Hair follicle defects and squamous cell carcinoma formation in Smad4 conditional knockout mouse skin

Qiao, Wenhui; Ag, Li; Owens, P. C.; Xu, Xiaowei; Wang, Xiujun; Cx, Deng

doi:10.1038/sj.onc.1209029

Cited by 96 publications

(126 citation statements)

References 45 publications

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“…In mice, loss of Smad4 results in early embryonic lethality because of impaired extraembryonic membrane formation and decreased epiblast proliferation (Sirard et al, 1998;Yang et al, 1998), whereas Smad4 heterozygous mice developed gastric polyposis and cancer because of haploinsufficiency (Takaku et al, 1999;Xu et al, 2000). Using tissue-specific knockout of Smad4 (Yang et al, 2002), we, along with others, showed that Smad4 deficiency could cause tumor formation in mammary tissue (Li et al, 2003), skin (Yang et al, 2005;Qiao et al, 2006), liver , forestomach (Teng et al, 2006) and colon (Kim et al, 2006). A recent study revealed that loss of Smad4 alone does not initiate pancreatic cancer formation, although it accelerates tumor formation on activation of oncogenic signaling, such as Kras (Izeradjene et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice

Ehdaie

Ohara

et al. 2009

Oncogene

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Mutations of SMAD4/DPC4 are found in about 60% of human invasive pancreatic ductal adenocarcinomas (PDACs); yet, the manner in which SMAD4 deficiency enhances tumorigenesis remains elusive. Using a CreLoxP approach, we generated a mutant mouse carrying a targeted deletion of Smad4 in the pancreas. We showed that the absence of Smad4 alone did not trigger pancreas tumor formation; however, it increased the expression of an inactivated form of Pten, suggesting a role of Pten in preventing Smad4-/-cells from undergoing malignancy. To investigate this, we disrupted both Pten and Smad4. We showed that Pten deficiency initiated widespread premalignant lesions, and a low tumor incidence that was significantly accelerated by Smad4-deficiency. The absence of Smad4 in a Pten-mutant background enhanced cell proliferation and triggered transdifferentiation from acinar, centroacinar and islet cells, accompanied by activation of Notch1 signaling. We showed that all tumors developed in the Smad4/Pten-mutant pancreas exhibited high levels of pAKT and mTOR, and that about 50 and 83% of human pancreatic cancers examined showed increased pAKT and pmTOR, respectively. Besides the similarity in gene expression, the pAKT and/or pmTORpositive human PDACs and mouse pancreatic tumors also shared some histopathological similarities. These observations indicate that Smad4/Pten-mutant mice mimic the tumor progression of human pancreatic cancers that are driven by activation of the AKT-mTOR pathway, and uncovered a synergistic action of Smad4 and Pten in repressing pancreatic tumorigenesis.

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Section: Introductionmentioning

confidence: 99%

Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice

Ehdaie

Ohara

et al. 2009

Oncogene

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“…19 Skin-specific disruption of Smad4 results in increased epidermal proliferation consequently leading to squamous cell carcinoma formation. 20,21 Antitumor activity of BMPs may also be regulated by extracellular BMP inhibitors: expression of the BMP antagonist gremlin increased in basal cell carcinomas, in which gremlin promotes and BMPs inhibit cell proliferation. 22 However, mechanisms and downstream targets that mediate tumor suppressor function of the BMP signaling pathway in skin remain to be explored.…”

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confidence: 99%

Bone Morphogenetic Protein Antagonist Noggin Promotes Skin Tumorigenesis via Stimulation of the Wnt and Shh Signaling Pathways

