Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice

Hahn, Jennifer; Falck, Vincent; Jirik, Frank R.

doi:10.1172/jci45114

Cited by 70 publications

(61 citation statements)

References 94 publications

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“…Smad4 mutation has been associated with cancers in human and mice (Hahn et al, 2011; Howe et al, 1998; Kim et al, 2006; Miyaki and Kuroki, 2003). The immune etiology is not entirely clear, although enhanced Th cell responses may contribute to cancer development (Hahn et al, 2011; Kim et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

“…Yet, mice with T cell specific deletion of Smad4 are grossly normal without apparent T cell activation (Yang et al, 2008b). In addition, when these mice are on a specific genetic background, they spontaneously develop cancer but not autoimmunity (Hahn et al, 2011; Kim et al, 2006). Similarly, people with germ-line mutations of Smad4 predispose to familial juvenile polyposis and gastrointestinal cancers (Howe et al, 1998; Miyaki and Kuroki, 2003) but not autoimmune disease.…”

Section: Introductionmentioning

confidence: 99%

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A Critical Role for Transcription Factor Smad4 in T Cell Function that Is Independent of Transforming Growth Factor β Receptor Signaling

Zhang

Wang

et al. 2015

Immunity

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Summary Transforming growth factor-beta (TGF-β) suppresses T cell function to maintain self-tolerance and to promote tumor immune evasion. Yet how Smad4, a transcription factor component of TGF-β signaling, regulates T cell function remains unclear. Here we have demonstrated an essential role for Smad4 in promoting T cell function during autoimmunity and anti-tumor immunity. Smad4 deletion rescued the lethal autoimmunity resulting from transforming growth factor-beta receptor (TGF-βR) deletion and compromised T-cell-mediated tumor rejection. While Smad4 was dispensable for T cell generation, homeostasis and effector function, it was essential for T cell proliferation following activation in vitro and in vivo. The transcription factor Myc was identified to mediate Smad4-controlled T cell proliferation. This study thus reveals a requirement of Smad4 for T-cell-mediated autoimmunity and tumor rejection, which is beyond the current paradigm. It highlights a TGF-βR-independent role for Smad4 in promoting T cell function, autoimmunity and anti-tumor immunity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Critical Role for Transcription Factor Smad4 in T Cell Function that Is Independent of Transforming Growth Factor β Receptor Signaling

Zhang

Wang

et al. 2015

Immunity

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“…Furthermore, in isolated murine T cells, JNK phosphorylation was inversely associated with Smad4 protein expression (data not shown). Previous studies have indicated that constitutive JNK activity may promote the malignancy of B and T cells (21,31), while mice with a Smad4 deletion were observed to spontaneously develop gastrointestinal cancer (32,33). The possibility that a Smad4 deletion may initiate pancreatic cancer in humans is unclear.…”

Section: Discussionmentioning

confidence: 99%

Smad4 inhibits cell migration via suppression of JNK activity in human pancreatic carcinoma PANC-1 cells

Zhang¹,

Cao²,

Pei³

et al. 2016

Oncology Letters

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Abstract. Smad4 is a common Smad and is a key downstream regulator of the transforming growth factor-β signaling pathway, in which Smad4 often acts as a potent tumor suppressor and functions in a highly context-dependent manner, particularly in pancreatic cancer. However, little is known regarding whether Smad4 regulates other signaling pathways involved in pancreatic cancer. The present study demonstrated that Smad4 downregulates c-Jun N-terminal kinase (JNK) activity using a Smad4 loss-of-function or gain-of-function analysis. Additionally, stable overexpression of Smad4 clearly affected the migration of human pancreatic epithelioid carcinoma PANC-1 cells, but did not affect cell growth. In addition, the present study revealed that upregulation of mitogen-activated protein kinase phosphatase-1 is required for the reduction of JNK activity by Smad4, leading to a decrease in vascular endothelial growth factor expression and inhibiting cell migration. Overall, the present findings indicate that Smad4 may suppress JNK activation and inhibit the tumor characteristics of pancreatic cancer cells.

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“…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.…”

Section: Deletion Of Smad4 and Pten In Murine Lgr5mentioning

confidence: 99%

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

Li¹,

Guan²,

Zhu³

et al. 2016

Cell Res

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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.

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Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice

Cited by 70 publications

References 94 publications

A Critical Role for Transcription Factor Smad4 in T Cell Function that Is Independent of Transforming Growth Factor β Receptor Signaling

A Critical Role for Transcription Factor Smad4 in T Cell Function that Is Independent of Transforming Growth Factor β Receptor Signaling

Smad4 inhibits cell migration via suppression of JNK activity in human pancreatic carcinoma PANC-1 cells

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

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