Displaying publications 1 - 20 of 47 in total

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  1. KRT13, FAIM2 and CYP2W1 mRNA expression in oral squamous cell carcinoma patients with risk habits
    Hartanto FK, Karen-Ng LP, Vincent-Chong VK, Ismail SM, Mustafa WM, Abraham MT, et al.
    Asian Pac J Cancer Prev, 2015;16(3):953-8.
    PMID: 25735388
    BACKGROUND: Expression of KRT13, FAIM2 and CYP2W1 appears to be influenced by risk habits, thus exploring the associations of these genes in oral squamous cell cancer (OSCC) with risk habits, clinico-pathological parameters and patient survival may be beneficial in identifying relevant biomarkers with different oncogenic pathways.

    MATERIALS AND METHODS: cDNAs from 41 OSCC samples with and without risk habits were included in this study. Quantitative real-time PCR was used to analyze KRT13, FAIM2 and CYP2W1 in OSCC. The housekeeping gene (GAPDH) was used as an endogenous control.

    RESULTS: Of the 41 OSCC samples, KRT13 was down-regulated in 40 samples (97.6%), while FAIM2 and CYP2W1 were down-regulated in 61.0% and 48.8%, respectively. Overall, there were no associations between KRT13, FAIM2 and CYP2W1 expression with risk habits, selected socio-demographic and clinico-pathological parameters and patient survival.

    CONCLUSIONS: Although this study was unable to show significance, there were some tendencies in the associations of KRT13, FAIM2 and CYP2W1 expression in OSCC with selected clinic-pathological parameters and survival.

