Serum Interleukin-6 Level but not Genotype Predicts Survival after Resection in Stages II and III Gastric Carcinoma

Liao, Wei‐Chih; Lin, Jaw Town; Wu, Chun Ying; Huang, Shih Pei; Lin, Ming Tsan; Wu, Ariel; Huang, Yu Jie; Wu, Ming Shiang

doi:10.1158/1078-0432.ccr-07-1032

Cited by 80 publications

(79 citation statements)

References 43 publications

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“…By inducing cytokines including IL6 and IL8, H. pylori plays important roles in gastric cancer development (4), including tumor initiation (5), promotion (6), and metastasis (7). IL6 that activates STAT3 has particularly important roles in the malignant transformation of gastric and intestinal epithelial cells (8).…”

Section: Introductionmentioning

confidence: 99%

Gastric Cancer Cell Proliferation and Survival Is Enabled by a Cyclophilin B/STAT3/miR-520d-5p Signaling Feedback Loop

Guo

Zhao

et al. 2017

Cancer Research

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Molecular links between inflammation and cancer remain obscure despite their great pathogenic significance. The JAK2/ STAT3 pathway activated by IL6 and other proinflammatory cytokines has garnered attention as a pivotal link in cancer pathogenesis, but the basis for its activation in cancer cells is not understood. Here we report that an IL6-triggered feedback loop involving STAT3-mediated suppression of miR-520d-5p and upregulation of its downstream target cyclophilin B (CypB) regulate the growth and survival of gastric cancer cells. In clinical specimens of gastric cancer, we documented increased expression of CypB and activation of STAT3. Mechanistic investigations identified miR-520d-5p as a regulator of CypB mRNA levels. This signaling axis regulated gastric cancer growth by modulating phosphorylation of STAT3. Furthermore, miR-520d-5p was identified as a direct STAT3 target and IL6-mediated inhibition of miR-520d-5p relied upon STAT3 activity. Our findings define a positive feedback loop that drives gastric carcinogenesis as influenced by H. pylori infections that involve proinflammatory IL6 stimulation. Cancer Res; 77(5);

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Section: Introductionmentioning

confidence: 99%

Gastric Cancer Cell Proliferation and Survival Is Enabled by a Cyclophilin B/STAT3/miR-520d-5p Signaling Feedback Loop

Guo

Zhao

et al. 2017

Cancer Research

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“…Previous studies have reported that -634G/C polymorphism is associated with the clinical outcome of breast, gastric, prostate and ovarian cancers (33)(34)(35)(36). One study investigated the association between VEGF polymorphism and the prognosis of osteosarcoma, but this previous study did not identify that the -634G/C polymorphism played a role in the clinical outcome of osteosarcoma (37).…”

Section: Discussionmentioning

confidence: 98%

Role of five small nucleotide polymorphisms in the VEGF gene on the susceptibility to osteosarcoma and overall survival of patients

