene polymorphisms and exposure to environmental carcinogens on the susceptibility of developing oral squamous cell carcinoma (OSCC) and the clinicopathological characteristics of the tumors.

Methodology and Principal Findings

Four single-nucleotide polymorphisms (SNPs) of the CA9 gene from 462 patients with oral cancer and 519 non-cancer controls were analyzed by a real-time polymerase chain reaction (PCR). While the studied SNPs (CA9 rs2071676, rs3829078, rs1048638 and +376 Del) were not associated with susceptibility to oral cancer, the GAA haplotype of 3 CA9 SNPs (rs2071676, rs3829078, and rs1048638) was related to a higher risk of oral cancer. Moreover, the four CA9 SNPs combined with betel quid chewing and/or tobacco consumption could robustly elevate susceptibility to oral cancer. Finally, patients with oral cancer who had at least one G allele of CA9 rs2071676 were at higher risk for developing lymph-node metastasis (p = 0.022), compared to those patients homozygous for AA.

Conclusions

Our results suggest that the haplotype of rs2071676, rs3829078, and rs1048638 combined has potential predictive significance in oral carcinogenesis. Gene-environment interactions of CA9 polymorphisms, smoking, and betel-quid chewing might alter oral cancer susceptibility and metastasis.     

Activation of TGF-β Pathway by Areca Nut Constituents: A Possible Cause of Oral Submucous Fibrosis

Oral submucous fibrosis (OSF) is a chronic inflammatory disease characterized by the accumulation of excess collagen, and areca nut chewing has been proposed as an important etiological factor for disease manifestation. Activation of transforming growth factor-β signaling has been postulated as the main causative event for increased collagen production in OSF. Oral epithelium plays important roles in OSF, and arecoline has been shown to induce TGF-β in epithelial cells. In an attempt to understand the role of areca nut constituents in the manifestation of OSF, we studied the global gene expression profile in epithelial cells (HaCaT) following treatment with areca nut water extract or TGF-β. Interestingly, 64% of the differentially regulated genes by areca nut water extract matches with the TGF-β induced gene expression profile. Out of these, expression of 57% of genes was compromised in the presence of ALK5 (TβRI) inhibitor and 7% were independently induced by areca nut, highlighting the importance of TGF-β in areca nut actions. Areca nut water extract treatment induced p-SMAD2 and TGF-β downstream targets in HaCaT cells but not in human gingival fibroblast cells (hGF), suggesting epithelial cells could be the source of TGF-β in promoting OSF. Water extract of areca nut consists of polyphenols and alkaloids. Both polyphenol and alkaloid fractions of areca nut were able to induce TGF-β signaling and its downstream targets. Also, SMAD-2 was phosphorylated following treatment of HaCaT cells by Catechin, Tannin and alkaloids namely Arecoline, Arecaidine and Guvacine. Moreover, both polyphenols and alkaloids induced TGF-β2 and THBS1 (activator of latent TGF-β) in HaCaT cells suggesting areca nut mediated activation of p-SMAD2 involves up-regulation and activation of TGF-β. These data suggest a major causative role for TGF-β that is induced by areca nut in OSF progression.     

中国西部3个亚高山森林土壤有机层和矿质层碳储量和生化特性

为了解土壤和植被界面的有机碳库和生化特性,分别将以云杉（Picea purpurea Masters）（SF）、冷杉（Abiesfaxoniana Rehder＆ E．H．Wilson）（FF）和白桦（Betulaplatyphylla Sukaczev）（BF）为优势树种的3个亚高山森林地表有机层（OL）分成新鲜凋落物层（LL）、半分解层（FL）和分解层（HL）,并同步测定了有机层和矿质土壤层（MS）的有机碳（OC）储量、微生物生物量碳（Cmic）、微生物生物量氮（N～）及转化酶、过氧化氢酶、脱氢酶和多酚氧化酶活性。云杉林、冷杉林和白桦林土壤有机层的有机碳储量分别为29．38Mghm^-2±1．28Mghm^-2、22．7Mghm^-2±1．12Mghm^-2和8．63Mghm^-2±0．95Mghm^-2,分别为总有机碳储量的62．2％、53．5％和36．6％。云杉林、冷杉林和白桦林土壤有机层和腐殖质层分别储存了92．8％、99．6％和78．7％的有机碳。所有林型中,HL具有最高的细菌数量、Cmic和Nmic及过氧化氢酶活性,FL具有最高的真菌、放线菌数量及转化酶、脱氢酶和多酚氧化酶活性。微生物数量、微生物生物量和酶活性的垂直分布格局意味着OL是土壤和植被之间最活跃的生态界面之一。     

