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Association of TGFβ1 and SMAD4 variants in the etiology of keloid scar in the Malay population

Emami A, Halim AS, Salahshourifar I, Yussof SJ, Khoo TL, Kannan TP

Arch. Dermatol. Res., 2012 Sep;304(7):541-7.
PMID: 22805880 DOI: 10.1007/s00403-012-1262-0

Keloid is a complex condition with environmental and genetic risk-contributing factors. Two candidate genes, TGFβ1 and SMAD4, located in the same signaling pathway are highly expressed in the keloid fibroblast cells. In a case-control design, TGFβ1 haplotypes showed association with the risk of keloid in the present study. The CC haplotype, composed of both c.29C>T and -509T>C variants, was observed more frequently among cases (Corrected p = 0.037, OR = 2.07, 95 % CI = 0.87-4.93), showing a 4.5-fold increased risk for keloid. The AG genotype of the SMAD4 c.5131A>G variant showed a trend of significance (p = 0.0573, OR = 1.75, 95 % CI = 0.99-3.13). Taken together, either of these variants is most probably causative at the expression level or is in linkage disequilibrium with other causative variants in a complex pattern together with the environmental factors that contribute to the condition. To the best of our knowledge, there is only one documented report on a relationship between TGFβ1 and keloid with no association within the Caucasian population, while there have not been any reports for SMAD4. Therefore, the present study is likely the first research showing a significant association between TGFβ1 variants and keloids in the Malay population.

Matched MeSH terms: Transforming Growth Factor beta/genetics*
Fulltext A common variant near TGFBR3 is associated with primary open angle glaucoma

Li Z, Allingham RR, Nakano M, Jia L, Chen Y, Ikeda Y, et al.

Hum Mol Genet, 2015 Jul 01;24(13):3880-92.
PMID: 25861811 DOI: 10.1093/hmg/ddv128

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.

Matched MeSH terms: Receptors, Transforming Growth Factor beta/genetics*
Fulltext In Silico Study and Effects of BDMC33 on TNBS-Induced BMP Gene Expressions in Zebrafish Gut Inflammation-Associated Arthritis

Mostofa F, Yasid NA, Shamsi S, Ahmad SA, Mohd-Yusoff NF, Abas F, et al.

Molecules, 2022 Nov 28;27(23).
PMID: 36500396 DOI: 10.3390/molecules27238304

The bone morphogenic protein (BMP) family is a member of the TGF-beta superfamily and plays a crucial role during the onset of gut inflammation and arthritis diseases. Recent studies have reported a connection with the gut-joint axis; however, the genetic players are still less explored. Meanwhile, BDMC33 is a newly synthesized anti-inflammatory drug candidate. Therefore, in our present study, we analysed the genome-wide features of the BMP family as well as the role of BMP members in gut-associated arthritis in an inflammatory state and the ability of BDMC33 to attenuate this inflammation. Firstly, genome-wide analyses were performed on the BMP family in the zebrafish genome, employing several in silico techniques. Afterwards, the effects of curcumin analogues on BMP gene expression in zebrafish larvae induced with TNBS (0.78 mg/mL) were determined using real time-qPCR. A total of 38 identified BMP proteins were revealed to be clustered in five major clades and contain TGF beta and TGF beta pro peptide domains. Furthermore, BDMC33 suppressed the expression of four selected BMP genes in the TNBS-induced larvae, where the highest gene suppression was in the BMP2a gene (an eight-fold decrement), followed by BMP7b (four-fold decrement), BMP4 (four-fold decrement), and BMP6 (three-fold decrement). Therefore, this study reveals the role of BMPs in gut-associated arthritis and proves the ability of BDMC33 to act as a potential anti-inflammatory drug for suppressing TNBS-induced BMP genes in zebrafish larvae.

Matched MeSH terms: Transforming Growth Factor beta/genetics
Fulltext Effect of cathepsin D and prostate specific antigen on latent transforming growth factor-beta in breast cancer cell lines

Wong SF, Seow HF, Lai LC

Malays J Pathol, 2003 Dec;25(2):129-34.
PMID: 16196369

Transforming growth factor-beta (TGFbeta) is present, predominantly in latent forms, in normal and malignant breast tissue. The mechanisms by which latent TGFbeta is activated physiologically remain largely an enigma. The objective of this study was to assess whether the proteases, cathepsin D and prostate specific antigen (PSA) could activate latent TGFbeta1 and TGFbeta2 in conditioned media of the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 human breast cancer cell lines, newly purchased from ATCC. Both of the cell lines were seeded in 6-well plates 2 days prior to treatment with varying concentrations of cathepsin D and PSA. Active TGFbeta1 and TGFbeta2 in the media were then measured by ELISA after 4, 8, 24 and 72 hours of treatment. TGFbeta1 and TGFbeta2 mRNA expression of both cell lines were measured by RT-PCR to determine whether any increase in level of active TGFbeta1 and TGFbeta2 was due to increased production. There was a significant increase in only active TGFbeta2 levels in the MDA-MB-231 cell line with both treatments. Cathepsin D and PSA did not have any effect on TGFbeta1 and TGFbeta2 mRNA expression. Cathepsin D and PSA were unable to activate latent TGFbeta1 and TGFbeta2 in these two breast cancer cell lines. A constant level of TGFbeta2 mRNA in the control and treated MDA-MB-231 cells suggests that the increase in level of active TGFbeta2 was not a result of increased production but was likely to be due to activation by a mechanism independent of cathepsin D and PSA.