    Matched MeSH terms: Mouth Neoplasms/genetics*
  2. Heterotrimeric G-protein alpha-12 (Gα12) subunit promotes oral cancer metastasis
    Gan CP, Patel V, Mikelis CM, Zain RB, Molinolo AA, Abraham MT, et al.
    Oncotarget, 2014 Oct 30;5(20):9626-40.
    PMID: 25275299
    Oral squamous cell carcinoma (OSCC) has a propensity to spread to the cervical lymph nodes (LN). The presence of cervical LN metastases severely impacts patient survival, whereby the two-year survival for oral cancer patients with involved LN is ~30% compared to over 80% in patients with non-involved LN. Elucidation of key molecular mechanisms underlying OSCC metastasis may afford an opportunity to target specific genes, to prevent the spread of OSCC and to improve patient survival. In this study, we demonstrated that expression of the heterotrimeric G-protein alpha-12 (Gα12) is highly up-regulated in primary tumors and LN of OSCC patients, as assessed by quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). We also found that exogenous expression of the constitutively activated-form of Gα12 promoted cell migration and invasion in OSCC cell lines. Correspondingly, inhibition of Gα12 expression by shRNA consistently inhibited OSCC cell migration and invasion in vitro. Further, the inhibition of G12 signaling by regulator of G-protein signaling (RGS) inhibited Gα12-mediated RhoA activation, which in turn resulted in reduced LN metastases in a tongue-orthotopic xenograft mouse model of oral cancer. This study provides a rationale for future development and evaluation of drug candidates targeting Gα12-related pathways for metastasis prevention.
    Matched MeSH terms: Mouth Neoplasms/genetics
  3. Oral cancer secretome: identification of cancer-associated proteins
    Chang HY, Hor SY, Lim KP, Zain RB, Cheong SC, Rahman MA, et al.
    Electrophoresis, 2013 Aug;34(15):2199-208.
    PMID: 23712713 DOI: 10.1002/elps.201300126
    This study aims to identify cancer-associated proteins in the secretome of oral cancer cell lines. We have successfully established four primary cell cultures of normal cells with a limited lifespan without human telomerase reverse transcriptase (hTERT) immortalization. The secretome of these primary cell cultures were compared with that of oral cancer cell lines using 2DE. Thirty five protein spots were found to have changed in abundance. Unambiguous identification of these proteins was achieved by MALDI TOF/TOF. In silico analysis predicted that 24 of these proteins were secreted via classical or nonclassical mechanisms. The mRNA expression of six genes was found to correlate with the corresponding protein abundance. Ingenuity Pathway Analysis (IPA) core analysis revealed that the identified proteins were relevant in, and related to, cancer development with likely involvements in tumor growth, metastasis, hyperproliferation, tumorigenesis, neoplasia, hyperplasia, and cell transformation. In conclusion, we have demonstrated that a comparative study of the secretome of cancer versus normal cell lines can be used to identify cancer-associated proteins.
    Matched MeSH terms: Mouth Neoplasms/genetics
  4. Fulltext 1'-Acetoxychavicol acetate inhibits growth of human oral carcinoma xenograft in mice and potentiates cisplatin effect via proinflammatory microenvironment alterations
    In LL, Arshad NM, Ibrahim H, Azmi MN, Awang K, Nagoor NH
    BMC Complement Altern Med, 2012;12:179.
    PMID: 23043547 DOI: 10.1186/1472-6882-12-179
    Oral cancers although preventable, possess a low five-year survival rate which has remained unchanged over the past three decades. In an attempt to find a more safe, affordable and effective treatment option, we describe here the use of 1'S-1'-acetoxychavicol acetate (ACA), a component of Malaysian ginger traditionally used for various medicinal purposes.
    Matched MeSH terms: Mouth Neoplasms/genetics
  5. Genome-wide analysis of oral squamous cell carcinomas revealed over expression of ISG15, Nestin and WNT11
    Vincent-Chong VK, Ismail SM, Rahman ZA, Sharifah NA, Anwar A, Pradeep PJ, et al.
    Oral Dis, 2012 Jul;18(5):469-76.
    PMID: 22251088 DOI: 10.1111/j.1601-0825.2011.01894.x
    Multistep pathways and mechanisms are involved in the development of oral cancer. Chromosomal alterations are one of such key mechanisms implicated oral carcinogenesis. Therefore, this study aims to determine the genomic copy number alterations (CNAs) in oral squamous cell carcinoma (OSCC) using array comparative genomic hybridization (aCGH) and in addition attempt to correlate CNAs with modified gene expression.
