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

Xu, Xiaoling; Ehdaie, Behfar; Ohara, Nobuya; Yoshino, Tadashi; Deng, Chu‐Xia

doi:10.1038/onc.2009.375

Cited by 42 publications

(36 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In these squamous carcinomas, inactivation of Smad2/3 signaling is correlated with strong activation of PI3K/Akt signaling that explains tumor overproliferation. The TGFβ inactivation-PI3K hyperactivation paradigm is of general importance in cancer development, as recently exemplified by studies in mice with prostatespecific or pancreas-specific deletion of the Smad4 gene (Ding et al 2011;Xu et al 2010). A key synergistic factor that helps tumorigenesis in addition to the loss of Smad4 is the loss of the PTEN (phosphatase and tensin homolog) phosphatase that leads to abnormal activation of the PI3K pathway.…”

Section: Perturbation Of Smad-induced Growth Arrest In Malignanciesmentioning

confidence: 98%

Role of Smads in TGFβ signaling

2011

View full text Add to dashboard Cite

Transforming growth factor-β (TGFβ) is the prototype for a large family of pleiotropic factors that signal via heterotetrameric complexes of type I and type II serine/threonine kinase receptors. Important intracellular mediators of TGFβ signaling are members of the Smad family. Smad2 and 3 are activated by C-terminal receptor-mediated phosphorylation, whereafter they form complexes with Smad4 and are translocated to the nucleus where they, in cooperation with other transcription factors, co-activators and co-repressors, regulate the transcription of specific genes. Smads have key roles in exerting TGFβ-induced programs leading to cell growth arrest and epithelial-mesenchymal transition. The activity and stability of Smad molecules are carefully regulated by a plethora of post-translational modifications, including phosphorylation, ubiquitination, sumoylation, acetylation and poly(ADP)-ribosylation. The Smad function has been shown to be perturbed in certain diseases such as cancer.

show abstract

Section: Perturbation Of Smad-induced Growth Arrest In Malignanciesmentioning

confidence: 98%

Role of Smads in TGFβ signaling

2011

View full text Add to dashboard Cite

show abstract

“…[10][11][12] PTEN has been recently shown to act in synergy with Smad4 in suppressing pancreatic ductal adenocarcinoma formation in mice. 20 More recently, it has been reported that inhibition of miR-21 in a pancreatic ductal adenocarcinoma cell line led to reduced cell proliferation and increased cell death, with a simultaneous increase in PDCD4. 21 In addition, the level of expression of PTEN, PDCD4, Maspin, and TPM1 was significantly reduced in drug-resistant pancreatic ductal adenocarcinoma cell lines.…”

Section: Discussionmentioning

confidence: 99%

Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma

et al. 2012

View full text Add to dashboard Cite

Since the discovery of small non-coding RNAs, the analyses of microRNA (miRNA) expression patterns in human cancer have provided new insights into cancer biology. miRNA-21 has been suggested to be one of the miRNAs that have an important role in the development or biological behavior of a variety of malignancies, including pancreatic cancer. This study was conducted to evaluate the relationship between the expression of miRNA-21 and that of its molecular targets, programmed cell death 4 (PDCD4) and tissue inhibitor of metalloproteinase (TIMP3), in pancreatic ductal adenocarcinoma. The study included 65 pancreatic ductal adenocarcinomas and 5 normal pancreatic tissue specimens for comparison. The miRNA expression profiling of five selected pancreatic ductal adenocarcinomas and five normal pancreatic specimens was performed using a microarray platform, and was evaluated by a hierarchical clustering analysis. The miRNA most highly expressed in pancreatic ductal adenocarcinomas (ie, miRNA-21) was further assessed by quantitative real-time reverse transcription PCR (RT-PCR) assays in the 65 pancreatic ductal adenocarcinoma cases. The expression pattern of its molecular targets (eg, PDCD4 and TIMP3) in pancreatic ductal adenocarcinoma was examined immunohistochemically. In the microarray analyses, 28 miRNAs were upregulated in pancreatic ductal adenocarcinoma compared with normal pancreatic tissue, whereas 48 miRNAs were downregulated. miRNA-21 was the most significantly overexpressed miRNA in the pancreatic ductal adenocarcinomas analyzed, and was also highly expressed in 75% of the 65 pancreatic ductal adenocarcinomas examined by real-time RT-PCR. High miRNA-21 expression was correlated with a worse prognosis in the pancreatic ductal adenocarcinoma patients (P ¼ 0.045). The immunohistochemical expression patterns of PDCD4 (reduced nuclear staining pattern) and TIMP3 (downregulated expression) were significantly associated with both the upregulated miR-21 expression (Po0.05) and the poor survival of the patients (Po0.001 and P ¼ 0.001, respectively). Our data suggest that an overexpression of miRNA-21 is, therefore, associated with the biological behavior of pancreatic ductal adenocarcinoma via the downregulation of the expression of tumor suppressors, PDCD4 and TIMP3, thus resulting in tumor progression and the adverse clinical course of pancreatic ductal adenocarcinoma.