Life cycle environmental and economic impact of a food waste recycling-farming system: a case study of organic vegetable farming in Japan

Purpose

Bio-based recycling systems and agricultural production using recycled materials are often evaluated separately. This study performs an environmental and socio-economic life cycle assessment (LCA) of a food waste treatment and spinach farming system in Japan. The environmental and economic tradeoffs of introducing a recycling system and the net environmental benefit of the substitution of market fertilizer considering operation changes are also examined.

Methods

Three scenarios were developed and compared. In the conventional (CV) scenario, food waste is collected, incinerated, and disposed of in landfill, and the farmer uses market organic fertilizer. The on-site composting (OC) scenario processes food waste using an on-site garbage disposer and transports compost to a nearby spinach farmer. Food waste in the centralized composting (CC) scenario is transported to a centralized composting facility and resultant compost is sent to the farm. Primary data were obtained from field experiments and interviews. Non-greenhouse gas (GHG) emissions from the field and nitrogen leaching to water systems were simulated using the denitrification–decomposition (DNDC) model.

The environmental LCA targeted climate change, eutrophication, and waste landfill. An input–output analysis estimated socio-economic indicators, namely gross added value and employment inducement effect.

Results and discussion

The scenario with the lowest impact is the CC scenario. Climate change and eutrophication impacts are highest in the OC scenario and waste landfill impacts are most significant in the CV scenario. The weighted impact by LIME2 can be reduced by 47% in the CC scenario and 17% in the OC scenario due to the recycling of food waste instead of dumping in the landfill. The difference in socio-economic indicators between the scenarios was relatively small, although the CV scenario encouraged more employment. The substitution effect of composting, as well as the environmental impact reduction of replacing market organic fertilizer with compost, will result in 28.7% of the avoided impacts in GHG emissions.

Conclusions

Both composting scenarios are feasible from an environmental and socio-economic perspective when compared with conventional organic production, although there is a tradeoff between waste landfill and GHG emissions for the on-site composting system. However, the OC scenario needs to save electricity to improve its environmental competitiveness with the CV scenario. When considering the substitution effect of composting, it is recommended to take into account that agricultural operation also changes.

     

Fungal response from oat (Avena sativa) plants and surface residue in relation to soil aggregation and organic carbon

Abstract

The influence of soil fungi on soil organic carbon (OC) from surface residue was tested in outdoor plots in southern Ontario, Canada, 2004. Fungal hyphal length, soil aggregation, OC and light and heavy fractions of organic matter were compared with factors of plant growth (with or without oat [Avena sativa]) and surface residue (no residue, oat straw (low C:N) or corn (Zea mays) stalks (high C:N)) in a factorial arrangement. Significant increases were observed in soil OC from the oat plants, and from corn stalks compared to straw residue, in the growing season with very moist, high OC, sandy soil. In treatments with corn stalk residue, fungal hyphal length was increased with interaction from the oat plants and residue and was positively correlated with the heavy fraction organic matter along with soil OC. Fungal hyphae, plant roots and high C:N residue were all factors in soil OC increases.     

Young adult cancer incidence trends in Taiwan and the U.S. from 2002 to 2016

BackgroundPrevious studies have not examined young adult cancer incidence trends in Taiwan, or comprehensively compared these trends at two nations with different population genetics, environmental exposures, and health care. Therefore, we compared the incidence rates and trends of the most common young adult cancers diagnosed at 20–39 years of age in Taiwan and the U.S.MethodsIncidence rates from 2002 to 2016 were calculated from the Taiwan National Health Insurance Research Datasets and the U.S. Surveillance, Epidemiology, and End Results Program. For trend assessment, average annual percent change (AAPC) values were calculated from 15 years of data using Joinpoint Regression Program. We also obtained sex or age of diagnosis stratified estimates.ResultsThe age-standardized overall young adult cancer incidence rate significantly increased from 2002 to 2016 in both Taiwan (AAPC=1.1%, 95% CI: 0.8–1.5%) and the U.S. (AAPC=1.8%, 95% CI: 1.1–2.4%). Cancers with significantly decreasing trends in Taiwan included cancers of the nasopharynx, liver, and tongue, which were not among the most common young adult cancers in the U.S. Cancers with significantly increasing trends in both Taiwan and the U.S. included colorectal, thyroid, and female breast cancers. Lymphoma, ovarian cancer, and lung and bronchus cancer had significantly increasing trends in Taiwan but not in the U.S. Although cervical cancer had significantly decreasing trends in both nations among those 30–39 years of age, its trend was significantly increasing in Taiwan but decreasing in the U.S. among those 20–29 years of age.ConclusionThe types of common young adult cancers as well as their incidence rates and trends differed in Taiwan and the U.S. Future studies should further understand the etiological factors driving these trends.     

