Stat3 Is a Negative Regulator of Intestinal Tumor Progression in ApcMin Mice

Kim

Journal of Biological Chemistry

et al. 2012

Background: STAT3 suppresses carcinogenesis of intestinal tumors in Apc min mice. Results: STAT3 suppresses expression of SNAI in intestinal epithelium by regulating GSK3␤ activity. Conclusion: STAT3 induces degradation of SNAI by promoting GSK3␤ activity and thereby suppresses adenoma-to-adenocarcinoma transition in Apc min mice. Significance: Our data provide a new insight into the role of STAT3 in colorectal cancer biology.

Section: Discussioncontrasting

confidence: 28%

Section: Stat3 Was Recently Reported To Suppress Tumor Invasion Inmentioning

confidence: 99%

Signal Transducer and Activator of Transcription 3 (STAT3) Protein Suppresses Adenoma-to-carcinoma Transition in Apc/+ Mice via Regulation of Snail-1 (SNAI) Protein Stability

Kim

Journal of Biological Chemistry

et al. 2012

“…Jak/Stat signaling activation in Apc-driven intestinal hyperplasia Understanding the contribution of Jak/Stat signaling to the Apc phenotype in the mammalian intestine has been complicated by genetic redundancy between Stat transcription factors. Constitutive deletion of Stat3 within the intestinal epithelium slowed tumor formation in the Apc Min/+ mouse, but the tumors that arose were more aggressive and ectopically expressed Stat1 (Musteanu et al, 2010). Using the Drosophila midgut we provide direct in vivo evidence that activation of Jak/Stat signaling downstream of Apc1/Myc mediates Apc1-dependent hyperproliferation.…”

Section: Research Articlementioning

confidence: 79%

Non-autonomous crosstalk between the Jak/Stat and Egfr pathways mediates Apc1-driven intestinal stem cell hyperplasia in the Drosophila adult midgut

et al. 2012

SUMMARYInactivating mutations within adenomatous polyposis coli (APC), a negative regulator of Wnt signaling, are responsible for most sporadic and hereditary forms of colorectal cancer (CRC). Here, we use the adult Drosophila midgut as a model system to investigate the molecular events that mediate intestinal hyperplasia following loss of Apc in the intestine. Our results indicate that the conserved Wnt target Myc and its binding partner Max are required for the initiation and maintenance of intestinal stem cell (ISC) hyperproliferation following Apc1 loss. Importantly, we find that loss of Apc1 leads to the production of the interleukin-like ligands Upd2/3 and the EGF-like Spitz in a Myc-dependent manner. Loss of Apc1 or high Wg in ISCs results in non-cell-autonomous upregulation of upd3 in enterocytes and subsequent activation of Jak/Stat signaling in ISCs. Crucially, knocking down Jak/Stat or Spitz/Egfr signaling suppresses Apc1-dependent ISC hyperproliferation. In summary, our results uncover a novel non-cell-autonomous interplay between Wnt/Myc, Egfr and Jak/Stat signaling in the regulation of intestinal hyperproliferation. Furthermore, we present evidence suggesting potential conservation in mouse models and human CRC. Therefore, the Drosophila adult midgut proves to be a powerful genetic system to identify novel mediators of APC phenotypes in the intestine.

“…Thus, after being identified as an oncogene in some cancer types, 31,33 recent work has highlighted its role as tumor suppressor in glioma, hepatoma, breast, intestinal, head and neck and thyroid cancer. 11,30,[34][35][36][37][38] Interestingly, Couth et al 11 found that an autocrine IL6/gp130/JAK loop is responsible for keeping high levels of phospho-STAT3 phosphorylation in thyroid carcinoma cell lines, which in turn suppress tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

et al. 2013

Genes of the Sprouty family (Spry1-4) are feedback inhibitors of receptor tyrosine kinase (RTK) signaling. As such, they restrain proliferation of many cell types and have been proposed as tumor-suppressor genes. Although their most widely accepted target is the Extracellular-regulated kinases (ERK) pathway, the mechanisms by which Spry proteins inhibit RTK signaling are poorly understood. In the present work, we describe a novel mechanism by which Spry1 restricts proliferation, independently of the ERK pathway. In vivo analysis of thyroid glands from Spry1 knockout mice reveals that Spry1 induces a senescence-associated secretory phenotype via activation of the NFjB pathway. Consistently, thyroids from Spry1 knockout mice are bigger and exhibit decreased markers of senescence including Ki67 labeling and senescence-associated b-galactosidase. Although such 'escape' from senescence is not sufficient to promote thyroid tumorigenesis in adult mice up to 5 months, the onset of Phosphatase and tensin homolog (Pten)-induced tumor formation is accelerated when Spry1 is concomitantly eliminated. Accordingly, we observe a reduction of SPRY1 levels in human thyroid malignancies when compared with non-tumoral tissue. We propose that Spry1 acts as a sensor of mitogenic activity that not only attenuates RTK signaling but also induces a cellular senescence response to avoid uncontrolled proliferation. The Sprouty family of genes is composed of four members in mammals (Spry1-4), orthologous to a single Drosophila melanogaster gene (dSpry). With some well-documented exceptions, Sprouty proteins function as feedback inhibitors of receptor tyrosine kinase (RTK) signaling. In Drosophila, dSpry inhibits signaling by FGF and EGF in the airways and the eye, respectively. Genetic experiments in mice establish that Spry1 and Spry2 are negative regulators of signaling by FGFR and Ret RTKs. Thus, the deletion of Spry2 and/or Spry4 causes different craniofacial abnormalities because of hypersensitivity to FGF. On the other hand, excessive Ret signaling underlies kidney and enteric nervous system defects found in Spry1 and Spry2 knockout mice, respectively (reviewed in Guy et al. 1 ). Although the most widely accepted targets of Spry are the ERK MAPK, the mechanisms by which Sprouty proteins restrain signaling by these RTKs remain poorly understood. 1,2 Spry family members have been proposed to function as tumor-suppressor genes in a growing list of cancerous malignancies. Thus, Spry1 and Spry2 levels are decreased in prostate and breast cancer, 3,4 whereas the downregulation of Spry2 has been described in hepatocellular carcinoma, B-cell lymphoma or endometrial carcinoma, among others. [5][6][7] Epigenetic silencing 3,5 or loss of heterozygosity 3 are the most widely observed molecular alterations of the Spry genes in tumoral tissue.In this work, we show that Spry1 null mice exhibit overgrowth of the thyroid gland owing to increased proliferation of thyrocytes. Surprisingly, such increase in cell proliferation does not correlate with eith...