Loss of expression, and mutations of Smad 2 and Smad 4 in human cervical cancer

Maliekal, Tessy Thomas; Antony, Marie Lue; Nair, Asha S.; Paulmurugan, Ramasamy; Karunagaran, Devarajan

doi:10.1038/sj.onc.1206806

Cited by 55 publications

(38 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In contrast, Smad4 staining in cervical intraepithelial neoplasia with mild or moderate dysplasia was unaltered as compared to the normal squamous epithelium and was only slightly reduced in four out of 20 cases with severe dysplasia. These results are in good agreement with data recently published by others who examined Smad4 expression in small numbers of preneoplastic and malignant cervical tissue samples by semiquantitative RT-PCR (Maliekal et al, 2003). They are also somewhat reminiscent to the situation in pancreatic carcinogenesis, where loss of Smad4 occurs concurrent with the acquisition of invasiveness (Wilentz et al, 2000b;Luettges et al, 2001).…”

Section: Discussionsupporting

confidence: 91%

See 1 more Smart Citation

Smad4 deficiency in cervical carcinoma cells

et al. 2004

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 91%

“…The absence of Smad4 protein and mRNA in HeLa was surprising, since lack of Smad4 expression had not been reported previously for this cell line (Lee et al, 2001;Maliekal et al, 2003). In order to clarify this apparent paradox, we analysed the Smad4 gene and its expression in HeLa cells obtained from different sources.…”

Section: Smad4-negative Hela Mutantmentioning

confidence: 86%

Smad4 deficiency in cervical carcinoma cells

et al. 2004

View full text Add to dashboard Cite

“…1 Although a number of studies have investigated the expression status and alterations in the canonical TGF-b signaling (Smad) pathway, the role of Smad signaling in the progression of cervical cancer remains unclear. 3,10,11,24 In this study, we investigated whether decreased Smad2 and Smad4 protein expression in primary cervical cancers was associated with molecular alterations at 18q21.1, mutations in the functional domains of Smad2 and Smad4 or hypermethylation, and we assessed the biological relevance of decreased Smad2 and Smad4 expression.…”

Section: Discussionmentioning

confidence: 99%

“…As LOH at 18q21.1 did not associate with weak Smad2 or weak Smad4 expression, genetic haplo-insufficiency of Only two studies have reported on mutations in the functional domains (MH1 and MH2) of Smad2 and Smad4 in cervical carcinoma. 10,11 Maliekal et al 11 identified a missense mutation in the MH1 domain of Smad2 in a cervical tumor and reported lack of mRNA expression of the C-terminal part of the MH2 domains in six tumors. We did not detect mutations in the MH1 and MH2 domains of Smad2 in the tumor samples; therefore, it remains uncertain whether cervical tumors contain inactivating mutations in the MH2 domain.…”

Section: Discussionmentioning

confidence: 99%

“…9 For cervical cancer, Smad4 mutations were reported in cervical cancer cell lines 10 and a Smad2 mutation in a cervical tumor has been described. 11 In addition to LOH and gene mutations, other mechanisms such as CpG methylation of the Smad promoter may play a role in downregulation of Smad expression. Recently, Smad4 promoter methylation was reported in Barrett's esophagus and gastric carcinoma as a mechanism for decreased Smad4 expression.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Expression of Smad2 and Smad4 in cervical cancer: absent nuclear Smad4 expression correlates with poor survival

et al. 2008

View full text Add to dashboard Cite

Alterations in transforming growth factor-b signaling, due to a decrease in Smad2 and especially Smad4 expression, has primarily been reported in pancreatic and colorectal cancers, although loss of the chromosomal region 18q21.1, containing the loci of Smad2 and Smad4, is among the most frequent molecular alterations in cervical cancer. The aim of our study was to investigate whether decreased Smad2 and Smad4 protein expression in primary cervical cancers is associated with molecular alterations at 18q21.1, mutations in the functional domains of Smad2 and Smad4 or hypermethylation, and to assess the biological relevance of decreased Smad2 and Smad4 expression. Subsequently, Smad2, Smad4 and p21 protein expression was determined by immunohistochemistry in 117 primary cervical carcinomas, assembled in a tissue array. Smad signaling was shown to be associated with p21 mRNA expression. All the tumors expressed Smad2 or Smad4. Weak cytoplasmic Smad2 or weak cytoplasmic Smad4 expression could not be attributed to loss of heterozygosity at 18q21.1. Despite weak/moderate Smad2 expression and absent nuclear Smad4 expression, the coding regions of the functional MH1 and MH2 domains of Smad2 and Smad4 were unchanged, as assessed by sequence analysis. The Smad4 promoter region was unmethylated in tumor samples with weak/moderate cytoplasmic Smad4 expression. Remarkably, both weak cytoplasmic Smad4 expression and absent nuclear Smad4 expression significantly correlated with poor disease-free (P ¼ 0.003 and P ¼ 0.003, respectively) and overall 5-year survival (P ¼ 0.003 and P ¼ 0.010, respectively). Our findings support the hypothesis that Smad4 is a target molecule for functional inactivation in cervical cancer.

show abstract

Elevated expression of CXC chemokines in pediatric osteosarcoma patients

Flores

et al. 2010

Cancer

View full text Add to dashboard Cite

BACKGROUND: Osteosarcoma is the most common malignant bone tumor in children. Despite the advent of chemotherapy, the survival of osteosarcoma patients has not been significantly improved recently. Chemokines are a group of signaling molecules that have been implicated in tumorigenesis and metastasis. METHODS: The authors used an antibody microarray to identify chemokines that were elevated in the plasma samples of osteosarcoma patients. The results were validated using enzyme-linked immunosorbent assays on an independent set of samples. The tumor expressions of 3 chemokines were examined in 2 sets of osteosarcoma tissue arrays. The authors also evaluated the proliferative effect of the chemokines in 4 osteosarcoma cell lines. RESULTS: The authors found that the plasma levels of CXCL4, CXCL6, and CXCL12 in the osteosarcoma patients were significantly higher than those in the controls, and the results were validated by an independent osteosarcoma cohort (P < .05). However, CXCL4 (100%) and CXCL6 (91%) were frequently expressed in osteosarcoma, whereas CXCL12 was only expressed in 4%. Survival analysis further showed that higher circulating levels of CXCL4 and CXCL6, but not CXCL12, were associated with a poorer outcome of osteosarcoma patients. Addition of exogenous chemokines significantly promoted the growth of different osteosarcoma cells (P < .05). CONCLUSIONS: The results demonstrate that CXCL4 and CXCL6 are frequently expressed in osteosarcoma, and that the plasma levels of these 2 chemokines are associated with patient outcomes. Further study of these circulating chemokines may provide a promising approach for prognostication of osteosarcoma. Targeting these chemokines or their receptors may also lead to a novel therapeutic invention. Cancer 2011;117:207-17.

show abstract

Loss of expression, and mutations of Smad 2 and Smad 4 in human cervical cancer

Cited by 55 publications

References 36 publications

Smad4 deficiency in cervical carcinoma cells

Smad4 deficiency in cervical carcinoma cells

Expression of Smad2 and Smad4 in cervical cancer: absent nuclear Smad4 expression correlates with poor survival

Elevated expression of CXC chemokines in pediatric osteosarcoma patients

Contact Info

Product

Resources

About