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  1. Differential expression of a subset of ribosomal protein genes in cell lines derived from human nasopharyngeal epithelium
    Sim EU, Ang CH, Ng CC, Lee CW, Narayanan K
    J Hum Genet, 2010 Feb;55(2):118-20.
    PMID: 19927161 DOI: 10.1038/jhg.2009.124
    Extraribosomal functions of human ribosomal proteins (RPs) include the regulation of cellular growth and differentiation, and are inferred from studies that linked congenital disorders and cancer to the deregulated expression of RP genes. We have previously shown the upregulation and downregulation of RP genes in tumors of colorectal and nasopharyngeal carcinomas (NPCs), respectively. Herein, we show that a subset of RP genes for the large ribosomal subunit is differentially expressed among cell lines derived from the human nasopharyngeal epithelium. Three such genes (RPL27, RPL37a and RPL41) were found to be significantly downregulated in all cell lines derived from NPC tissues compared with a nonmalignant nasopharyngeal epithelial cell line. The expression of RPL37a and RPL41 genes in human nasopharyngeal tissues has not been reported previously. Our findings support earlier suspicions on the existence of NPC-associated RP genes, and indicate their importance in human nasopharyngeal organogenesis.
    Matched MeSH terms: Carcinoma/metabolism*
  2. Fulltext Human Ribosomal Proteins RPeL27, RPeL43, and RPeL41 Are Upregulated in Nasopharyngeal Carcinoma Cell Lines
    Sim EU, Chan SL, Ng KL, Lee CW, Narayanan K
    Dis Markers, 2016;2016:5179594.
    PMID: 28018022 DOI: 10.1155/2016/5179594
    Apart from their canonical role in ribosome biogenesis, there is increasing evidence of ribosomal protein genes' involvement in various cancers. A previous study by us revealed significant differential expression of three ribosomal protein genes (RPeL27, RPeL41, and RPeL43) between cell lines derived from tumor and normal nasopharyngeal epithelium. However, the results therein were based on a semiquantitative assay, thus preliminary in nature. Herein, we provide findings of a deeper analysis of these three genes in the context to nasopharyngeal carcinoma (NPC) tumorigenesis. Their expression patterns were analyzed in a more quantitative manner at transcript level. Their protein expression levels were also investigated. We showed results that are contrary to previous report. Rather than downregulation, these genes were significantly overexpressed in NPC cell lines compared to normal control at both transcript and protein levels. Nevertheless, their association with NPC has been established. Immunoprecipitation pulldown assays indicate the plausible interaction of either RPeL27 or RPeL43 with POTEE/TUBA1A and ACTB/ACTBL2 complexes. In addition, RPeL43 is shown to bind with MRAS and EIF2S1 proteins in a NPC cell line (HK1). Our findings support RPeL27, RPeL41, and RPeL43 as potential markers of NPC and provide insights into the interaction targets of RPeL27 and RPeL43 proteins.
    Matched MeSH terms: Carcinoma/metabolism*
  3. Fulltext Integrated pathway analysis of nasopharyngeal carcinoma implicates the axonemal dynein complex in the Malaysian cohort
    Chin YM, Tan LP, Abdul Aziz N, Mushiroda T, Kubo M, Mohd Kornain NK, et al.
    Int J Cancer, 2016 10 15;139(8):1731-9.
    PMID: 27236004 DOI: 10.1002/ijc.30207
    Nasopharyngeal carcinoma (NPC) is an epithelial squamous cell carcinoma on the mucosal lining of the nasopharynx. The etiology of NPC remains elusive despite many reported studies. Most studies employ a single platform approach, neglecting the cumulative influence of both the genome and transcriptome toward NPC development. We aim to employ an integrated pathway approach to identify dysregulated pathways linked to NPC. Our approach combines imputation NPC GWAS data from a Malaysian cohort as well as published expression data GSE12452 from both NPC and non-NPC nasopharynx tissues. Pathway association for GWAS data was performed using MAGENTA while for expression data, GSA-SNP was used with gene p values derived from differential expression values from GEO2R. Our study identified NPC association in the gene ontology (GO) axonemal dynein complex pathway (pGWAS-GSEA  = 1.98 × 10(-2) ; pExpr-GSEA  = 1.27 × 10(-24) ; pBonf-Combined  = 4.15 × 10(-21) ). This association was replicated in a separate cohort using gene expression data from NPC and non-NPC nasopharynx tissues (pAmpliSeq-GSEA  = 6.56 × 10(-4) ). Loss of function in the axonemal dynein complex causes impaired cilia function, leading to poor mucociliary clearance and subsequently upper or lower respiratory tract infection, the former of which includes the nasopharynx. Our approach illustrates the potential use of integrated pathway analysis in detecting gene sets involved in the development of NPC in the Malaysian cohort.