Liu¹,

Bai²,

Duan³

et al. 2015

Oncology Letters

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Abstract. The present study aimed to investigate the association between five common small nucleotide polymorphisms (SNPs) in the VEGF gene and the risk of osteosarcoma. An additional aim was to investigate the role of these five SNPs on the prognosis of osteosarcoma. A total of 186 patients with osteosarcoma and 186 age-and sex-matched healthy controls were enrolled into the present study. A polymerase chain reaction-restriction fragment length polymorphism assay was conducted to determine the incidence of the VEGF-2578 C/A, -1156 G/A, +1612 G/A, +936 C/T and -634 G/C polymorphisms. Conditional logistic regression analyses revealed that individuals carrying the -634 GG genotype possessed a significantly increased risk of osteosarcoma, with an adjusted odds ratio [(95% confidence interval (CI)] of 2.00 (1.07-3.75). In the Cox proportional hazards model, subsequent to adjusting for potential confounding factors, patients with osteosarcoma carrying the -634 GG genotype were found to demonstrate a shorter overall survival time (hazard ratio, 3.10; 95% CI, 1.17-8.38). The VEGF-634 G/C polymorphism may therefore be used as a genetic marker for the prediction of the risk and clinical outcome of osteosarcoma. IntroductionOsteosarcoma is derived from mesenchymal tissues and often occurs in the distal femur, proximal tibia and humeral metaphysis. Osteosarcoma is one of the most common malignant tumors in children and adolescents. It is estimated that the annual incidence of osteosarcoma is 4-5 cases per 1,000,000 individuals worldwide, and osteosarcoma is a leading cause of cancer-associated mortalities in children and young adults (1-3).The development of osteosarcoma is a complex, multistep and multifactorial process in which numerous factors are implicated (4-6). Several studies have been performed to investigate cancer stem cells and the potential of these cells to cause tumors (7,8). The concept that genetic factors are involved in the development of osteosarcoma has led to numerous studies investigating genetic determinants for osteosarcoma in the past decade (10-13).Vascular endothelial growth factor (VEGF) is one of the most potent endothelial cell mitogens, and performs an important role in angiogenesis (14,15). The VEGF gene, which consists of eight exons that undergo alternative splicing to form a family of proteins, is located at chromosome 6p21.3. It is well known that the VEGF gene results in several alternatively spliced isoforms, and the regulation of VEGF expression can reveal the difference between normal and tumor tissues. It is estimated that there are >30 types of single nucleotide polymorphism (SNP) in the VEGF gene (16), and several SNPs in the VEGF gene have been reported to affect the expression of the VEGF gene (16). Among these SNPs, five common SNPs in the VEGF gene, consisting of -2578C/A, -1156G/A, +1612G/A, +936C/T and -634G/C, are reported to be associated with VEGF protein synthesis (17). The -2578C/A and -1156G/A SNPs are located at the VEGF promoter region, and the +1612G/A, +936C/T and...

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“…Various clinical studies have correlated high pretreatment serum IL6 level with poor outcome in patients with different types of cancer including head and neck squamous cell carcinoma (28), stage II and III gastric carcinoma (29), prostate cancer (30), metastatic renal cell carcinoma (31), metastatic breast cancer (32), and ovarian cancer (33). Elevated levels of IL6 in cancer patients could be due to increased expression in normal immune cells as a consequence of chronic (systemic) inflammation, and/or from stromal or cancer cells within tumors.…”

Section: Discussionmentioning

confidence: 99%

Resistance to Anti-VEGF Therapy Mediated by Autocrine IL6/STAT3 Signaling and Overcome by IL6 Blockade

Eichten

Adler

et al. 2016

Cancer Research

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Anti-VEGF therapies benefit several cancer types, but drug resistance that limits therapeutic response can emerge. We generated cell lines from anti-VEGF-resistant tumor xenografts to investigate the mechanisms by which resistance develops. Of all tumor cells tested, only A431 (A431-V) epidermoid carcinoma cells developed partial resistance to the VEGF inhibitor aflibercept. Compared with the parental tumors, A431-V tumors secreted greater amounts of IL6 and exhibited higher levels of phospho-STAT3. Notably, combined blockade of IL6 receptor (IL6R) and VEGF resulted in enhanced activity against A431-V tumors. Similarly, inhibition of IL6R enhanced the antitumor effects of aflibercept in DU145 prostate tumor cells that displays high endogenous IL6R activity. In addition, post hoc stratification of data obtained from a clinical trial investigating aflibercept efficacy in ovarian cancer showed poorer survival in patients with high levels of circulating IL6. These results suggest that the activation of the IL6/STAT3 pathway in tumor cells may provide a survival advantage during anti-VEGF treatment, suggesting its utility as a source of response biomarkers and as a therapeutic target to heighten efficacious results.

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Serum Interleukin-6 Level but not Genotype Predicts Survival after Resection in Stages II and III Gastric Carcinoma

Cited by 80 publications

References 43 publications

Gastric Cancer Cell Proliferation and Survival Is Enabled by a Cyclophilin B/STAT3/miR-520d-5p Signaling Feedback Loop

Gastric Cancer Cell Proliferation and Survival Is Enabled by a Cyclophilin B/STAT3/miR-520d-5p Signaling Feedback Loop

Role of five small nucleotide polymorphisms in the VEGF gene on the susceptibility to osteosarcoma and overall survival of patients

Resistance to Anti-VEGF Therapy Mediated by Autocrine IL6/STAT3 Signaling and Overcome by IL6 Blockade

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