Prognostic impact of the expression of Hedgehog proteins in cervical carcinoma FIGO stages I–IV treated with radiotherapy or chemoradiotherapy

Mordhorst, Louise Bohr; Ahlin, Cecilia; Sorbe, Bengt

doi:10.1016/j.ygyno.2014.08.026

Cited by 8 publications

(8 citation statements)

References 24 publications

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“…Our data, and that of others, have shown that increased expression of Hh pathway members before definitive RTCT is associated with poor outcome (Chaudary et al , 2012b; Bohr Mordhorst et al , 2014). Here we explored the Hh pathway in the context of a unique orthotopic, patient-derived cervical cancer pre-clinical model that exhibits the stromal characteristics and metastatic behaviour of cervical cancer in the clinic (Chaudary et al , 2011, 2012b).…”

Section: Discussionsupporting

confidence: 80%

“…We demonstrated that upregulation of SMO and of >3 of the Hh pathway members was associated with a worse recurrence-free patient survival (Chaudary et al , 2012b). Bohr Mordhorst et al (2014) also demonstrated, using immunohistochemistry, an association between poor outcome and expression of PTCH, SMO and GLi2. The aim of the current study, using early passage orthotopic, patient-derived, cervical cancer xenograft models, was to further define the role of the Hh pathway in cervical cancer and to investigate the therapeutic potential of Hh inhibition in combination with fractionated radiation and chemotherapy.…”

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confidence: 82%

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Hedgehog inhibition enhances efficacy of radiation and cisplatin in orthotopic cervical cancer xenografts

et al. 2016

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Background:The Hedgehog (Hh) pathway is upregulated in cervical cancer and associated with poor outcome. We explored the effects of Hh pathway inhibition in combination with RTCT in a patient derived orthotopic cervical cancer xenograft model (OCICx).Methods:5E1, a monoclonal antibody for SHH, or Sonidegib (LDE225), a clinical SMO inhibitor (Novartis) were added to RTCT. We investigated tumour growth delay, metastasis and GI toxicity using orthotopic cervical cancer xenografts models. The xenografts were treated with radiotherapy (15 × 2 Gy daily fractions over 3 weeks) and weekly cisplatin 4 mg kg−1 concurrently, with or without 5E1 or Sonidegib (LDE225). The Hh inhibitors were administered by subcutaneous injection (5E1; 20 mg kg−1 weekly for 3 weeks), or by oral gavage (Sonidegib; 60 mg kg−1 daily for 3 weeks).Results:We observed that both Hh inhibitors administered with RTCT were well tolerated and showed increased tumour growth delay, and reduced metastasis, with no increase in acute GI-toxicity relative to RTCT alone.Conclusions:Our data suggest Hh can be a valid therapeutic target in cervical cancer and supports data suggesting a potential therapeutic role for targeting Hh in patients undergoing RTCT. This warrants further investigation in clinical trials.

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Section: Discussionsupporting

confidence: 80%

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confidence: 82%

Hedgehog inhibition enhances efficacy of radiation and cisplatin in orthotopic cervical cancer xenografts

et al. 2016

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“…Nevertheless, presence of Smo/GLI and loss of negative regulator Sufu in HPV positive cancer cells in comparison to HPV negative C33a is suggestive of an influence of HPV infection on GLI pathway. The mediators of GLI-signaling are found absent in normal tissues whereas upon carcinogenic transformation some of the key mediators are detected at abnormally high levels in cervical cancer cells 20 21 22 25 and established cell lines, SiHa, Hela, Caski and C33a 23 . Not just the magnitude of the signaling molecules but also the increase in number of dysregulated pathway genes was found associated with local recurrence of late stage tumors 21 .…”

Section: Discussionmentioning

confidence: 99%

Cross-talk between Human Papillomavirus Oncoproteins and Hedgehog Signaling Synergistically Promotes Stemness in Cervical Cancer Cells

