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  1. Fulltext The uS8, uS4, eS31, and uL14 Ribosomal Protein Genes Are Dysregulated in Nasopharyngeal Carcinoma Cell Lines
    Sim EU, Ng KL, Lee CW, Narayanan K
    Biomed Res Int, 2017;2017:4876954.
    PMID: 28791303 DOI: 10.1155/2017/4876954
    The association of ribosomal proteins with carcinogenesis of nasopharyngeal carcinoma (NPC) has been established in a limited subset of ribosomal protein genes. To date, three ribosomal protein genes, eL27 (L27), eL41 (L41), and eL43 (L37a), have been found to be differentially expressed in cell lines derived from NPC tumors. This raises the possibility of more ribosomal protein genes that could be associated with NPC. In this study, we investigated the expression profiles of eight ribosomal protein genes, uS8 (S8), uS4 (S9), eS31 (S27a), eL6 (L6), eL18 (L18), uL14 (L23), eL24 (L24), and eL30 (L30), in six NPC-derived cell lines (HONE-1, SUNE1, HK1, TW01, TW04, and C666-1). Their expression levels were compared with that of a nonmalignant nasopharyngeal epithelial cell line (NP69) using quantitative real-time PCR (RT-qPCR) assay. Of the eight genes studied, the expressions of four ribosomal protein genes uS8 (S8), uS4 (S9), eS31 (S27a), and uL14 (L23) were found to be significantly downregulated in NPC cell lines relative to NP69. Our findings provide novel empirical evidence of these four ribosomal protein genes as NPC-associated genetic factors and reinforce the relevance of ribosomal proteins in the carcinogenesis of nasopharyngeal cancer.
    Matched MeSH terms: Carcinoma/genetics*
  2. 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/genetics
  3. Fulltext Lack of Rb2/p130 genetic alteration in Malaysian nasopharyngeal carcinoma
    Hoe SL, Lee ES, Khoo AS, Peh SC
    Malays J Pathol, 2009 Jun;31(1):53-6.
    PMID: 19694314 MyJurnal
    The retinoblastoma-related gene Rb2/p130 has been reported to be mutated in several malignancies such as lung cancer and Burkitt's lymphoma. Nasopharyngeal carcinoma (NPC) is a common cancer in Malaysia especially amongst the ethnic Chinese. We screened for Rb2/p130 gene (exons 19 to 21) mutations in 53 archival NPC samples via PCR-SSCP-direct sequencing approach. Only one sample had a base change which involved a serine to glycine substitution at codon 995 (S995G). We conclude that Rb2/p130 genetic alterations are infrequent in NPC and may not be essential for the pathogenesis of the disease.
    Matched MeSH terms: Carcinoma/genetics*
  4. MicroRNAs and Lymph Node Metastasis in Papillary Thyroid Cancers
    Mutalib NS, Yusof AM, Mokhtar NM, Harun R, Muhammad R, Jamal R
    Asian Pac J Cancer Prev, 2016;17(1):25-35.
    PMID: 26838219
    Lymph node metastasis (LNM) in papillary thyroid cancer (PTC) has been shown to be associated with increased risk of locoregional recurrence, poor prognosis and decreased survival, especially in older patients. Hence, there is a need for a reliable biomarker for the prediction of LNM in this cancer. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene translation or degradation and play key roles in numerous cellular functions including cell-cycle regulation, differentiation, apoptosis, invasion and migration. Various studies have demonstrated deregulation of miRNA levels in many diseases including cancers. While a large number of miRNAs have been identified from PTCs using various means, association of miRNAs with LNM in such cases is still controversial. Furthermore, studies linking most of the identified miRNAs to the mechanism of LNM have not been well documented. The aim of this review is to update readers on the current knowledge of miRNAs in relation to LNM in PTC.
    Matched MeSH terms: Carcinoma/genetics*
  5. Immunogenetic aspects of nasopharyngeal carcinoma: I. Differences in HL-A antigen profiles between patients and control groups
    Simons MJ, Wee GB, Day NE, Morris PJ, Shanmugaratnam K, De-Thé GB
    Int J Cancer, 1974 Jan 15;13(1):122-34.