    Matched MeSH terms: Mouth Neoplasms/genetics*
  6. Fulltext Genetically-defined novel oral squamous cell carcinoma cell lines for the development of molecular therapies
    Fadlullah MZ, Chiang IK, Dionne KR, Yee PS, Gan CP, Sam KK, et al.
    Oncotarget, 2016 May 10;7(19):27802-18.
    PMID: 27050151 DOI: 10.18632/oncotarget.8533
    Emerging biological and translational insights from large sequencing efforts underscore the need for genetically-relevant cell lines to study the relationships between genomic alterations of tumors, and therapeutic dependencies. Here, we report a detailed characterization of a novel panel of clinically annotated oral squamous cell carcinoma (OSCC) cell lines, derived from patients with diverse ethnicity and risk habits. Molecular analysis by RNAseq and copy number alterations (CNA) identified that the cell lines harbour CNA that have been previously reported in OSCC, for example focal amplications in 3q, 7p, 8q, 11q, 20q and deletions in 3p, 5q, 8p, 18q. Similarly, our analysis identified the same cohort of frequently mutated genes previously reported in OSCC including TP53, CDKN2A, EPHA2, FAT1, NOTCH1, CASP8 and PIK3CA. Notably, we identified mutations (MLL4, USP9X, ARID2) in cell lines derived from betel quid users that may be associated with this specific risk factor. Gene expression profiles of the ORL lines also aligned with those reported for OSCC. By focusing on those gene expression signatures that are predictive of chemotherapeutic response, we observed that the ORL lines broadly clustered into three groups (cell cycle, xenobiotic metabolism, others). The ORL lines noted to be enriched in cell cycle genes responded preferentially to the CDK1 inhibitor RO3306, by MTT cell viability assay. Overall, our in-depth characterization of clinically annotated ORL lines provides new insight into the molecular alterations synonymous with OSCC, which can facilitate in the identification of biomarkers that can be used to guide diagnosis, prognosis, and treatment of OSCC.
    Matched MeSH terms: Mouth Neoplasms/genetics*
  7. Cancer-associated fibroblasts regulate keratinocyte cell-cell adhesion via TGF-β-dependent pathways in genotype-specific oral cancer
    Cirillo N, Hassona Y, Celentano A, Lim KP, Manchella S, Parkinson EK, et al.
    Carcinogenesis, 2017 01;38(1):76-85.
    PMID: 27803052 DOI: 10.1093/carcin/bgw113
    The interrelationship between malignant epithelium and the underlying stroma is of fundamental importance in tumour development and progression. In the present study, we used cancer-associated fibroblasts (CAFs) derived from genetically unstable oral squamous cell carcinomas (GU-OSCC), tumours that are characterized by the loss of genes such as TP53 and p16INK4A and with extensive loss of heterozygosity, together with CAFs from their more genetically stable (GS) counterparts that have wild-type TP53 and p16INK4A and minimal loss of heterozygosity (GS-OSCC). Using a systems biology approach to interpret the genome-wide transcriptional profile of the CAFs, we show that transforming growth factor-β (TGF-β) family members not only had biological relevance in silico but also distinguished GU-OSCC-derived CAFs from GS-OSCC CAFs and fibroblasts from normal oral mucosa. In view of the close association between TGF-β family members, we examined the expression of TGF-β1 and TGF-β2 in the different fibroblast subtypes and showed increased levels of active TGF-β1 and TGF-β2 in CAFs from GU-OSCC. CAFs from GU-OSCC, but not GS-OSCC or normal fibroblasts, induced epithelial-mesenchymal transition and down-regulated a broad spectrum of cell adhesion molecules resulting in epithelial dis-cohesion and invasion of target keratinocytes in vitro in a TGF-β-dependent manner. The results demonstrate that the TGF-β family of cytokines secreted by CAFs derived from genotype-specific oral cancer (GU-OSCC) promote, at least in part, the malignant phenotype by weakening intercellular epithelial adhesion.
    Matched MeSH terms: Mouth Neoplasms/genetics
  8. Significant association of high-risk human papillomavirus (HPV) but not of p53 polymorphisms with oral squamous cell carcinomas in Malaysia
    Saini R, Tang TH, Zain RB, Cheong SC, Musa KI, Saini D, et al.
    J Cancer Res Clin Oncol, 2011 Feb;137(2):311-20.
    PMID: 20419384 DOI: 10.1007/s00432-010-0886-8
    PURPOSE: The purpose of this study was to evaluate the role of HPV and p53 polymorphisms in oral squamous cell carcinomas (OSCC) affecting Malaysian population.