Vishnoi

Mahata

Tyagi

et al. 2016

Sci Rep

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Viral oncoproteins E6/E7 play key oncogenic role in human papillomavirus (HPV)-mediated cervical carcinogenesis in conjunction with aberrant activation of cellular signaling events. GLI-signaling has been implicated in metastasis and tumor recurrence of cervical cancer. However, the interaction of GLI-signaling with HPV oncogenes is unknown. We examined this relationship in established HPV-positive and HPV-negative cervical cancer cell lines using specific GLI inhibitor, cyclopamine and HPVE6/E7 siRNAs. Cervical cancer cell lines showed variable expression of GLI-signaling components. HPV16-positive SiHa cells, overexpressed GLI1, Smo and Patch. Inhibition by cyclopamine resulted in dose-dependent reduction of Smo and GLI1 and loss of cell viability with a higher magnitude in HPV-positive cells. Cyclopamine selectively downregulated HPVE6 expression and resulted in p53 accumulation, whereas HPVE7 and pRb level remained unaffected. siRNA-mediated silencing of HPV16E6 demonstrated reduced GLI1 transcripts in SiHa cells. Cervical cancer stem-like cells isolated by side population analysis, displayed retention of E6 and GLI1 expression. Fraction of SP cells was reduced in cyclopamine-treated cultures. When combined with E6-silencing cyclopamine resulted in loss of SP cell’s sphere-forming ability. Co-inhibition of GLI1 and E6 in cervical cancer cells showed additive anti-cancer effects. Overall, our data show existence of a cooperative interaction between GLI signaling and HPVE6.

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“…Several studies have reported correlation between HH pathway activity and its role in cervical carcinogenesis. It has been shown that HH signaling pathway is activated in both cervical squamous cell carcinoma and adenocarcinoma and also in cervical intraepithelial neoplasia [ 30 , 52 ]. HH signaling proteins, PTCH, SMO, and GLI2 seem to have prognostic value in cases with residual carcinoma, local recurrences, and for GLI2 distant relapses [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that HH signaling pathway is activated in both cervical squamous cell carcinoma and adenocarcinoma and also in cervical intraepithelial neoplasia [ 30 , 52 ]. HH signaling proteins, PTCH, SMO, and GLI2 seem to have prognostic value in cases with residual carcinoma, local recurrences, and for GLI2 distant relapses [ 52 ]. Also, there are data presenting a role of HH pathway in repopulation after chemoradiation of cervical carcinoma patients [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

SOX18 Is a Novel Target Gene of Hedgehog Signaling in Cervical Carcinoma Cell Lines

et al. 2015

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Although there is much evidence showing functional relationship between Hedgehog pathway, in particular Sonic hedgehog, and SOX transcription factors during embryonic development, scarce data are available regarding their crosstalk in cancer cells. SOX18 protein plays an important role in promoting tumor angiogenesis and therefore emerged as a promising potential target in antiangiogenic tumor therapy. Recently it became evident that expression of SOX18 gene in tumors is not restricted to endothelium of accompanying blood and lymphatic vessels, but in tumor cells as well.In this paper we have identified human SOX18 gene as a novel target gene of Hedgehog signaling in cervical carcinoma cell lines. We have presented data showing that expression of SOX18 gene is regulated by GLI1 and GLI2 transcription factors, final effectors of Hedgehog signaling, and that modulation of Hedgehog signaling activity in considerably influence SOX18 expression. We consider important that Hedgehog pathway inhibitors reduced SOX18 expression, thus showing, for the first time, possibility for manipulationwith SOX18 gene expression. In addition, we analyzed the role of SOX18 in malignant potential of cervical carcinoma cell line, and showed that its overexpression has no influence on cells proliferation and viability, but substantially promotes migration and invasion of cells in vitro. Pro-migratory effect of SOX18 suggests its role in promoting malignant spreading, possibly in response to Hedgehog activation.

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Prognostic impact of the expression of Hedgehog proteins in cervical carcinoma FIGO stages I–IV treated with radiotherapy or chemoradiotherapy

Cited by 8 publications

References 24 publications

Hedgehog inhibition enhances efficacy of radiation and cisplatin in orthotopic cervical cancer xenografts

Hedgehog inhibition enhances efficacy of radiation and cisplatin in orthotopic cervical cancer xenografts

Cross-talk between Human Papillomavirus Oncoproteins and Hedgehog Signaling Synergistically Promotes Stemness in Cervical Cancer Cells

SOX18 Is a Novel Target Gene of Hedgehog Signaling in Cervical Carcinoma Cell Lines

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