    Matched MeSH terms: Carcinoma/metabolism*
  4. Fulltext An Oncogenic Role for Four-Jointed Box 1 (FJX1) in Nasopharyngeal Carcinoma
    Chai SJ, Ahmad Zabidi MM, Gan SP, Rajadurai P, Lim PVH, Ng CC, et al.
    Dis Markers, 2019;2019:3857853.
    PMID: 31236144 DOI: 10.1155/2019/3857853
    Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer prevalent in Southern China and Southeast Asia. The current knowledge on the molecular pathogenesis of NPC is still inadequate to improve disease management. Using gene expression microarrays, we have identified the four-jointed box 1 (FJX1) gene to be upregulated in primary NPC tissues relative to nonmalignant tissues. An orthologue of human FJX1, the four-jointed (fj) gene in Drosophila and Fjx1 in mouse, has reported to be associated with cancer progression pathways. However, the exact function of FJX1 in human is not well characterized. The overexpression of FJX1 mRNA was validated in primary NPC tissue samples, and the level of FJX1 protein was significantly higher in a subset of NPC tissues (42%) compared to the normal epithelium, where no expression of FJX1 was observed (p = 0.01). FJX1 is also found to be overexpressed in microarray datasets and TCGA datasets of other cancers including head and neck cancer, colorectal, and ovarian cancer. Both siRNA knockdown and overexpression experiments in NPC cell lines showed that FJX1 promotes cell proliferation, anchorage-dependent growth, and cellular invasion. Cyclin D1 and E1 mRNA levels were increased following FJX1 expression indicating that FJX1 enhances proliferation by regulating key proteins governing the cell cycle. Our data suggest that the overexpression of FJX1 contributes to a more aggressive phenotype of NPC cells and further investigations into FJX1 as a potential therapeutic target for NPC are warranted. The evaluation of FJX1 as an immunotherapy target for NPC and other cancers is currently ongoing.
    Matched MeSH terms: Carcinoma/metabolism
  5. Fulltext DK1 Induces Apoptosis via Mitochondria-Dependent Signaling Pathway in Human Colon Carcinoma Cell Lines In Vitro
    Hussin Y, Aziz MNM, Che Rahim NF, Yeap SK, Mohamad NE, Masarudin MJ, et al.
    Int J Mol Sci, 2018 Apr 11;19(4).
    PMID: 29641445 DOI: 10.3390/ijms19041151
    Extensive research has been done in the search for innovative treatments against colon adenocarcinomas; however, the incidence rate of patients remains a major cause of cancer-related deaths in Malaysia. Natural bioactive compounds such as curcumin have been substantially studied as an alternative to anticancer drug therapies and have been surmised as a potent agent but, nevertheless, remain deficient due to its poor cellular uptake. Therefore, efforts now have shifted toward mimicking curcumin to synthesize novel compounds sharing similar effects. A synthetic analog, (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylprop-2-ene-1-one (DK1), was recently synthesized and reported to confer improved bioavailability and selectivity toward human breast cancer cells. This study, therefore, aims to assess the anticancer mechanism of DK1 in relation to the induction of in vitro cell death in selected human colon cancer cell lines. Using the3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay, the cytotoxicity of DK1 towards HT29 and SW620 cell lines were investigated. Acridine orange/propidium iodide (AO/PI) dual-staining assay and flow cytometry analyses (cell cycle analysis, Annexin/V-FITC and JC-1 assays) were incorporated to determine the mode of cell death. To further determine the mechanism of cell death, quantitative real-time polymerase chain reaction (qRT-PCR) and proteome profiling were conducted. Results from this study suggest that DK1 induced changes in cell morphology, leading to a decrease in cell viability and subsequent induction of apoptosis. DK1 treatment inhibited cell viability and proliferation 48 h post treatment with IC50 values of 7.5 ± 1.6 µM for HT29 cells and 14.5 ± 4.3 µM for SW620 cells, causing cell cycle arrest with increased accumulation of cell populations at the sub-G₀/G₁phaseof 74% and 23%, respectively. Flow cytometry analyses showed that DK1 treatment in cancer cells induced apoptosis, as indicated by DNA fragmentation and depolarization of the mitochondrial membrane. qRT-PCR results show significant upregulation in the expression of caspase-9 in both HT29 and SW620 cell lines, further supporting that cell death induction by DK1 is via an intrinsic pathway. These outcomes, therefore, demonstrate DK1 as a potential anticancer agent for colon adenocarcinoma due to its anti-apoptotic attributes.