    METHODS: We analysed frozen samples from 105 OSCC as well as 105 oral specimens derived from healthy individuals. PCR assays targeting two regions of the virus were used. PCR amplification for the analysis of p53 codon 72 arginine/proline alleles was carried out in a separate reaction.

    RESULTS: HPV DNA was detected in 51.4% OSCC samples, while 24.8% controls were found to be HPV positive. HPV was found to be significantly associated with OSCC (P 

    Matched MeSH terms: Mouth Neoplasms/genetics
  9. Fulltext Mitochondrial DNA alterations may influence the cisplatin responsiveness of oral squamous cell carcinoma
    Aminuddin A, Ng PY, Leong CO, Chua EW
    Sci Rep, 2020 May 12;10(1):7885.
    PMID: 32398775 DOI: 10.1038/s41598-020-64664-3
    Cisplatin is the first-line chemotherapeutic agent for the treatment of oral squamous cell carcinoma (OSCC). However, the intrinsic or acquired resistance against cisplatin remains a major obstacle to treatment efficacy in OSCC. Recently, mitochondrial DNA (mtDNA) alterations have been reported in a variety of cancers. However, the role of mtDNA alterations in OSCC has not been comprehensively studied. In this study, we evaluated the correlation between mtDNA alterations (mtDNA content, point mutations, large-scale deletions, and methylation status) and cisplatin sensitivity using two OSCC cell lines, namely SAS and H103, and stem cell-like tumour spheres derived from SAS. By microarray analysis, we found that the tumour spheres profited from aberrant lipid and glucose metabolism and became resistant to cisplatin. By qPCR analysis, we found that the cells with less mtDNA were less responsive to cisplatin (H103 and the tumour spheres). Based on the findings, we theorised that the metabolic changes in the tumour spheres probably resulted in mtDNA depletion, as the cells suppressed mitochondrial respiration and switched to an alternative mode of energy production, i.e. glycolysis. Then, to ascertain the origin of the variation in mtDNA content, we used MinION, a nanopore sequencer, to sequence the mitochondrial genomes of H103, SAS, and the tumour spheres. We found that the lower cisplatin sensitivity of H103 could have been caused by a constellation of genetic and epigenetic changes in its mitochondrial genome. Future work may look into how changes in mtDNA translate into an impact on cell function and therefore cisplatin response.
    Matched MeSH terms: Mouth Neoplasms/genetics*
  10. Fulltext Genetic alterations of chromosome 8 genes in oral cancer
    Yong ZW, Zaini ZM, Kallarakkal TG, Karen-Ng LP, Rahman ZA, Ismail SM, et al.
    Sci Rep, 2014;4:6073.
    PMID: 25123227 DOI: 10.1038/srep06073
    The clinical relevance of DNA copy number alterations in chromosome 8 were investigated in oral cancers. The copy numbers of 30 selected genes in 33 OSCC patients were detected using the multiplex ligation-dependent probe amplification (MLPA) technique. Amplifications of the EIF3E gene were found in 27.3% of the patients, MYC in 18.2%, RECQL4 in 15.2% and MYBL1 in 12.1% of patients. The most frequent gene losses found were the GATA4 gene (24.2%), FGFR1 gene (24.2%), MSRA (21.2) and CSGALNACT1 (12.1%). The co-amplification of EIF3E and RECQL4 was found in 9% of patients and showed significant association with alcohol drinkers. There was a significant association between the amplification of EIF3E gene with non-betel quid chewers and the negative lymph node status. EIF3E amplifications did not show prognostic significance on survival. Our results suggest that EIF3E may have a role in the carcinogenesis of OSCC in non-betel quid chewers.
    Matched MeSH terms: Mouth Neoplasms/genetics*
  11. Changed expression of E-cadherin and galectin-9 in oral squamous cell carcinomas but lack of potential as prognostic markers
    Chan SW, Kallarakkal TG, Abraham MT
    Asian Pac J Cancer Prev, 2014;15(5):2145-52.
    PMID: 24716948