Quantitative dimensions of histopathological attributes and status of GSTM1-GSTT1 in oral submucous fibrosis

Oral submucous fibrosis (OSF) is a precancerous condition of the oral cavity and oropharynx and a significant number of such cases transform into oral squamous cell carcinoma (OSCC). Presently, diagnosis of OSF is done mainly through qualitative histopathological techniques and in the level of diagnostic molecular biology no specific genetic marker is evident. Keeping these facts in mind this study evaluates histopathological changes in the epithelium and subepithelial connective tissue of OSF through quantitative digital image analysis in respect to specific candidate features and analyses null mutations in the GSTM1 and GSTT1 by PCR amplification. The analysis revealed that there are subtle quantitative differences in the histological images of OSF compared to NOM. The thickness of the epithelium and cell population in its different zones, radius of curvature of rete-ridges and connective tissue papillae were decreased but length of rete-ridges and connective tissue papillae, fibrocity and the number of cellular components (predominantly inflammatory cells) in the subepithelial connective tissue were increased in OSF. The PCR study revealed that there is no significant difference in the allelic variants in GSTM1 between OSF and normal, while GSTT1 null gene showed significantly higher frequencies in this precancerous condition. This study establishes a distinct quantitative difference between normal oral mucosa (NOM) and OSF in respect to their histological features and GST null gene frequencies.     

A preliminary health risk assessment of heavy metals in local and imported rice grains marketed in Trinidad and Tobago,W.I.

Abstract

Within recent times, heavy metal contamination in rice (Oryza Sativa) has been of growing concern particularly due to its implications on human health via consumption. Twenty-one different brands of rice marketed in Trinidad and Tobago were investigated for their heavy metal content (Cd, Cr, Cu, Mn, Ni, Pb and Zn) using Flame Atomic Absorption Spectroscopy. Lead was not detected in any of the samples, while both Cadmium and Nickel were detected in only one sample each at 0.27 and 1.79?µg/g, respectively. The average metal concentrations decreased in the following order: Zinc?> Manganese?> Copper?>?Chromium with concentrations ranging from 1.00–4.35, 1.72–29.92, 5.87–43.56 and 0.06–1.16?µg/g, respectively. The target hazard quotient (THQ) and hazard index (HI) values for all samples were less than one, indicating no risk of non-carcinogenic effects to consumers.     

A review on remediation technologies for nickel-contaminated soil

Abstract

With the rapid pace of industrialization and urbanization, the environmental safety of soil is a worldwide concern. In China alone, one-fifth of the arable land is reported to be contaminated with heavy metals including nickel. In this review, current research on nickel remediation, specifically the various remediation technologies including physical and chemical remediation methods, such as immobilization, soil washing, encapsulation, soil replacement, and electrokinetic methods; phytoremediation; and bioremediation, is summarized. Further, the mechanisms underlying the presented remediation technologies, along with their advantages and disadvantages, are discussed. The lacunae in available technologies for nickel remediation are also briefly discussed. The review concludes with a scheme for successful soil remediation.     

The cortical effect of chewing gum during hand movements: A functional MRI study

Abstract

Nine right-handed normal subjects were recruited for this study. We compared the cortical activation during execution of hand movements (right finger flexion–extension) with that during execution of hand movements while chewing gum (right side chewing). We found that execution of hand movements while chewing gum induced less activation in the contralateral SM1 than hand movements alone. Based on our findings, it appears chewing gum during execution of hand movements enhanced the efficiency of hand movements.     

