REG3A accelerates pancreatic cancer cell growth under IL-6-associated inflammatory condition: Involvement of a REG3A–JAK2/STAT3 positive feedback loop (original) (raw)
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Cancer discovery, 2014
Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here, we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote Kras(G12D)-driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in Kras(G12D) mice, whereas genetic or pharmacologic ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer-promoter communications at jointly regulated genes involved in oncogenesis, for example, Cyclin, EGFR and WNT family members. The NFATc1-STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of infl...
REG Iα protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells
Carcinogenesis, 2008
Signal transducer and activator of transcription 3 (STAT3) signaling plays roles in inflammation-associated carcinogenesis. Regenerating gene (REG) Ia protein, an interleukin (IL)-6-inducible gene, is suggested to be involved in the gastritis-gastric cancer sequence. We investigated the involvement of IL-6/STAT3 signaling in REG Ia protein expression and examined whether REG Ia protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells. The effects of IL-6/STAT3 signaling on REG Ia protein expression were examined using a STAT3 small interfering RNA system in gastric cancer cells. The element responsible for IL-6-induced REG Ia promoter activation was determined by a promoter deletion assay. The anti-apoptotic effects of STAT3 signaling and its induced REG Ia protein were examined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatase nick-end labeling and caspase assay in vitro. Human gastric cancer specimens were analyzed by immunohistochemistry for phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and REG Ia protein. IL-6 treatment enhanced the expression of REG Ia protein through STAT3 activation in gastric cancer cells. The IL-6-responsive element was determined to lie in the sequence from 2142 to 2134 of the REG Ia promoter region. REG Ia protein mediated the anti-apoptotic effects of STAT3 signaling in gastric cancer cells by enhancing Akt activation, Bad phosphorylation and Bcl-xL expression. The expression of REG Ia protein was significantly correlated with that of p-STAT3 in gastric cancer tissues. REG Ia protein may play a pivotal role in anti-apoptosis in gastric tumorigenesis under STAT3 activation.
REG I protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells
Carcinogenesis, 2007
Signal transducer and activator of transcription 3 (STAT3) signaling plays roles in inflammation-associated carcinogenesis. Regenerating gene (REG) Ia protein, an interleukin (IL)-6-inducible gene, is suggested to be involved in the gastritis-gastric cancer sequence. We investigated the involvement of IL-6/STAT3 signaling in REG Ia protein expression and examined whether REG Ia protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells. The effects of IL-6/STAT3 signaling on REG Ia protein expression were examined using a STAT3 small interfering RNA system in gastric cancer cells. The element responsible for IL-6-induced REG Ia promoter activation was determined by a promoter deletion assay. The anti-apoptotic effects of STAT3 signaling and its induced REG Ia protein were examined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatase nick-end labeling and caspase assay in vitro. Human gastric cancer specimens were analyzed by immunohistochemistry for phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and REG Ia protein. IL-6 treatment enhanced the expression of REG Ia protein through STAT3 activation in gastric cancer cells. The IL-6-responsive element was determined to lie in the sequence from 2142 to 2134 of the REG Ia promoter region. REG Ia protein mediated the anti-apoptotic effects of STAT3 signaling in gastric cancer cells by enhancing Akt activation, Bad phosphorylation and Bcl-xL expression. The expression of REG Ia protein was significantly correlated with that of p-STAT3 in gastric cancer tissues. REG Ia protein may play a pivotal role in anti-apoptosis in gastric tumorigenesis under STAT3 activation.
The IL-6/JAK/Stat3 Feed-Forward Loop Drives Tumorigenesis and Metastasis
Neoplasia, 2013
We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels of IL-6 were found at the tumor leading edge and positively correlated with advanced stage, suggesting a mechanistic link between tumor cell production of IL-6 and invasion. In support of this hypothesis, we showed that the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (Stat3) pathway drives tumor progression through the stroma and metastatic niche. Overexpression of IL-6 in tumor cell lines promoted myeloid cell recruitment, angiogenesis, and induced metastases. We demonstrated the therapeutic
Oncology reports, 2017
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Involvement of interleukin-6 and androgen receptor signaling in pancreatic cancer
Genes & cancer, 2010
Pancreatic cancer remains one of the "difficult-to-treat" cancers. Signaling of androgen receptor (AR), one of the nuclear receptors, in the pancreas may be related to carcinogenesis. Higher interleukin-6 (IL-6) levels have been observed in pancreatic cancer patients. It is also well known that IL-6 affects the AR signaling pathway and that AR is important for cell migration activities. We demonstrated that IL-6 enhances the phosphorylation of STAT3 and MAPK, which in turn enhances AR-mediated transcription in pancreatic cancer cell lines. This activity was blocked by a pharmacological inhibitor of the JAK/STAT signaling pathway, AG490, and one of the MAPK signaling pathways, U0126. IL-6 also enhances pancreatic cancer cell migration in the presence of AR. This activity is blocked by AR-siRNA. IL-6 acts as a positive regulator in AR signaling, providing further insight into the progression of pancreatic carcinogenesis.
Loss of Activating Transcription Factor 3 prevents KRAS-mediated pancreatic cancer
The unfolded protein response (UPR) is activated in pancreatic pathologies and suggested as a target for therapeutic intervention. In this study, wxe examined Activating Transcription Factor 3 (ATF3), a mediator of the UPR which promotes acinar-to-ductal metaplasia (ADM) in response to pancreatic injury. Since ADM is an initial step in the progression to pancreatic ductal adenocarcinoma (PDAC), we hypothesized ATF3 is required for initiation and progression of PDAC. We generated mice carrying a germ line mutation of Atf3 (Atf3-/-) combined with acinar-specific induction of oncogenic KRAS (Ptf1acreERT/+KrasLSL-G12D). Atf3-/- mice with (termed APK) and without KRASG12D were exposed to cerulein-induced pancreatitis. In response to recurrent pancreatitis, Atf3-/- mice showed decreased ADM and enhanced regeneration based on morphological and biochemical analysis. Similarly, an absence of ATF3 reduced spontaneous pancreatic intraepithelial neoplasia formation and PDAC in Ptf1acreERT/+Kras...
Gastroenterology, 2016
One treatment strategy for pancreatic ductal adenocarcinoma is to modify, rather than deplete, the tumor stroma. Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) is associated with progression of pancreatic and other solid tumors. We investigated whether loss of P53 function contributes to persistent activation of STAT3 and modification of the pancreatic tumor stroma in patients and mice. Stat3, Il6st (encodes gp130), or Trp53 were disrupted, or a mutant form of P53 (P53R172H) or transgenic sgp130 were expressed, in mice that developed pancreatic tumors due to expression of activated KRAS (KrasG12D, KC mice). Pancreata were collected and analyzed by immunohistochemistry, in situ hybridization, quantitative reverse-transcription PCR, or immunoblot assays; fluorescence-activated cell sorting to identify immune cells. We obtained frozen pancreatic tumor specimens from patients and measured levels of phosphorylated STAT3 and P53 by immunohistoche...