    BACKGROUND: The survival rate for oral squamous cell carcinoma (OSCC) has remained generally unchanged in the past three decades, underlining the need for more biomarkers to be developed to aid prognostication and effective management. The prognostic potential of E-cadherin expression in OSCCs has been variable in previous studies while galectin-9 expression has been correlated with improved prognosis in other cancers. The aim of the present study was to investigate the expression of galectin-9 and E-cadherin in OSCC and their potential as prognostic biomarkers.

    MATERIALS AND METHODS: E-cadherin and Galectin-9 expression was examined by immunohistochemistry in 32 cases of OSCC of the buccal mucosa (13 with and 19 without lymph node metastasis), as well as 6 samples of reactive lesions and 5 of normal buccal mucosa.

    RESULTS: The expression of E-cadherin in OSCC was significantly lower than the control tissues but galectin-9 expression was conversely higher. Median E-cadherin HSCOREs between OSCCs positive and negative for nodal metastasis were not significantly different. Mean HSCOREs for galectin-9 in OSCC without lymph node metastasis (127.7 ± 81.8) was higher than OSCC with lymph node metastasis (97.9 ± 62.9) but this difference was not statistically significant.

    CONCLUSIONS: E-cadherin expression is reduced whilst galectin-9 expression is increased in OSCC. However, the present results suggest that E-cadherin and galectin-9 expression may not be useful as prognostic markers for OSCC.

    Matched MeSH terms: Mouth Neoplasms/genetics*
  12. Combined effects of isothiocyanate intake, glutathione S-transferase polymorphisms and risk habits for age of oral squamous cell carcinoma development
    Karen-Ng LP, Marhazlinda J, Rahman ZA, Yang YH, Jalil N, Cheong SC, et al.
    Asian Pac J Cancer Prev, 2011;12(5):1161-6.
    PMID: 21875259
    Dietary isothiocyanates (ITCs) found in cruciferous vegetables (Brassica spp.) has been reported to reduce cancer risk by inducing phase II conjugating enzymes, in particular glutathione S-transferases (GSTs). This case-control study was aimed at determining associations between dietary ITCs, GSTs polymorphisms and risk habits (cigarette smoking, alcohol drinking and betel-quid chewing) with oral cancer in 115 cases and 116 controls. Information on dietary ITC intake from cruciferous vegetables was collected via a semi-quantitative food frequency questionnaire (FFQ). Peripheral blood lymphocytes were obtained for genotyping of GSTM1, GSTT1 and GSTP1 using PCR multiplex and PCR-RFLP. Chi-square and logistic regression were performed to determine the association of ITC and GSTs polymorphism and risk of oral cancer. When dietary ITC was categorized into high (greater than/equal to median) and low (less than median) intake, there was no significant difference between cases and control group. Logistic regression yielding odd ratios resulted in no significant association between dietary ITC intake, GSTM1, GSTT1 or GSTP1 genotypes with oral cancer risk overall. However, GSTP1 wild-type genotype was associated with later disease onset in women above 55 years of age (p= 0.017). Among the men above 45 years of age, there was clinical significant difference of 17 years in the age of onset of oral cancer between GSTP1 wild-type + low ITC intake and GSTP1 polymorphism + high ITC intake (p= 0.001). Similar conditions were also seen among men above 45 years of age with risk habits like drinking and chewing as the earlier disease onset associated with GSTP1 polymorphism and high ITC intake (p< 0.001). This study suggests that combination effects between dietary ITCs, GSTP1 polymorphism and risk habits may be associated with the risk of oral cancer and modulate the age of disease onset.
    Matched MeSH terms: Mouth Neoplasms/genetics
  13. Cyclin D1 amplification in tongue and cheek squamous cell carcinoma
    Mahdey HM, Ramanathan A, Ismail SM, Abraham MT, Jamaluddin M, Zain RB
    Asian Pac J Cancer Prev, 2011;12(9):2199-204.
    PMID: 22296356
    INTRODUCTION: Several molecular markers have been studied for their usefulness as prognostic markers in oral squamous cell carcinoma (OSCC). One such molecular marker is cyclin D1 which is a proto-oncogene located on 11q13 in humans.

