IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma

Gu, Fangming; Li, Quan‐Lin; Gao, Qiang; Jiang, Jiahao; Zhu, Kai; Huang, Xiaoyong; Pan, Jinfeng; Yan, Jun; Hu, Jinhui; Wang, Zheng; Dai, Zhi; Fan, Jia; Zhou, Jian

doi:10.1186/1476-4598-10-150

Cited by 179 publications

(161 citation statements)

References 34 publications

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“…25 Compelling molecular evidence has demonstrated a role for STAT3 in tumor initiation and progression. 19,26,27 In line with these previous findings, STAT3 phosphorylation at Tyr705 and Ser727 was evident in gp130 f/f livers 40 weeks after DEN injection. As expected, pSTAT3 expression was strongly inhibited in gp130…”

Section: Hcc Initiation In Gp130supporting

confidence: 88%

Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model

et al. 2015

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Chronic liver inflammation is a crucial event in the development and growth of hepatocellular carcinoma (HCC). Compelling evidence has shown that interleukin-6 (IL-6)/gp130-dependent signaling has a fundamental role in liver carcinogenesis. Thus, in the present study we aimed to investigate the role of gp130 in hepatocytes for the initiation and progression of HCC. Hepatocytespecific gp130 knockout mice (gp130 Δhepa ) and control animals (gp130 f/f ) were treated with diethylnitrosamine (DEN). The role of gp130 for acute injury (0-144 h post treatment), tumor initiation (24 weeks) and progression (40 weeks) was analyzed. After acute DEN-induced liver injury we observed a reduction in the inflammatory response in gp130Δhepa animals as reflected by decreased levels of IL-6 and oncostatin M. The loss of gp130 slightly attenuated the initiation of HCC 24 weeks after DEN treatment. In contrast, 40 weeks after DEN treatment, male and female gp130Δhepa mice showed smaller tumors and reduced tumor burden, indicating a role for hepatocyte-specific gp130 expression during HCC progression. Oxidative stress and DNA damage were substantially and similarly increased by DEN in both gp130 f/f and gp130 Δhepa animals. However, gp130 Δhepa livers revealed aberrant STAT5 activation and decreased levels of transforming growth factor-β (TGFβ), pSMAD2/3 and SMAD2, whereas phosphorylation of STAT3 at Tyr705 and Ser727 was absent. Our results indicate that gp130 deletion in hepatocytes reduces progression, but not HCC initiation in the DEN model. Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGFdependent signaling. Hence, blocking gp130 in hepatocytes might be an interesting therapeutic target to inhibit the growth of HCC.

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Section: Hcc Initiation In Gp130supporting

confidence: 88%

Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model

et al. 2015

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“…It has been suggested that PKB mediated inactivation of FOXO1a down-regulates expression of IL6 [71]. Conversely, IL17 robustly induces IL6 expression and STAT3 activation in a PKB-dependent manner in HCC [72]. These distinct observations seem to be context dependent given the dynamic regulation of IL6 expression via different transcription factors.…”

Section: Role Of Tumor-derived Pkb Activity In Inflammationmentioning

confidence: 99%

PKB/Akt-dependent regulation of inflammation in cancer

Tang

Wang

Hemmings

et al. 2018

Seminars in Cancer Biology

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A B S T R A C TChronic inflammation is a major cause of human cancer. Clinical cancer therapies against inflammatory risk factors are strategically determined. To rationally guide a novel drug development, an improved mechanistic understanding on the pathological connection between inflammation and carcinogenesis is essential. PI3K-PKB signaling axis has been extensively studied and shown to be one of the key oncogenic drivers in most types of cancer. Pharmacological inhibition of the components along this signaling axis is of great interest for developing novel therapies. Interestingly, emerging studies have shown a close association between PKB activation and inflammatory activity in the vicinity of the tumor, and either blockade of PKB or attenuation of para-tumoral inflammation reveals a mutual-interactive pattern through pathway crosstalk. In this review, we intend to discuss recent advances of PKB-regulated chronic inflammation and its potential impacts on tumor development.

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“…Cytokines and chemokines from tumor cells also modify their normal surrounding non-malignant stroma by modulating the function of epithelial cells, endothelial cells, fibroblasts and inflammatory cells to generate a supportive microenvironment [37][38][39]. For instance, TNFα, IL-6 and IL-17 were shown to promote tumor growth by modifying the function of stromal cells surrounding the tumor [40][41][42]. TNFα produced by tumor cells or inflammatory cells in the tumor microenvironment can promote tumor cell survival through the induction of NFκB-dependent anti-apoptotic molecules [43].…”

Section: Niche-dependent Neutrophil Functionmentioning

confidence: 99%

“…TNFα was also shown to promote angiogenesis [44], and induce the expression of VEGF and HIF-1α in tumor cells [45]. IL-6 promotes angiogenesis and the expression of VEGF [46] through JAK2/STAT3 signaling [42] and the tumorpromoting effects of IL-17 are in part mediated through upregulation of IL-6 [42].…”

Section: Niche-dependent Neutrophil Functionmentioning

confidence: 99%

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

Sionov

Fridlender

Granot

2014

Cancer Microenvironment

317

243

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Neutrophils are myeloid cells that constitute 50-70 % of all white blood cells in the human circulation. Traditionally, neutrophils are viewed as the first line of defense against infections and as a major component of the inflammatory process. In addition, accumulating evidence suggest that neutrophils may also play a key role in multiple aspects of cancer biology. The possible involvement of neutrophils in cancer prevention and promotion was already suggested more than half a century ago, however, despite being the major component of the immune system, their contribution has often been overshadowed by other immune components such as lymphocytes and macrophages. Neutrophils seem to have conflicting functions in cancer and can be classified into anti-tumor (N1) and pro-tumor (N2) sub-populations. The aim of this review is to discuss the varying nature of neutrophil function in the cancer microenvironment with a specific emphasis on the mechanisms that regulate neutrophil mobilization, recruitment and activation.

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IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma

Abstract: Background: The Th17 subset and IL-17 have been found in increased frequencies within certain tumors. However, their relevance in cancer biology remains controversial. This study aimed to clarify the biological action of IL-17 on hepatocellular carcinoma (HCC).

Cited by 179 publications

References 34 publications

Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model

Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model

PKB/Akt-dependent regulation of inflammation in cancer

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

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