Matched MeSH terms: Transforming Growth Factor beta/genetics
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: Transforming Growth Factor beta/genetics*
Emerging strategies for sensitization of therapy resistant tumors toward cancer therapeutics by targeting the Bcl-2 family, TGF-β, Wnt/β-Catenin, RASSF and miRNA regulated signaling pathways

Veerasamy T, Eugin Simon S, Tan KO

Int J Biochem Cell Biol, 2021 08;137:106016.
PMID: 34082133 DOI: 10.1016/j.biocel.2021.106016

Conventional chemotherapy relies on the cytotoxicity of chemo-drugs to inflict destructive effects on tumor cells. However, as most tumor cells develop resistance to chemo-drugs, small doses of chemo-drugs are unlikely to provide significant clinical benefits in cancer treatment while high doses of chemo-drugs have been shown to impact normal human cells negatively due to the non-specific nature and cytotoxicity associated with chemo-drugs. To overcome this challenge, sensitizations of tumor cells with bioactive molecules that specifically target the pro-survival and pro-apoptosis signaling pathways of the tumor cells are likely to increase the therapeutic impacts and improve the clinical outcomes by reducing the dependency and adverse effects associated with using high doses of chemo-drugs in cancer treatment. This review focuses on emerging strategies to enhance the sensitization of tumor cells toward cancer therapies based on our understanding of tumor cell biology and underlying signaling pathways.

Matched MeSH terms: Transforming Growth Factor beta/genetics
Preliminary assessment of differential expression of candidate genes associated with atherosclerosis

Blin J, Ahmad Z, Rampal LR, Mohtarrudin N, Tajudin AK, Adnan RS

Genes Genet Syst, 2013;88(3):199-209.
PMID: 24025248

Identifying susceptible genes associated with the pathogenesis of atherosclerosis (ATH) may contribute toward better management of this condition. This preliminary study was aimed at assessing the expression levels of 11 candidate genes, namely tumor protein (TP53), transforming growth factor, beta receptor II (TGFBR2), cysthathionenine-beta-synthase (CBS), insulin receptor substrate 1 (IRS1), lipoprotein lipase (LPL), methylenetetrahydrofolate reductase (MTHFR), thrombomodulin (THBD), lecithin-cholesterol acyltransferase (LCAT), matrix metallopeptidase 9 (MMP9), low density lipoprotein receptor (LDLR), and arachidonate 5-lipoxygenase-activating protein (ALOX5AP) genes associated with ATH. Twelve human coronary artery tissues (HCATs) were obtained from deceased subjects who underwent post-mortem procedures. Six atherosclerotic coronary artery tissue (ACAT) samples representing the cases and non-atherosclerotic coronary artery tissue (NCAT) samples as controls were gathered based on predetermined inclusion and exclusion criteria. Gene expression levels were assessed using the GenomeLab Genetic Analysis System (GeXP). The results showed that LDLR, TP53, and MMP9 expression levels were significantly increased in ACAT compared to NCAT samples (p < 0.05). Thus, LDLR, TP53, and MMP9 genes may play important roles in the development of ATH in a Malaysian study population.

Matched MeSH terms: Receptors, Transforming Growth Factor beta/genetics
Fulltext Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Hampras SS, Sucheston-Campbell LE, Cannioto R, Chang-Claude J, Modugno F, Dörk T, et al.

Oncotarget, 2016 10 25;7(43):69097-69110.
PMID: 27533245 DOI: 10.18632/oncotarget.10215

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer.
METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients.
RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively).
CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Matched MeSH terms: Receptors, Transforming Growth Factor beta/genetics*
Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73

Wong SW, Tiong KH, Kong WY, Yue YC, Chua CH, Lim JY, et al.

Breast Cancer Res Treat, 2011 Jul;128(2):301-13.
PMID: 20686837 DOI: 10.1007/s10549-010-1055-0

Recent gene expression profiling studies have identified five breast cancer subtypes, of which the basal-like subtype is the most aggressive. Basal-like breast cancer poses serious clinical challenges as there are currently no targeted therapies available to treat it. Although there is increasing evidence that these tumors possess specific sensitivity to cisplatin, its success is often compromised due to its dose-limiting nephrotoxicity and the development of drug resistance. To overcome this limitation, our goal was to maximize the benefits associated with cisplatin therapy through drug combination strategies. Using a validated kinase inhibitor library, we showed that inhibition of the mTOR, TGFβRI, NFκB, PI3K/AKT, and MAPK pathways sensitized basal-like MDA-MB-468 cells to cisplatin treatment. Further analysis demonstrated that the combination of the mTOR inhibitor rapamycin and cisplatin generated significant drug synergism in basal-like MDA-MB-468, MDA-MB-231, and HCC1937 cells but not in luminal-like T47D or MCF-7 cells. We further showed that the synergistic effect of rapamycin plus cisplatin on basal-like breast cancer cells was mediated through the induction of p73. Depletion of endogenous p73 in basal-like cells abolished these synergistic effects. In conclusion, combination therapy with mTOR inhibitors and cisplatin may be a useful therapeutic strategy in the treatment of basal-like breast cancers.

Matched MeSH terms: Receptors, Transforming Growth Factor beta/genetics