Exosome-derived long non-coding RNA ADAMTS9-AS2 suppresses progression of oral submucous fibrosis via AKT signalling pathway

Oral submucosal fibrosis (OSF) is one of the pre-cancerous lesions of oral squamous cell carcinoma (OSCC). Its malignant rate is increasing, but the mechanism of malignancy is not clear. We previously have elucidated the long non-coding RNA (lncRNA) expression profile during OSF progression at the genome-wide level. However, the role of lncRNA ADAMTS9-AS2 in OSF progression via extracellular communication remains unclear. lncRNA ADAMTS9-AS2 is down-regulated in OSCC tissues compared with OSF and normal mucous tissues. Low ADAMTS9-AS2 expression is associated with poor overall survival. ADAMTS9-AS2 is frequently methylated in OSCC tissues, but not in normal oral mucous and OSF tissues, suggesting tumour-specific methylation. Functional studies reveal that exosomal ADAMTS9-AS2 suppresses OSCC cell growth, migration and invasion in vitro. Mechanistically, exosomal ADAMTS9-AS2 inhibits AKT signalling pathway and regulates epithelial-mesenchymal transition markers. Through profiling miRNA expression profile regulated by exosomal ADAMTS9-AS2, significantly enriched pathways include metabolic pathway, PI3K-Akt signalling pathway and pathways in cancer, indicating that exosomal ADAMTS9-AS2 exerts its functions through interacting with miRNAs during OSF progression. Thus, our findings highlight the crucial role of ADAMTS9-AS2 in the cell microenvironment during OSF carcinogenesis, which is expected to become a marker for early diagnosis of OSCC.     

Determination of the Heavy Metal Levels in Panax notoginseng and the Implications for Human Health Risk Assessment

ABSTRACT

High levels of heavy metals in Panax notoginseng (Sanchi), a valued traditional Chinese medicine, have drawn increasing concern regarding the safe usage of Sanchi preparations. Here, we measured the concentrations of six heavy metals in Sanchi samples from 20 major plantations, investigated the pharmaceutical processes and usages of Sanchi preparations, and assessed the associated potential health risks to consumers. The average concentrations of chromium (Cr), copper (Cu), nickel (Ni), zinc (Zn), lead (Pb), and arsenic (As) in the Sanchi samples were 2.7, 3.7, 6.2, 22.1, 2.0, and 1.4 mg/kg, respectively. The hazard quotients (HQs) for these six single metals and the hazard index (HI) of these metals’ combination were all far less than 1, indicating the absence of a non-carcinogenic health hazard to consumers. The carcinogenic risk of As was 2.1 × 10^?6, which is higher than the allowable level suggested by the U.S. Environmental Protection Agency but less than the level suggested by the World Health Organization (WHO). The probabilities of consumers’ exposure due to daily medicine consumption exceeding the allowable daily intakes from medicine (ADIs_drug, 1% of the ADI) suggested by the WHO were 0.0%, 0.1%, 0.1%, 0.0%, 1.6%, and 27.3% for Cr, Ni, Cu, Zn, Pb, and As, respectively.     

The severity of chewing disorders is related to gross motor function and trunk control in children with cerebral palsy

Abstract

Purpose: The frequency of chewing disorders increases with decreasing level of gross motor function in children with cerebral palsy (CP). Besides its frequency, the severity of chewing disorders is also important. The aim of this study was to determine the relationship between chewing performance level and gross motor function, and trunk postural control in children with CP.

Materials and methods: The study included 119 children with CP (age 2–10 years). Chewing performance level was determined by the Karaduman Chewing Performance Scale (KCPS). The Gross Motor Function Classification System (GMFCS) was used to determine the level of gross motor function. Segmental Assessment of Trunk Control (SATCo) was used to measure trunk control.

Results: Children with spastic CP with a median age of 4?years were evaluated, of which 50.4% were male. The percentages of patients classified to GMFCS levels I to V were 43.7%, 6.7%, 9.2%, 5.0%, and 35.3%, respectively. The median KCPS score was 3 (min?=?0, max?=?4). A good correlation was found between KCPS and GMFCS (p?<?.001, r?=?0.70). Negative, excellent correlations between KCPS and SATCo static, SATCo active, and SATCo reactive postural controls were found (p?<?.001, r?=?–0.75, r?=?–0.77, r?=?–0.79; respectively).

Conclusions: The severity of chewing disorders is related to the level of gross motor function and trunk postural control in children with CP.