    OBJECTIVE: To explore the feasibility of using cyclin D1 as a prognostic marker in tongue and cheek SCC by the fluorescent-in-situ hybridization (FISH) method.

    METHODS: Fifty paraffin-embedded samples (25 each of cheek and tongue SCCs) were obtained from the archives of the Oral Pathology Diagnostic Laboratory. Sociodemographic data, histopathologic diagnoses, lymph node status and survival data were obtained from the Malaysian Oral Cancer Database and Tissue Bank System (MOCDTBS)coordinated by the Oral Cancer Research and Coordinating Centre (OCRCC), University of Malaya. The FISH technique was used to detect the amplification of cyclin D1 using the Vysis protocol. Statistical correlations of cyclin D1 with site and lymph node status were analyzed using the Fisher exact test. Kaplan-Meier and Log Rank (Mantel-Cox) test were used to analyze cyclin D1 amplification and median survival time.

    RESULTS: Positive amplification of cyclin D1 was detected in 72% (36) of OSCCs. Detection of positive amplification for cyclin D1 was observed in 88% (22) and 56% (14) of the tongue and cheek tumors, respectively, where the difference was statistically significant (P=0.012). Lymph node metastasis of cheek SCCs showed a trend towards a significant association (P= 0.098) with cyclin D1 amplification whereas the lymph node metastasis of tongue SCC was clearly not significant (P=0.593).There was a statistically significant correlation between cyclin D1 positivity and survival rate (P=0.009) for overall SCC cases and (P<0.001) for cheek SCC cases.

    CONCLUSION: The present study found that cyclin D1 amplification may differ in different subsites of OSCC (tongue vs cheek) and its positive amplification implies an overall poor survival in OSCCs, particularly those arising in cheeks.

    Matched MeSH terms: Mouth Neoplasms/genetics*
  14. p53 Expression as a marker of microinvasion in oral squamous cell carcinoma
    Heah KG, Hassan MI, Huat SC
    Asian Pac J Cancer Prev, 2011;12(4):1017-22.
    PMID: 21790244
    INTRODUCTION: Oral squamous cell carcinoma (OSCC) has high local recurrence, partly caused by the lack of clear margin identification on surgical removal of cancerous tissues. Direct visualization by immunostaining and fluorescent in situ hybridization (FISH) in tissue sections gives more definite information about genetic damage at margins with appropriately selected biomarkers.

    AIMS: To determine the usefulness of immunohistochemical techniques and FISH of the tumour suppressor TP 53 gene to identify microinvasion in marginal tissue sections and to relate the possible correlation between protein expression and genetic aberrations in OSCC cases in Malaysia.

    METHODS: Immunohistochemistry and FISH of TP 53 genes were applied on 26 OSCC formalin fixed paraffin embed (FFEP) blocks selected from two oral cancer referral centers in Malaysia.

