Endocervical Cancer Is Associated with an Increase in the Ligands and Receptors for Transforming Growth Factor-β and a Contrasting Decrease in p27Kip1

Farley, John H.; Gray, Karen; Nycum, Lawrence R.; Prentice, Margaret; Birrer, Michael J.; Jakowlew, Sonia B.

doi:10.1006/gyno.2000.5879

Cited by 20 publications

(14 citation statements)

References 54 publications

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“…Contradicting studies and the lack of detailed analysis of TGF-h expression in cervical cancer, as well as our observations showing induction of c-fms expression by TGF-h1, prompted us to examine levels of TGF-h in cervical carcinomas (31,32,38). Data presented here show a decrease in TGF-h1 levels in cervical tumor cells and in associated stromal cells compared with normal tissue.…”

Section: Discussionmentioning

confidence: 75%

Elevated Expression of the Oncogene c-fms and Its Ligand, the Macrophage Colony-Stimulating Factor-1, in Cervical Cancer and the Role of Transforming Growth Factor-β1 in Inducing c-fms Expression

et al. 2007

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Cervical cancer is the third most common gynecologic cancer in the United States. The presence and possible involvement of several cytokines have been studied in cervical cancer; however, very little data, if any, are available on whether cervical tumors are responsive to stimulation by the macrophage colony-stimulating factor-1 (CSF-1). Given the involvement of c-fms and its ligand CSF-1 in gynecologic cancers, such as that of the uterus and the ovaries, we have examined the expression of c-fms and CSF-1 in cervical tumor (n = 17) and normal cervix (n = 8) samples. The data show that c-fms and its ligand are significantly higher in cervical carcinomas compared with normal samples. Immunohistochemistry not only showed that tumor cells expressed significantly higher levels of c-fms but also c-fms levels were markedly higher in tumor cells than tumor-associated stromal cells. Blocking c-fms activity in cervical cancer cells, which express CSF-1 and c-fms, resulted in increased apoptosis and decreased motility compared with control, suggesting that CSF-1/c-fms signaling may be involved in enhanced survival and possibly invasion by cervical cancer cells via an autocrine mechanism. Combined, the data show for the first time the induction of CSF-1 and c-fms in cervical carcinomas and suggest that c-fms activation may play a role in cervical carcinogenesis. Additionally, our data suggest that transforming growth factor-B1 may be a factor in inducing the expression of c-fms in cervical cancer cells. The data suggest that c-fms may be a valuable therapeutic target in cervical cancer. [Cancer Res 2007;67(5):1918-26]

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Section: Discussionmentioning

confidence: 75%

Elevated Expression of the Oncogene c-fms and Its Ligand, the Macrophage Colony-Stimulating Factor-1, in Cervical Cancer and the Role of Transforming Growth Factor-β1 in Inducing c-fms Expression

et al. 2007

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“…Cdk4 and Cdk2 have been implicated as the G 1 kinases responsible for phosphorylating and inactivating pRb in mid to late G 1 . TGF-␤ causes the accumulation of unphosphorylated pRb in responsive cells through the suppression of Cdk4 synthesis and Cdk2 activity (9,24). In Mv1Lu cells expressing HPV 16 E7, TGF-␤ was unable to down-regulate the expression of Cdk4 and Cdk2, whereas a hyperphosphorylated form of pRb was increased even in the presence of TGF-␤.…”

Section: Figmentioning

confidence: 94%

“…Our results suggest that inactivation of Smad-mediated signaling is necessary to block the tumor suppressor functions of TGF-␤ and that inactivation of pRb and p53 must be tightly coupled with the targeted inactivation of Smads for efficient transformation. By inactivating each of the most important brakes on their proliferation, HPV-infected cells can then multiply at high rates and show highly elevated TGF-␤ ligand and receptor expression (24). This considerable inhibition of TGF-␤ signaling by E7 thus provides a uniquely favorable environment for the development of cervical cancer.…”