Sharov

Mardaryev

Sharova

et al. 2009

The American Journal of Pathology

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Bone morphogenetic proteins (BMPs) play pivotal roles in the regulation of skin development. To study the role of BMPs in skin tumorigenesis, BMP antagonist noggin was used to generate keratin 14-targeted transgenic mice. In contrast to wild-type mice, transgenic mice developed spontaneous hair follicle-derived tumors, which resemble human trichofolliculoma. Global gene expression profiles revealed that in contrast to anagen hair follicles of wild-type mice, Skin cancer is the most common cancer in the United States, Europe, and other countries, and the incidence continues to increase. 1 During the last decade, considerable progress has been achieved in identification of molecular mechanisms underlying the development of the major cutaneous cancers, such as malignant melanoma, basal cell carcinoma, and squamous cell carcinoma. 2,3 In particular, it was shown that mechanisms controlling skin development and carcinogenesis appear to be very similar, and key signaling pathways (Wnt, hedgehog, notch, transforming growth factor-␤, etc) that regulate skin development are also implicated in the pathobiology of cutaneous neoplasias [reviewed in [1][2][3][4][5] ].Bone morphogenetic protein (BMP) signaling plays pivotal roles in the control of cutaneous development and also possesses a potent antitumor activity in postnatal skin [for review see 6,7 ]. BMP signaling is activated by binding of the BMP ligands to BMP receptors (BMPRs) followed by activation of the BMP-Smad and/or BMP-MAP kinase pathways.

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“…The tumor suppressor, Smad4, which has been demonstrated to function constitutively in the transforming growth factor-β signaling pathway, is often mutated or deleted in various malignant neoplasms, including prostate, pancreatic and colorectal cancer (25). A previous study has demonstrated that conditional knockout of Smad4 was associated with hair follicle defects and cSCC formation in mice (26). In addition, our previous study identified the downregulation of Smad4 in a human cSCC (A431) cell line (14).…”

Section: A B C Dmentioning

confidence: 99%

Antitumor effects of recombinant human adenovirus-p53 against human cutaneous squamous cell carcinoma in mice

Wang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The present study was conducted to identify the anti-tumor effects of rAd/p53, which is a recombinant human serotype 5 adenovirus, in cutaneous squamous cell carcinoma (cSCC). Mouse models of human cSCC were constructed by injecting human cutaneous squamous cell carcinoma cells into both flanks of nude mice. Subsequently, the 75 nude mice with cSCC xenograft tumors were randomly divided into recombinant human serotype 5 adenovirus (rAd)/p53, rAd/p53 + 5-fluorouracil (5-Fu) and 5-Fu groups. One side of the tumors was administered the therapeutic agents as the therapeutic group, whereas the remaining side was treated with medical saline as the control. At 24, 48, 72, 120 and 168 h post-intratumoral injection, alterations in tumor volume, tumor necrosis and the expression of several tumor-associated genes, including Smad4, Brca1 and matrix metalloproteinase (MMP-2), were analyzed. Compared with its control group, the rAd/P53 group exhibited a significantly increased tumor necrosis ratio. In addition, Smad4 and Brca1 expression levels increased significantly at various time points (P<0.05), and MMP-2 expression decreased significantly (P<0.05). In the rAd/p53 + 5-Fu group, the tumor necrosis ratio, and Smad4 and Brca1 expression levels also significantly increased at various time points (P<0.05). MMP-2 gene transcription gradually decreased, high expression of Smad4 was prolonged, and high expression of Brca1 was observed in the early period following treatment compared with the rAd/P53 group. In addition, p53 expression exhibited a positive correlation with the tumor necrosis ratio and Smad4 expression, and showed a negative correlation with MMP-2 gene transcription (P<0.05). These findings indicate that rAd/p53 has a potent anti-tumor effect in cSCC via the promotion of tumor necrosis and regulating the expression of various tumor-associated genes.

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Hair follicle defects and squamous cell carcinoma formation in Smad4 conditional knockout mouse skin

Cited by 96 publications

References 45 publications

Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice

Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice

Bone Morphogenetic Protein Antagonist Noggin Promotes Skin Tumorigenesis via Stimulation of the Wnt and Shh Signaling Pathways

Antitumor effects of recombinant human adenovirus-p53 against human cutaneous squamous cell carcinoma in mice

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