Clinical trial number: NCT03241160     

CYP1AI and CYP2E1 gene polymorphisms may increase susceptibility to Oral Submucous Fibrosis among betel quid chewers of Eastern India

Chewing betel quid may release chemical carcinogens including xenobiotics resulting in oral malignancy cases preceded by potential malignant lesions and conditions — Oral Submucous Fibrosis (OSF) being one of them. The cytochrome P4501A1 (CYP1A1) enzyme is central to the metabolic activation of these xenobiotics, whereas CYP2E1 metabolizes the nitrosamines and tannins. The present study investigated the association of polymorphisms at CYP1A1m1 (T3801C), m2 (A2455G), and CYP2E1 PstI site (nucleotide 21259) with the risk of OSF. The study was conducted on 75 OSF patients and 150 controls from an eastern Indian population. The above polymorphisms were analyzed by PCR-RFLP method. Analyses of data show that polymorphisms in CYP1A1m2 [OR = 8.25 (4.31–15.80)]; CYP1A1m1 [OR = 2.88 (1.57–5.24)] and CYP2E1 PstI site [OR = 3.16 (1.10–9.04)] revealed significant association with OSF. Our results suggest that polymorphism in CYP1A1 and CYP2E1 may confer an increased risk for Oral Submucous Fibrosis.     

Epidemiology of areca (betel) nut use in the mariana islands: Findings from the University of Guam/University of Hawai`i cancer center partnership program

BackgroundAreca (betel) nut is considered a Group 1 human carcinogen shown to be associated with other chronic diseases in addition to cancer. This paper describes the areca (betel) nut chewing trend in Guam, and health behaviors of chewers in Guam and Saipan.MethodsThe areca (betel) nut module in the Guam Behavioral Risk Factor Surveillance Survey was used to calculate the 5-year (2011–2015) chewing trend. To assess the association between areca (betel) nut chewing and health risks in the Mariana Islands, a cross-section of 300 chewers, ≥18 years old, were recruited from households in Guam and Saipan. Self-reported socio-demographics, oral health behaviors, chronic disease status, diet, and physical activity were collected. Anthropometry was measured. Only areca (betel) nut-specific and demographic information were collected from youth chewers in the household.ResultsThe 5-year areca (betel) nut chewing prevalence in Guam was 11% and increased among Non-Chamorros, primarily other Micronesians, from 2011 (7%) to 2015 (13%). In the household survey, most adult chewers (46%) preferred areca nut with betel leaf, slaked lime, and tobacco. Most youth chewers (48%) preferred areca nut only. Common adult chronic conditions included diabetes (14%), hypertension (26%), and obesity (58%).ConclusionThe 5-year areca (betel) nut chewing prevalence in Guam is comparable to the world estimate (10–20%), though rising among Non-Chamorros. Adult and youth chewers may be at an increased risk for oral cancer. Adult chewers have an increased risk of other chronic health conditions. Cancer prevention and intervention strategies should incorporate all aspects of health.     

Identification of a BRAF/PA28γ/MEK1 signaling axis and its role in epithelial-mesenchymal transition in oral submucous fibrosis

Oral submucous fibrosis (OSF) is a chronic and insidious oral potentially malignant disorder associated with a 4–17% risk of oral squamous cell carcinoma (OSCC). Our previous study found that proteasomal activator 28 gamma (PA28γ) is frequently overexpressed in oral squamous cell carcinoma and negatively correlated with poor patient prognosis. However, the role of PA28γ in the occurrence and development of OSF remains unclear. Here, we screened PA28γ-related genes and investigated their function in OSF. We demonstrated that the expression of PA28γ was positively associated with MEK1 and gradually elevated from normal to progressive stages of OSF tissue. Arecoline, a pathogenic component of OSF, could upregulate the protein levels of PA28γ and phosphorylated MEK1 and contribute to epithelial to mesenchymal transition (EMT) in epithelial cells. Notably, PA28γ could interact with MEK1 and upregulate its phosphorylation level. Furthermore, arecoline upregulated BRAF, which can interact with PA28γ and upregulate its protein level. Additionally, BRAF, PA28γ, and MEK1 could form protein complexes and then enhance the MEK1/ERK signaling pathways. The concrete mechanism of the protein stability of PA28γ is that BRAF mediates its degradation by inhibiting its ubiquitination. These findings underscore the instrumental role of PA28γ in the BRAF/MEK1 pathway and enhanced EMT through MEK1/ERK activation in OSF.Subject terms: Mechanisms of disease, Oral cancer