    PMID: 4131857
    Matched MeSH terms: Carcinoma/genetics
  6. A rare case of metastatic lung carcinoma with t(15;19)(q13;p13.1) and trisomy 12
    Tay Za K, Bee PC, Shanmugam H
    Pathology, 2020 Feb;52(2):273-276.
    PMID: 31883672 DOI: 10.1016/j.pathol.2019.10.013
    Matched MeSH terms: Carcinoma/genetics*
  7. 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/genetics
  8. Fulltext Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma
    Chow YP, Tan LP, Chai SJ, Abdul Aziz N, Choo SW, Lim PV, et al.
    Sci Rep, 2017 03 03;7:42980.
    PMID: 28256603 DOI: 10.1038/srep42980
    In this study, we first performed whole exome sequencing of DNA from 10 untreated and clinically annotated fresh frozen nasopharyngeal carcinoma (NPC) biopsies and matched bloods to identify somatically mutated genes that may be amenable to targeted therapeutic strategies. We identified a total of 323 mutations which were either non-synonymous (n = 238) or synonymous (n = 85). Furthermore, our analysis revealed genes in key cancer pathways (DNA repair, cell cycle regulation, apoptosis, immune response, lipid signaling) were mutated, of which those in the lipid-signaling pathway were the most enriched. We next extended our analysis on a prioritized sub-set of 37 mutated genes plus top 5 mutated cancer genes listed in COSMIC using a custom designed HaloPlex target enrichment panel with an additional 88 NPC samples. Our analysis identified 160 additional non-synonymous mutations in 37/42 genes in 66/88 samples. Of these, 99/160 mutations within potentially druggable pathways were further selected for validation. Sanger sequencing revealed that 77/99 variants were true positives, giving an accuracy of 78%. Taken together, our study indicated that ~72% (n = 71/98) of NPC samples harbored mutations in one of the four cancer pathways (EGFR-PI3K-Akt-mTOR, NOTCH, NF-κB, DNA repair) which may be potentially useful as predictive biomarkers of response to matched targeted therapies.
    Matched MeSH terms: Carcinoma/genetics
  9. Nasopharyngeal carcinoma and histocompatibility antigens
    Simons MJ, Chan SH, Wee GB, Shanmugaratnam K, Goh EH, Ho JH, et al.
    IARC Sci Publ, 1978.
    PMID: 730194
    New data are presented concerning the relationship between NPC and HLA antigens among Chinese. When attention is confined to newly diagnosed cases, it can be shown that, apart from the increased risk associated with the joint occurrence of A2 and B-Sin 2, there is also an increased risk associated with BW17 and a decrease in risk associated with A11. Among long-term survivors, however, BW17 is appreciably decreased, whereas A2 in the absence of B-Sin 2 or BW17 is increased. Among Malays, a non-Chinese group, there is an excess among NPC patients of a locus A blank, a blank which is probably associated with the AW19 complex.
    Matched MeSH terms: Carcinoma/genetics
  10. Fulltext Pathogenic Role of Exosomes in Epstein-Barr Virus (EBV)-Associated Cancers
    Teow SY, Liew K, Khoo AS, Peh SC
    Int J Biol Sci, 2017;13(10):1276-1286.