    RESULTS: For p53 protein immunohistochemistry, 96% of the 26 OSCC studied showed positive immunostaining at the excision margins. In FISH assay, 48.9±9.7% of the cancerous cells were monoploid for p53 probe signals, 41.0±9.5 % were diploid, and 10.2±7.8 % were polyploid. A correlation between p53 immunostaining and TP53 gene aberrations was noted (p< 0.05).

    CONCLUSIONS: Immunohistochemical analysis of p53 protein expression and FISH of TP53 gene could be applied as screening tool for microinvasion of OSCC.

    Matched MeSH terms: Mouth Neoplasms/genetics*
  15. Gene expression in human oral squamous cell carcinoma is influenced by risk factor exposure
    Cheong SC, Chandramouli GV, Saleh A, Zain RB, Lau SH, Sivakumaren S, et al.
    Oral Oncol, 2009 Aug;45(8):712-9.
    PMID: 19147396 DOI: 10.1016/j.oraloncology.2008.11.002
    Oral squamous cell carcinoma (OSCC) is a world health problem and is associated with exposure to different risk factors. In the west, smoking and alcohol consumption are considered to be the main risk factors whilst in India and southeast Asia, betel quid (BQ) chewing is predominant. In this study, we compared the gene expression patterns of oral cancers associated with BQ chewing to those caused by smoking using Affymetrix microarrays. We found that 281 genes were differentially expressed between OSCC and normal oral mucosa regardless of aetiological factors including MMP1, PLAU, MAGE-D4, GNA12, IFITM3 and NMU. Further, we identified 168 genes that were differentially expressed between the BQ and smoking groups including CXCL-9, TMPRSS2, CA12 and RNF24. The expression of these genes was validated using qPCR using independent tissue samples. The results demonstrate that whilst common genes/pathways contribute to the development of oral cancer, there are also other gene expression changes that are specific to certain risk factors. The findings suggest that different carcinogens activate or inhibit specific pathways during cancer development and progression. These unique gene expression profiles should be taken into consideration when developing biomarkers for future use in prognostic or therapeutic applications.
    Matched MeSH terms: Mouth Neoplasms/genetics*
  16. Fulltext Genome wide analysis of chromosomal alterations in oral squamous cell carcinomas revealed over expression of MGAM and ADAM9
    Vincent-Chong VK, Anwar A, Karen-Ng LP, Cheong SC, Yang YH, Pradeep PJ, et al.
    PLoS One, 2013;8(2):e54705.
    PMID: 23405089 DOI: 10.1371/journal.pone.0054705
    Despite the advances in diagnosis and treatment of oral squamous cell carcinoma (OSCC), mortality and morbidity rates have not improved over the past decade. A major drawback in diagnosis and treatment of OSCC is the lack of knowledge relating to how genetic instability in oral cancer genomes affects oral carcinogenesis. Hence, the key aim of this study was to identify copy number alterations (CNAs) that may be cancer associated in OSCC using high-resolution array comparative genomic hybridization (aCGH). To our knowledge this is the first study to use ultra-high density aCGH microarrays to profile a large number of OSCC genomes (n = 46). The most frequently amplified CNAs were located on chromosome 11q11(52%), 2p22.3(52%), 1q21.3-q22(54%), 6p21.32(59%), 20p13(61%), 7q34(52% and 72%),8p11.23-p11.22(80%), 8q11.1-q24.4(54%), 9q13-q34.3(54%), 11q23.3-q25(57%); 14q21.3-q31.1(54%); 14q31.3-q32.33(57%), 20p13-p12.3(54%) and 20q11.21-q13.33(52%). The most frequently deleted chromosome region was located on 3q26.1 (54%). In order to verify the CNAs from aCGH using quantitative polymerase chain reaction (qPCR), the three top most amplified regions and their associated genes, namely ADAM5P (8p11.23-p11.22), MGAM (7q34) and SIRPB1 (20p13.1), were selected in this study. The ADAM5P locus was found to be amplified in 39 samples and deleted in one; MGAM (24 amplifications and 3 deletions); and SIRPB1 (12 amplifications, others undetermined). On the basis of putative cancer-related annotations, two genes, namely ADAM metallopeptidase domain 9 (ADAM9) and maltase-glucoamylase alpha-glucosidase (MGAM), that mapped to CNA regions were selected for further evaluation of their mRNA expression using reverse transcriptase qPCR. The over-expression of MGAM was confirmed with a 6.6 fold increase in expression at the mRNA level whereas the fold change in ADAM9 demonstrated a 1.6 fold increase. This study has identified significant regions in the OSCC genome that were amplified and resulted in consequent over-expression of the MGAM and ADAM9 genes that may be utilized as biological markers for OSCC.
    Matched MeSH terms: Mouth Neoplasms/genetics*
  17. Caveolin 1 (Cav-1) and actin-related protein 2/3 complex, subunit 1B (ARPC1B) expressions as prognostic indicators for oral squamous cell carcinoma (OSCC)
    Auzair LB, Vincent-Chong VK, Ghani WM, Kallarakkal TG, Ramanathan A, Lee CE, et al.
    Eur Arch Otorhinolaryngol, 2016 Jul;273(7):1885-93.
    PMID: 26138391 DOI: 10.1007/s00405-015-3703-9
    Caveolin-1 (Cav-1) and Actin-Related Protein 2/3 Complex, Subunit 1B (ARPC1B) have been implicated in various human cancers, yet its role in tumorigenesis remains controversial. Therefore, this study aims to determine the protein expression of these two genes in oral squamous cell carcinomas (OSCCs) and to evaluate the clinical and prognostic impact of these genes in OSCC. Protein expressions of these two genes were determined by immunohistochemistry technique. The association between Cav-1 and ARPC1B with clinico-pathological parameters was evaluated by Chi-square test (or Fisher exact test where appropriate). Correlation between the protein expressions of these 2 genes with survival was analyzed using Kaplan-Meier and Cox regression models. Cav-1 and ARPC1B were found to be significantly over-expressed in OSCC compared to normal oral mucosa (p = 0.002 and p = 0.033, respectively). Low level of ARPC1B protein expression showed a significant correlation with lymph node metastasis (LNM) (p = 0.010) and advanced tumor staging (p = 0.003). Kaplan-Meier survival analyses demonstrated that patients with over-expression of Cav-1 protein were associated with poor prognosis (p = 0.030). Adjusted multivariate Cox regression model revealed that over-expression of Cav-1 remained as an independent significant prognostic factor for OSCC (HRR = 2.700, 95 % CI 1.013-7.198, p = 0.047). This study demonstrated that low-expression of ARPC1B is significantly associated with LNM and advanced tumor staging whereas high expression of Cav-1 can be a prognostic indicator for poor prognosis in OSCC patients.
    Matched MeSH terms: Mouth Neoplasms/genetics*
  18. Fulltext DNA methylation profiling revealed promoter hypermethylation-induced silencing of p16, DDAH2 and DUSP1 in primary oral squamous cell carcinoma
    Khor GH, Froemming GR, Zain RB, Abraham MT, Omar E, Tan SK, et al.
    Int J Med Sci, 2013;10(12):1727-39.
    PMID: 24155659 DOI: 10.7150/ijms.6884
    BACKGROUND: Hypermethylation in promoter regions of genes might lead to altered gene functions and result in malignant cellular transformation. Thus, biomarker identification for hypermethylated genes would be very useful for early diagnosis, prognosis, and therapeutic treatment of oral squamous cell carcinoma (OSCC). The objectives of this study were to screen and validate differentially hypermethylated genes in OSCC and correlate the hypermethylation-induced genes with demographic, clinocopathological characteristics and survival rate of OSCC.