    Matched MeSH terms: Carcinoma/metabolism*
  6. HER2 testing by immunohistochemistry in breast cancer: A multicenter proficiency ring study
    Md Pauzi SH, Masir N, Yahaya A, Mohammed F, Tizen Laim NMS, Mustangin M, et al.
    Indian J Pathol Microbiol, 2021 10 22;64(4):677-682.
    PMID: 34673585 DOI: 10.4103/IJPM.IJPM_983_20
    Background: Human epidermal growth factor receptor 2 (HER2) over-expression in breast cancer is associated with aggressive tumor behavior and predicts response to targeted therapy. Accurate HER2 result is paramount for optimal patient management. However, routine HER2 immunohistochemistry (IHC) testing are subjected to intra- and inter-laboratory variability.

    Objective: This study aims to determine inter-laboratory variation in HER2 IHC testing through a slide-exchange program between five main reference laboratories.

    Method: A total of 20 breast carcinoma cases with different known HER2 expression and gene status were selected by the central laboratory in five testing rounds. Three unstained tissue sections from each case were sent to participating laboratories, which immunostained and interpreted the HER2 immunohistochemistry result. One of the stained slides was sent to one designated participating laboratory for evaluation. Results were analyzed by the central laboratory.

    Results: A complete concordance was achieved in six IHC-positive and six IHC-negative cases, its gene status of which was confirmed by in-situ-hybridization (ISH) study. The discordant results were observed in six equivocal cases, one negative case and one positive case with a concordance rate of 50-88.3%. Interestingly, the negative discordant case actually displays tumor heterogeneity. Good inter-observer agreement was achieved for all participating laboratories (k = 0.713-1.0).

    Conclusion: Standardization of HER2 testing method is important to achieve optimum inter-laboratory concordance. Discordant results were seen mainly in equivocal cases. Intra-tumoral heterogeneity may impact the final HER2 IHC scoring. The continuous quality evaluation is therefore paramount to achieve reliable HER2 results.

    Matched MeSH terms: Carcinoma/metabolism*
  7. Fulltext Pattern of hMLH1, hMSH2 and hMSH6 expression and clinical characteristics in a sample of Malaysian colorectal carcinoma cases
    Khoo JJ, Gunn A, Peh SC
    Malays J Pathol, 2013 Jun;35(1):45-57.
    PMID: 23817394 MyJurnal
    Malignant transformation from normal colonic mucosa to carcinomas may be accelerated by genetic loss or inactivation of genes of the DNA mismatch repair system. The aim of the study was to determine the local incidence and pattern of immunohistochemical expression of mismatch repair proteins namely: hMLH1, hMSH2 and hMSH6 in a series of colorectal carcinomas (CRCs) and correlate this to their clinical and pathological features. Forty-three out of 298 cases of CRCs (14.4%) showed abnormal staining pattern for mismatch repair proteins with a majority (65.1%) showing single hMLH1 loss. Tumours with mismatch repair defect (MMR-d) were frequently found at the right side of colon (p<0.001), poorly differentiated carcinomas (p<0.001), produced more mucin (p=0.007), exophytic growth (p=0.007) and were bigger (p=0.002) than tumours with no mismatch repair defect. Immunohistochemical stains for mismatch repair proteins could be done in local laboratories on these selected cases before referring for the expensive molecular test.
    Matched MeSH terms: Carcinoma/metabolism*
  8. Fulltext DACH1, a zona glomerulosa selective gene in the human adrenal, activates transforming growth factor-β signaling and suppresses aldosterone secretion
    Zhou J, Shaikh LH, Neogi SG, McFarlane I, Zhao W, Figg N, et al.