    PMID: 29104494 DOI: 10.7150/ijbs.19531
    Exosomes are 40- to 100-nm membrane-bound small vesicles that carry a great variety of cellular cargoes including proteins, DNA, messenger RNAs (mRNAs), and microRNAs (miRNAs). These nanovesicles are detected in various biological fluids such as serum, urine, saliva, and seminal fluids. Exosomes serve as key mediators in intercellular communication by facilitating the transfer and exchange of cellular components from cells to cells. They contain various pathogenic factors whereby their adverse effects have been implicated in multiple viral infections and cancers. Interestingly, accumulating evidences showed that exosomes derived from tumour viruses or oncoviruses, exacerbate virus-associated cancers by remodelling the tumour microenvironment. In this review, we summarize the contributing factors of Epstein-Barr virus (EBV) products-containing exosomes in viral pathogenesis and their potential implications in EBV-driven malignancies. Understanding the biological role of these exosomes in the disease would undoubtedly boost the development of a more comprehensive strategy to combat EBV-associated cancers and to better predict the therapeutic outcomes. Furthermore, we also highlight the potentials and challenges of EBV products-containing exosomes being employed as diagnostic markers and therapeutic targets for EBV-related cancers. Since these aspects are rather underexplored, we attempt to underline interesting areas that warrant further investigations in the future.
    Matched MeSH terms: Carcinoma/genetics
  11. Li-Fraumeni syndrome in a Malaysian kindred
    Ariffin H, Martel-Planche G, Daud SS, Ibrahim K, Hainaut P
    Cancer Genet. Cytogenet., 2008 Oct;186(1):49-53.
    PMID: 18786442 DOI: 10.1016/j.cancergencyto.2008.06.004
    We report on a Malaysian kindred with Li-Fraumeni syndrome. The proband was an 8-year-old girl who presented with embryonal rhabdomyosarcoma of the trunk at the age of 8 months and developed a brain recurrence at the age of 7 years, which was 5 years after remission. A younger sister later developed adrenocortical carcinoma at the age of 6 months. Their mother and maternal grandmother were diagnosed with breast cancer at the ages of 26 and 38 years, respectively. TP53 mutation detection in this family revealed a duplication of a GGCGTG motif starting at nucleotide 17579 in exon 10, resulting in an in-frame insertion of two amino acids between residues 334 and 336 in the tetramerization domain of the p53 protein. This mutation was found in the proband and her affected sister as well as her mother. In addition, the mutation was detected in two other siblings (a brother aged 3 years and a sister aged 18 months) who have not yet developed any malignancy. Sequencing of TP53 in the father and two other asymptomatic siblings revealed wild-type TP53. To our knowledge, this is a first report of a Li-Fraumeni syndrome family in Southeast Asia.
    Matched MeSH terms: Carcinoma/genetics
  12. 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/genetics*
  13. Childhood adrenocortical carcinoma as a sentinel cancer for detecting families with germline TP53 mutations
    Choong SS, Latiff ZA, Mohamed M, Lim LL, Chen KS, Vengidasan L, et al.
    Clin Genet, 2012 Dec;82(6):564-8.
    PMID: 22233476 DOI: 10.1111/j.1399-0004.2012.01841.x
    Li-Fraumeni syndrome (LFS) is a highly penetrant, autosomal dominant disorder where affected individuals carry a 50% risk of developing cancer before 30 years of age. It is most commonly associated with mutations in the tumour suppressor gene, TP53. Adrenocortical carcinoma (ACC) is a very rare paediatric cancer, and up to 80% of affected children are found to carry germline TP53 mutations. Hence, we propose using childhood ACC incidence as selection criteria for referral for TP53 mutation testing, independent of familial cancer history. Under the auspices of the Malaysian Society of Paediatric Haematology-Oncology, four eligible children diagnosed with ACC over a 30-month study period were referred for mutation testing. Three had a germline TP53 mutation. Subsequent TP53 testing in relatives showed two inherited mutations and one de novo mutation. These findings strongly support paediatric ACC as a useful sentinel cancer for initiating a germline TP53/LFS detection programme, particularly in countries where the lack of structured oncogenetic practice precludes the identification of families with LFS features.
    Matched MeSH terms: Adrenocortical Carcinoma/genetics
  14. 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/genetics*
  15. Immunogenetic aspects of nasopharyngeal carcinoma. II. Analysis of ABO, rhesus and MNSs red cell systems
    Hawkins BR, Simons MJ, Goh EH, Chia KB, Shanmugaratnam K
    Int J Cancer, 1974 Jan 15;13(1):116-21.