show abstract

“…Our group and other research groups have demonstrated cooperative functionality between Smad4 and PTEN signaling in suppressing tumorigenesis in various tumor mouse models of different tissues, such as squamous cell carcinoma in the skin and esophagus and adenocarcinoma in the prostate and pancreas [24,[36][37][38]. Here, we demonstrated the synergetic effect between Smad4 and PTEN deletion in driving gastric tumor initiation in the context of tissue stem cells.…”

Section: Discussionmentioning

confidence: 67%

Gastric Lgr5+ stem cells are the cellular origin of invasive intestinal-type gastric cancer in mice

Li¹,

Guan²,

Zhu³

et al. 2016

Cell Res

View full text Add to dashboard Cite

The cellular origin of gastric cancer remains elusive. Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is the first identified marker of gastric stem cells. IntroductionGastric cancer is the fifth most common malignancy and the third leading cause of cancer mortality worldwide [1]. The vast majority of gastric cancer is adenocarcinoma, which consists of the intestinal-type and diffuse-type according to the Lauren classification, and it is thought to arise from the gastric epithelium via sequentially acquired mutations in specific genes. The gastric epithelium is organized into multiple gastric units that are fueled by a pool of stem cells capable of self-renewal and multilineage differentiation. In the adult gastric antrum, Results Deletion of Smad4 and PTEN in murine Lgr5 + stem cells resulted in gastric tumorSmad4, a central mediator of TGF-β signaling, is a well-known tumor suppressor, as evidenced by various murine models of different cancer types, including gastric cancer [12]. However, all of these murine models of gastric cancer arise from the germline heterozygous or T cell-specific deletion of Smad4 [13][14][15][16]. The epithelium-autonomous role of Smad4 in suppressing gastric cancer has not yet been clearly defined. Our previous study has demonstrated that PTEN deletion in the entire gastric epithelium leads to adenoma in the corpus and slight hyperplasia in the antrum [17] + cells. Cre-mediated recombination within the reporter locus activates the expression of a red fluorescent protein variant, tdTomato, which indelibly marks the recombined cells and their progenies through their entire lifespan. Due to the previously reported low activity of Lgr5-Cre ERT2 transgenic mice, tamoxifen was administered for 6 consecutive days in 6-week-old mice, and no morphological abnormality associated with tamoxifen was observed in the gastric antral epithelium (Supplementary information, Figure S1A Table 1). In addition, red polyps adjacent to forestomach, where a few Lgr5 + cells at the base of corpus glands near forestomach/esophageal border act as stem cells [2], were found in 25% (5/20) of mice lacking Smad4 and PTEN ( Figure 1B, blue arrowhead). Afterwards, double-mutant mice exhibited progressive weakness and died within 5 months ( Figure 1C).Red polyps indicated that the lesions might arise as a result of Cre activity in mutant Lgr5 + cells ( Figure 1B, arrowheads). Consistent with this, immunohistochemistry (IHC) analysis displayed clear loss of Smad4 and PTEN as well as consequent p-Akt activation, which were further supported by the western blot results ( Figure 1D and 1E). Taken together, the above data demonstrate that mutant gastric Lgr5 + cells produced gastric tumors.

show abstract

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

Cited by 42 publications

References 57 publications

Role of Smads in TGFβ signaling

Role of Smads in TGFβ signaling

Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma

Gastric Lgr5+ stem cells are the cellular origin of invasive intestinal-type gastric cancer in mice

Contact Info

Product

Resources

About