    METHODS: DNA methylation profiling was utilized to screen the differentially hypermethylated genes in OSCC. Three selected differentially-hypermethylated genes of p16, DDAH2 and DUSP1 were further validated for methylation status and protein expression. The correlation between demographic, clinicopathological characteristics, and survival rate of OSCC patients with hypermethylation of p16, DDAH2 and DUSP1 genes were analysed in the study.

    RESULTS: Methylation profiling demonstrated 33 promoter hypermethylated genes in OSCC. The differentially-hypermethylated genes of p16, DDAH2 and DUSP1 revealed positivity of 78%, 80% and 88% in methylation-specific polymerase chain reaction and 24% and 22% of immunoreactivity in DDAH2 and DUSP1 genes, respectively. Promoter hypermethylation of p16 gene was found significantly associated with tumour site of buccal, gum, tongue and lip (P=0.001). In addition, DDAH2 methylation level was correlated significantly with patients' age (P=0.050). In this study, overall five-year survival rate was 38.1% for OSCC patients and was influenced by sex difference.

    CONCLUSIONS: The study has identified 33 promoter hypermethylated genes that were significantly silenced in OSCC, which might be involved in an important mechanism in oral carcinogenesis. Our approaches revealed signature candidates of differentially hypermethylated genes of DDAH2 and DUSP1 which can be further developed as potential biomarkers for OSCC as diagnostic, prognostic and therapeutic targets in the future.

    Matched MeSH terms: Mouth Neoplasms/genetics*
  19. Fulltext Autophagy is deregulated in cancer-associated fibroblasts from oral cancer and is stimulated during the induction of fibroblast senescence by TGF-β1
    Tan ML, Parkinson EK, Yap LF, Paterson IC
    Sci Rep, 2021 01 12;11(1):584.
    PMID: 33436723 DOI: 10.1038/s41598-020-79789-8
    Many of the characteristics ascribed to cancer-associated fibroblasts (CAFs) are shared by activated, autophagic and senescent fibroblasts. Whilst most oral squamous cell carcinomas (OSCCs) are genetically unstable (GU-OSCC), genetically stable variants (GS-OSCC) have been described and, notably, CAF activation (myofibroblast differentiation) and senescence are characteristics particularly associated with GU-OSCCs. However, it is not known whether autophagy is disrupted in these cells or whether autophagy regulates the development of the myofibroblast and senescent phenotypes. In this study, we show that senescent CAFs from GU-OSCCs contained more autophagosomes than normal human oral fibroblasts (NHOFs) and CAFs from GS-OSCCs possibly due to autophagic impairment. Further, we show that deregulation of autophagy in normal fibroblasts, either by inhibition with autophagy inhibitor, SAR405, or activation with TGF-β1, induced fibroblast activation and senescence: In response to TGF-β1, autophagy was induced prior to the development of the activated and senescent phenotypes. Lastly, we show that both SAR405- and TGF-β1-treated NHOFs enhance OSCC cell migration but only TGF-β1-treated cells increase OSCC invasion through Matrigel, indicating that TGF-β1 has additional effects that are independent of fibroblast activation/senescence. These results suggest a functional role for autophagy in the development of myofibroblast and CAF phenotypes.
    Matched MeSH terms: Mouth Neoplasms/genetics*
  20. Association of Interleukin-10 Genotypes and Oral Cancer Susceptibility in Selected Malaysian Population: A Case- Control Study
    Goud EVSS, Malleedi S, Ramanathan A, Wong GR, Hwei Ern BT, Yean GY, et al.
    Asian Pac J Cancer Prev, 2019 Mar 26;20(3):935-941.
    PMID: 30912418
    Background: Interleukin-10 (IL10) genotypes have been closely correlated to the susceptibility for oral squamous cell
    carcinoma. More than half of oral cancers in the world occur in Asia with estimated 168,850 new cases were diagnosed
    in this geographical region alone. Considering the rising numbers of oral cancer cases in Malaysia, association of IL10
    A1082G gene polymorphism was correlated. Methodology: 41 oral squamous cell carcinoma (OSCC) cases and 48
    healthy controls of comparable age, gender, and with habits like smoking, alcohol consumption and betel quid chewing
    were selected. In this case-control study, samples were collected from the Oral Cancer Research and Coordinating
    Centre (OCRCC), Faculty of Dentistry, University of Malaya, Malaysia. Genotyping conditions were evaluated by
    polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The PCR products were subjected
    to digestion by MnlI enzyme (NEB, UK) to screen for the IL10 A-1082G. Digested DNA products were analyzed by
    electrophoresis on 4% (w/v) agarose gel, stained with ethidium bromide and imaged under UV illumination. Chi-square
    test and Fisher’s Exact test were used in statistical analysis. Results: AG genotypes were present in 81.3% and 86.0% of
    healthy control and OSCC cases respectively (OR=0.468, 95% CI=0.133-1.653). No significant association was found
    between IL10 A1082G polymorphism with risk habits, clinico-pathological parameters and 5-years overall survival.
    The findings also show no significant correlation between the IL10 genotype and features of OSCC within the case
    group as measured by tumor size, lymph node involvement, stage, invasive front, grading, depth, pattern of invasion.
    Conclusion: This study suggests that functional polymorphism AG of IL10 A1082G may have no influence with OSCC
    susceptibility. However, further investigation with larger sample sizes can be conducted to provide additional evidence
    to support the lack of association of IL10 A1082G polymorphism in oral cancer.
    Matched MeSH terms: Mouth Neoplasms/genetics*
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