    PMID: 4206461 DOI: 10.1002/ijc.2910130113
    Matched MeSH terms: Carcinoma/genetics
  16. 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/genetics*
  17. Fulltext Predominance of G to A codon 12 mutation K-ras gene in Dukes' B colorectal cancer
    Zulhabri O, Rahman J, Ismail S, Isa MR, Wan Zurinah WN
    Singapore Med J, 2012 Jan;53(1):26-31.
    PMID: 22252179
    K-ras gene mutations in codons 12 and 13 are one of the earliest events in colon carcinogenesis.
    Matched MeSH terms: Carcinoma/genetics*
  18. Fulltext Alterations of microRNA expression patterns in human cervical carcinoma cells (Ca Ski) toward 1'S-1'-acetoxychavicol acetate and cisplatin
    Phuah NH, In LL, Azmi MN, Ibrahim H, Awang K, Nagoor NH
    Reprod Sci, 2013 May;20(5):567-78.
    PMID: 23012319 DOI: 10.1177/1933719112459220
    The aims of this study were to investigate the combined effects of a natural compound 1'S-1'-acetoxychavicol acetate (ACA) with cisplatin (CDDP) on HPV-positive human cervical carcinoma cell lines (Ca Ski-low cisplatin sensitivity and HeLa-high cisplatin sensitivity), and to identify microRNAs (miRNAs) modulated in response toward ACA and/or CDDP. It was revealed that both ACA and CDDP induced dose- and time-dependent cytotoxicity when used as a stand-alone agent, while synergistic effects were observed when used in combination with a combination index (CI) value of 0.74 ± 0.01 and 0.85 ± 0.01 in Ca Ski and HeLa cells, respectively. A total of 25 miRNAs were found to be significantly differentially expressed in response to ACA and/or CDDP. These include hsa-miR-138, hsa-miR-210, and hsa-miR-744 with predicted gene targets involved in signaling pathways regulating apoptosis and cell cycle progression. In conclusion, ACA acts as a chemosensitizer which synergistically potentiates the cytotoxic effect of CDDP in cervical cancer cells. The altered miRNA expression upon administration of ACA and/or CDDP suggests that miRNAs play an important role in anticancer drug responses, which can be manipulated for therapeutic purposes.
    Matched MeSH terms: Carcinoma/genetics*
  19. Fulltext Homozygous Wildtype of XPD K751Q Polymorphism Is Associated with Increased Risk of Nasopharyngeal Carcinoma in Malaysian Population
    Lye MS, Visuvanathan S, Chong PP, Yap YY, Lim CC, Ban EZ
    PLoS One, 2015;10(6):e0130530.
    PMID: 26086338 DOI: 10.1371/journal.pone.0130530
    The xeroderma pigmentosum group D (XPD) gene encodes a DNA helicase, an important component in transcription factor IIH (TFIIH) complex. XPD helicase plays a pivotal role in unwinding DNA at the damaged region during nucleotide excision repair (NER) mechanism. Dysfunctional XPD helicase protein from polymorphic diversity may contribute to increased risk of developing cancers. This study aims to determine the association between XPD K751Q polymorphism (rs13181) and risk of nasopharyngeal carcinoma (NPC) in the Malaysian population. In this hospital-based matched case-control study, 356 controls were matched by age, gender and ethnicity to 356 cases. RFLP-PCR was used to genotype the XPD K751Q polymorphism. A significant association was observed between XPD K751Q polymorphism and the risk of NPC using conditional logistic regression. Subjects with homozygous Lys/Lys (wildtype) genotype have 1.58 times higher odds of developing NPC compared to subjects with recessive combination of heterozygous Lys/Gln and homozygous Gln/Gln genotypes (OR = 1.58, 95% CI = 1.05-2.38 p = 0.028) adjusted for cigarette smoking, alcohol and salted fish consumption. Our data suggests that Lys/Lys (wildtype) of XPD K751Q contributes to increased risk of NPC in the Malaysian population.
    Matched MeSH terms: Carcinoma/genetics*
  20. 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/genetics*
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