    Hypertension, 2015 May;65(5):1103-10.
    PMID: 25776071 DOI: 10.1161/HYP.0000000000000025
    Common somatic mutations in CACNAID and ATP1A1 may define a subgroup of smaller, zona glomerulosa (ZG)-like aldosterone-producing adenomas. We have therefore sought signature ZG genes, which may provide insight into the frequency and pathogenesis of ZG-like aldosterone-producing adenomas. Twenty-one pairs of zona fasciculata and ZG and 14 paired aldosterone-producing adenomas from 14 patients with Conn's syndrome and 7 patients with pheochromocytoma were assayed by the Affymetrix Human Genome U133 Plus 2.0 Array. Validation by quantitative real-time polymerase chain reaction was performed on genes >10-fold upregulated in ZG (compared with zona fasciculata) and >10-fold upregulated in aldosterone-producing adenomas (compared with ZG). DACH1, a gene associated with tumor progression, was further analyzed. The role of DACH1 on steroidogenesis, transforming growth factor-β, and Wnt signaling activity was assessed in the human adrenocortical cell line, H295R. Immunohistochemistry confirmed selective expression of DACH1 in human ZG. Silencing of DACH1 in H295R cells increased CYP11B2 mRNA levels and aldosterone production, whereas overexpression of DACH1 decreased aldosterone production. Overexpression of DACH1 in H295R cells activated the transforming growth factor-β and canonical Wnt signaling pathways but inhibited the noncanonical Wnt signaling pathway. Stimulation of primary human adrenal cells with angiotensin II decreased DACH1 mRNA expression. Interestingly, there was little overlap between our top ZG genes and those in rodent ZG. In conclusion, (1) the transcriptome profile of human ZG differs from rodent ZG, (2) DACH1 inhibits aldosterone secretion in human adrenals, and (3) transforming growth factor-β signaling pathway is activated in DACH1 overexpressed cells and may mediate inhibition of aldosterone secretion in human adrenals.
    Matched MeSH terms: Adrenocortical Carcinoma/metabolism
  9. Immunohistochemical analysis of p53 expression in primary breast carcinomas
    Naidu R, Yadav M, Nair S, Kutty KK
    Anticancer Res, 1998 Jan-Feb;18(1A):65-70.
    PMID: 9568057
    Expression of p53 protein was investigated by immunohistochemical techniques in archival cases of 134 primary breast carcinomas comprising 13 comedo ductal carcinoma in situ (DCIS), 105 invasive ductal carcinomas, 7 contained the comedo DCIS component adjacent to the invasive ductal component, 5 invasive lobular carcinomas, three colloid carcinomas and one medullary carcinoma. Overexpression of p53 gene product was studied to determine the association with clinico-pathological parameters and also its relationship to c-erbB2. Overexpression of p53 protein was observed in 31% (4/13) of comedo DCIS, 37% (39/105) of invasive ductal carcinomas, 57% (4/7) of carcinomas containing both the in situ and invasive lesions and all medullary carcinomas. A significant relationship (p < 0.05) was observed between strong immunoreactivity of p53 protein and absence of estrogen receptor, histological grade and c-erbB2 but not with lymph node metastases or age of patient. These observations suggest that overexpression of p53 protein may play an important role in tumor progression from noninvasive to invasive in some breast carcinomas and may have potential as an indicator for poorer prognosis.
    Matched MeSH terms: Carcinoma/metabolism*
  10. Molecular alterations of Ras-Raf-mitogen-activated protein kinase and phosphatidylinositol 3-kinase-Akt signaling pathways in colorectal cancers from a tertiary hospital at Kuala Lumpur, Malaysia
    Yip WK, Choo CW, Leong VC, Leong PP, Jabar MF, Seow HF
    APMIS, 2013 Oct;121(10):954-66.