Section: Figmentioning

confidence: 99%

The Human Papilloma Virus E7 Oncoprotein Inhibits Transforming Growth Factor-β Signaling by Blocking Binding of the Smad Complex to Its Target Sequence

Lee¹,

Kim²,

Kim³

et al. 2002

Journal of Biological Chemistry

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The human papillomavirus (HPV) oncoprotein E7 is implicated in the etiology of cervical cancer associated with infection by HPV. HPV-positive cells develop resistance to TGF-␤ growth inhibitory activity through the inhibition of hypophosphorylation of pRb by papillomavirus type 16 E7 oncoprotein. In this study, we examined whether E7, in addition to its well known effects on pRb, might directly target the Smad proteins that mediate TGF-␤ signaling. Here, we show that E7 significantly blocks both Smad transcriptional activity and the ability of TGF-␤ to inhibit DNA synthesis. We found that E7 interacts constitutively with Smad2, Smad3, and Smad4. Confocal microscopic studies confirm that E7 and Smads co-localize in vivo. Using a canonical Smad DNA binding sequence, we found that E7 blocks Smad3 binding to its target sequence on DNA. These results suggest that suppression of Smad-mediated signaling by E7 may contribute to HPV-associated carcinogenesis.

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“…Regarding metastasis, inhibition of TGF-β suppresses experimental metastasis to multiple organs (33,34). Inhibin A, inhibin B and activin A were detected in normal and malignant human uterine tissues, including cervical cancer (35), and the neoplastic transformation of the human cervix might also be related to dysregulation of TGF-β, leading to loss of cell cycle control (36).…”

Section: Discussionmentioning

confidence: 99%

Inhibin-α subunit in normal and malignant human cervical tissue and cervical cancer cell lines

Mylonas

Dian²

2011

Oncol Rep

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Abstract. Inhibins are dimeric glycoproteins composed of an α-subunit and one of two possible β-subunits (βA or βB), with substantial roles in human reproduction and in endocrineresponsive tumours. Four normal cervical tissue samples together with 10 specimens of well-differentiated squamous cervical cancer and adenocarcinoma of the cervix were immunohistochemically analysed for the expression of the inhibin-α subunit. Additionally, two cervical carcinoma cell lines (HeLa and CaSKi) were analysed with immunofluorescence and RT-PCR for the expression of the inhibin-α subunit. We demonstrated for the first time an immunolabelling of the inhibin-α subunit in normal and malignant cervical tissue, as well as cervical cancer cells. However, the immunoreactive reaction was albeit weak and mostly confined to mitotic cells in the analysed cervical tissues. Additionally, the expression pattern of this subunit was rather inconsistent. Therefore, the immunohistochemical evaluation of this subunit in cervical tissue cannot be used as a prognostic marker as suggested for endometrial cancer. However, since the expression of the inhibin-α subunit is minimal in HeLa cells as assessed by immunofluorescence and RT-PCR, the CaSKi cell line might be a better model for further functional experiments regarding cervical pathogenesis.

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Endocervical Cancer Is Associated with an Increase in the Ligands and Receptors for Transforming Growth Factor-β and a Contrasting Decrease in p27Kip1

Cited by 20 publications

References 54 publications

Elevated Expression of the Oncogene c-fms and Its Ligand, the Macrophage Colony-Stimulating Factor-1, in Cervical Cancer and the Role of Transforming Growth Factor-β1 in Inducing c-fms Expression

Elevated Expression of the Oncogene c-fms and Its Ligand, the Macrophage Colony-Stimulating Factor-1, in Cervical Cancer and the Role of Transforming Growth Factor-β1 in Inducing c-fms Expression

The Human Papilloma Virus E7 Oncoprotein Inhibits Transforming Growth Factor-β Signaling by Blocking Binding of the Smad Complex to Its Target Sequence

Inhibin-α subunit in normal and malignant human cervical tissue and cervical cancer cell lines

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