TGFβ Receptor I Conditional Knockout Mice Develop Spontaneous Squamous Cell Carcinoma

Honjo, Yasuko; Bian, Yansong; Kawakami, Koji; Molinolo, Alfredo A.; Longenecker, Glenn; Boppana, Ramanamurthy; Larsson, Jonas; Karlsson, Stefán; Gutkind, J. Silvio; Puri, Raj K.; Kulkarni, Ashok B.

doi:10.4161/cc.6.11.4268

Cited by 29 publications

(30 citation statements)

References 44 publications

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“…A more frequent event is a reduction in the expression of TβRII [75]. This is evident in knockout mouse models where there is an increase in the penetrance and rate of tumor formation, and metastases in various tissues [76][77][78][79][80][81][82][83][84]. TβRII expression has been shown to be affected by: a) mutations in the promoter region of the gene [85,86]; b) activated oncogene activity, including Cyclin D1, and Ras [87,88]; c) epigenetic regulation [89].…”

Section: Genetic Alteration In Preneoplastic Lesionsmentioning

confidence: 99%

Molecular mechanisms of head and neck cancer

Deshpande

Wong²

2008

Expert Review of Anticancer Therapy

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Background-With a global incidence rank of eight and a significant portion of head and neck malignancies (~90%), oral squamous cell carcinoma (OSCC) poses a major health risk and is one of the leading cause of mortality in developing nations [1]. Distribution of the incidence of OSCC varies across the world with south-central Asia and Africa leading, followed by eastern and central Europe, and to a lesser extent Australia, Japan, and the United States. Over the past few years there has been a drastic increase in the incidence of oral cancer in most parts of the world [2]. In the United States alone, with about 17 new cases/100,000, oral cancer is the fifth most common and sixth leading cause of cancer-related mortality per year [3].While men tend to have a higher incidence of OSCC (6.6/100,000) compared to women (2.9/100,000), there is an equal mortality rate between the sexes (50%).

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Section: Genetic Alteration In Preneoplastic Lesionsmentioning

confidence: 99%

Molecular mechanisms of head and neck cancer

Deshpande

Wong²

2008

Expert Review of Anticancer Therapy

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“…Transition zones are unique regions between two distinct types of epithelia (McNairn and Guasch, 2011), which develop spontaneous malignant tumors when TGFβ is compromised. These spontaneous tumors occur at the anorectal (Guasch et al, 2007;Honjo et al, 2007;Yoshinaga et al, 2008), the gastrointestinal (Bleuming et al, 2007) and the gastric transition zones (Nam et al, 2012). Loss of TGFβ signaling is not sufficient on its own to cause spontaneous tumors in non-transition zone epithelia, including the tongue (Bian et al, 2009), the skin (Guasch et al, 2007), the pancreas (Ijichi et al, 2006), the intestine (Takaku et al, 1999) or the colon (Maggio-Price et al, 2006), in which additional insults are required to drive carcinogenesis.…”

Section: Loss Of Tgfβ Signaling In the Ocular Surface Epithelium Is Nmentioning

confidence: 99%

TGFβ signaling inhibits goblet cell differentiation via SPDEF in conjunctival epithelium

et al. 2014

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The ocular surface epithelia, including the stratified but nonkeratinized corneal, limbal and conjunctival epithelium, in concert with the epidermal keratinized eyelid epithelium, function together to maintain eye health and vision. Abnormalities in cellular proliferation or differentiation in any of these surface epithelia are central in the pathogenesis of many ocular surface disorders. Goblet cells are important secretory cell components of various epithelia, including the conjunctiva; however, mechanisms that regulate goblet cell differentiation in the conjunctiva are not well understood. Herein, we report that conditional deletion of transforming growth factor β receptor II (Tgfbr2) in keratin 14-positive stratified epithelia causes ocular surface epithelial hyperplasia and conjunctival goblet cell expansion that invaginates into the subconjunctival stroma in the mouse eye. We found that, in the absence of an external phenotype, the ocular surface epithelium develops properly, but young mice displayed conjunctival goblet cell expansion, demonstrating that TGFβ signaling is required for normal restriction of goblet cells within the conjunctiva. We observed increased expression of SAM-pointed domain containing ETS transcription factor (SPDEF) in stratified conjunctival epithelial cells in Tgfbr2 cKO mice, suggesting that TGFβ restricted goblet cell differentiation directly by repressing Spdef transcription. Gain of function of Spdef in keratin 14-positive epithelia resulted in the ectopic formation of goblet cells in the eyelid and peripheral cornea in adult mice. We found that Smad3 bound two distinct sites on the Spdef promoter and that treatment of keratin 14-positive cells with TGFβ inhibited SPDEF activation, thereby identifying a novel mechanistic role for TGFβ in regulating goblet cell differentiation.

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“…It would also be of interest to achieve a better understanding of the putative role for TGFβ in the pro-apoptotic effect induced by ATM, as the activity of Par6 is known to be modulated by TGFβ in the EMT pathway. 25,26 TGFβ is a key regulator in carcinogenesis, as it can act either as a shield against development of cancer, 27 but also for promoting cancer initiation and progression, due to its capability to facilitate we proved that in PC3U cells there is a specific dose-dependent downregulation of AKT and that this pattern is specifically induced only in prostate cancer cells and not in normal epithelial prostate cells. It is known that AKT is a protein kinase which plays an important role in prostate cancer for survival.…”

Section: Discussionmentioning

confidence: 66%

Pro-apoptotic effect of aurothiomalate in prostate cancer cells

Trani¹,

Sorrentino²,

Busch³

et al. 2009

Cell Cycle

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It has been recently demonstrated that small gold compounds could have a potential anti-tumoral activity. Here, we report that aurothiomalate (ATM), a gold compound already used in clinical therapy for the treatment of rheumatoid arthritis, has a pro-apoptotic effect in aggressive prostate cancer (PC3U) cells. In contrast, treatment of human primary epithelial prostate cells (PrEC) with ATM did not cause apoptosis. We demonstrated that ATM is able to disrupt the PKCι-Par6 complex in PC3U cells and that this disruption leads to the activation of ERK in a dose-dependent manner. Interestingly, we also showed that ERK acts upstream of the activation of caspase 3, leading to apoptosis. ATM treatment also causes activation of p38 and JNK MAP kinases. Moreover we could link ATM treatment to activation of the mitochondrial or so called intrinsic pathway, as we observed release of cytochrome c from mitochondria to cytoplasm, suggesting that the mitochondrial pathway is involved in the pro-apoptotic effect mediated by ATM. Taken together our data suggest that ATM could be a new promising drug for the treatment of advanced prostate cancer.

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TGFβ Receptor I Conditional Knockout Mice Develop Spontaneous Squamous Cell Carcinoma

Cited by 29 publications

References 44 publications

Molecular mechanisms of head and neck cancer

Molecular mechanisms of head and neck cancer

TGFβ signaling inhibits goblet cell differentiation via SPDEF in conjunctival epithelium

Pro-apoptotic effect of aurothiomalate in prostate cancer cells

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