    PMID: 23992303 DOI: 10.1111/apm.12152
    Molecular alterations in KRAS, BRAF, PIK3CA, and PTEN have been implicated in designing targeted therapy for colorectal cancer (CRC). The present study aimed to determine the status of these molecular alterations in Malaysian CRCs as such data are not available in the literature. We investigated the mutations of KRAS, BRAF, and PTEN, the gene amplification of PIK3CA, and the protein expression of PTEN and phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110α) by direct DNA sequencing, quantitative real-time PCR, and immunohistochemistry, respectively, in 49 CRC samples. The frequency of KRAS (codons 12, 13, and 61), BRAF (V600E), and PTEN mutations, and PIK3CA amplification was 25.0% (11/44), 2.3% (1/43), 0.0% (0/43), and 76.7% (33/43), respectively. Immunohistochemical staining demonstrated loss of PTEN protein in 54.5% (24/44) of CRCs and no significant difference in PI3K p110α expression between CRCs and the adjacent normal colonic mucosa (p = 0.380). PIK3CA amplification was not associated with PI3K p110α expression level, but associated with male cases (100% of male cases vs 56% of female cases harbored amplified PIK3CA, p = 0.002). PI3K p110α expression was significantly higher (p = 0.041) in poorly/moderately differentiated carcinoma compared with well-differentiated carcinoma. KRAS mutation, PIK3CA amplification, PTEN loss, and PI3K p110α expression did not correlate with Akt phosphorylation or Ki-67 expression. KRAS mutation, PIK3CA amplification, and PTEN loss were not mutually exclusive. This is the first report on CRC in Malaysia showing comparable frequency of KRAS mutation and PTEN loss, lower BRAF mutation rate, higher PIK3CA amplification frequency, and rare PTEN mutation, as compared with published reports.
    Matched MeSH terms: Carcinoma/metabolism
  11. Apoptotic effects of Physalis minima L. chloroform extract in human breast carcinoma T-47D cells mediated by c-myc-, p53-, and caspase-3-dependent pathways
    Ooi KL, Tengku Muhammad TS, Lim CH, Sulaiman SF
    Integr Cancer Ther, 2010 Mar;9(1):73-83.
    PMID: 20150224 DOI: 10.1177/1534735409356443
    The chloroform extract of Physalis minima produced a significant growth inhibition against human T-47D breast carcinoma cells as compared with other extracts with an EC(50) value of 3.8 microg/mL. An analysis of cell death mechanisms indicated that the extract elicited an apoptotic cell death. mRNA expression analysis revealed the coregulation of apoptotic genes, that is, c-myc , p53, and caspase-3. The c-myc was significantly induced by the chloroform extract at the earlier phase of treatment, followed by p53 and caspase-3. Biochemical assay and ultrastructural observation displayed typical apoptotic features in the treated cells, including DNA fragmentation, blebbing and convolution of cell membrane, clumping and margination of chromatin, and production of membrane-bound apoptotic bodies. The presence of different stages of apoptotic cell death and phosphatidylserine externalization were further reconfirmed by annexin V and propidium iodide staining. Thus, the results from this study strongly suggest that the chloroform extract of P. minima induced apoptotic cell death via p53-, caspase-3-, and c-myc-dependent pathways.
    Matched MeSH terms: Carcinoma/metabolism
  12. Fulltext Deregulation of lipid metabolism pathway genes in nasopharyngeal carcinoma cells
    Daker M, Bhuvanendran S, Ahmad M, Takada K, Khoo AS
    Mol Med Rep, 2013 Mar;7(3):731-41.
    PMID: 23292678 DOI: 10.3892/mmr.2012.1253
    Nasopharyngeal carcinoma (NPC) is a unique tumour of epithelial origin with a distinct geographical distribution, closely associated with the Epstein‑Barr virus (EBV). EBV‑encoded RNAs (EBERs) are small non‑polyadenylated RNAs that are abundantly expressed in latent EBV‑infected NPC cells. To study the role of EBERs in NPC, we established stable expression of EBERs in HK1, an EBV‑negative NPC cell line. Cells expressing EBERs consistently exhibited an increased growth rate. However, EBERs did not confer resistance towards cisplatin‑induced apoptosis or promote migration or invasion ability in the cells tested. Using microarray gene expression profiling, we identified potential candidate genes that were deregulated in NPC cells expressing EBERs. Gene Ontology analysis of the data set revealed that EBERs upregulate the cellular lipid metabolic process. Upregulation of low‑density lipoprotein receptor (LDLR) and fatty acid synthase (FASN) was observed in EBER‑expressing cells. NPC cells exhibited LDL‑dependent cell proliferation. In addition, a polyphenolic flavonoid compound, quercetin, known to inhibit FASN, was found to inhibit proliferation of NPC cells.
    Matched MeSH terms: Carcinoma/metabolism
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