IL-35 expression in hepatocellular carcinoma cells is associated with tumor progression

Long, Jun; Guo, Hongyan; Cui, Shujuan; Zhang, Haiyan; Liu, Xinmin; Li, Danning; Han, Zimeng; Xi, Linfeng; Kou, Wenyi; Xu, Jiangnan; Li, Tao‐Sheng; Ding, Yaozhong

doi:10.18632/oncotarget.10141

Cited by 39 publications

(42 citation statements)

References 33 publications

(35 reference statements)

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“…Interleukin-35 (IL-35) is a newly discovered member of the interleukin family with anti-inflammatory and immune inhibitory effects [7,8]. Recently, it has been demonstrated that IL-35 plays an important role in tumor progression, including lung cancer [9], pancreatic cancer [10], nasopharyngeal carcinoma [11], gastric cancer [12], hepatocellular carcinoma [13][14][15], breast cancer [16,17], renal cell carcinoma [18] and colorectal cancer [19,20]. However, the underlying mechanisms of IL-35 in NSCLC remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-35 Expression in Non-Small Cell Lung Cancer is Associated with Tumor Progression

Sun¹,

Zheng²,

Meng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lung cancer continues to be the leading cause of cancer related deaths worldwide due to its high incidence, malignant behavior and lack of major advancements in treatment strategy. The occurrence and development of lung cancer is closely related to inflammation. Thus, we conducted the present study to investigate the effects of IL-35 (Interleukin 35), a newly identified anti-inflammatory factor, on non-small cell lung cancer (NSCLC), which accounts for about 85% of all lung cancers. Methods: We first evaluated the IL-35 expression in 384 pairs of NSCLC samples and their adjacent normal mucosa by realtime PCR, ELISA (Enzyme-linked immunoassay) and tissue microarrays. Then the role of IL-35 on patient survival rates, cancer progression and their sensitivity to chemotherapy drugs were assessed. Results: IL-35 was barely expressed in the NSCLC tissues but highly expressed in the adjacent normal tissues. The down-regulation of IL-35 was significantly correlated with the results of American Joint Committee on Cancer stage, differentiation and it was also shown to be an independent prognostic indicator of disease-free survival and overall survival for patients with NSCLC. Overexpression of IL-35 in NSCLC cells suppressed cell migration, invasion, proliferation, colony formation through suppressing β-catenin. IL-35 inhibited NSCLC formation in the mice model and sensitize the cancer cells to chemotherapy drugs. Conclusion: Our results showed that IL-35 plays an inhibitory role in NSCLC development and function as a novel prognostic indicator and a potential therapeutic target.

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Section: Introductionmentioning

confidence: 99%

Interleukin-35 Expression in Non-Small Cell Lung Cancer is Associated with Tumor Progression

Sun¹,

Zheng²,

Meng³

et al. 2018

Cell Physiol Biochem

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“…21,23,26,72 Although a majority of investigations points to IL-35 as a cytokine promoting tumor growth and metastasis, 8,10,15,53,61,71 there is one evidence suggesting IL-35 acting as anti-cancer cytokine 24 and another one suggesting IL-35 as a factor limiting tumor metastasis. 61 Moreover, it was reported that accumulation of CD39 1 Foxp31 Treg cells and enhanced IL-35 in hepatocellular carcinoma (HCC) samples was associated with HCC aggressiveness and recurrence after resection. 60 CD39 is an extracellular ectonucleoside triphosphate diphosphohydrolase-1 enzyme that catalyzes the conversion of extracellular ATP to adenosine, being the latter a suppressor of effector T cell functions.…”

Section: Il-35 and Cancermentioning

confidence: 99%

“…73 In contrast to these findings, in another study, it was also shown that IL-35 expression was significantly lower in HCC in advanced stages than in early disease. 61 Studies in vitro have revealed that overexpression of IL-35 in HepG2 hepatic cell line was associated with several effects such as, reduced matrix metalloproteinase-2 (MMP2) and MMP9 activities, restriction of cell migration ability, as well as upregulation of MCH class I and CD95 death receptor on the cell surface of cancer cells. 61 These effects may explain the reported antimetastatic activity of IL-35 in HCC (Fig.…”

Section: Il-35 and Cancermentioning

confidence: 99%

IL‐35, a hallmark of immune‐regulation in cancer progression, chronic infections and inflammatory diseases

Teymouri

Pirro

Fallarino

et al. 2018

Intl Journal of Cancer

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Cytokine members of the IL-12 family have attracted enormous attention in the last few years, with IL-35 being the one of the most attractive-suppressive cytokine. IL-35 is an important mediator of regulatory T cell function. Regulatory T cells play key roles in restoring immune homeostasis after facing challenges such as infection by specific pathogens. Moreover, a crucial role for regulatory T cell populations has been demonstrated in several physiological processes, including establishment of fetal-maternal tolerance, maintenance of self-tolerance and prevention of autoimmune diseases. However, a deleterious involvement of immune regulatory T cells has been documented in specific inhibition of immune responses against tumor cells, promotion of chronic infections and establishment of chronic inflammatory disorders. In this review, we attempt to shed light on the concept of immune-homoeostasis on the aforementioned issues, taking IL-35 as the hallmark of regulatory responses. The dilemma between immune-mediated cancer treatment and inflammation is discussed. Histopathological indications of chronic vs. acute infections are elaborated. Moreover, the evidence that IL-35 requires additional immune-regulatory cytokines, such as IL-10 and TGF-β, to induce effective and maximal anti-inflammatory effects suggest that immune-regulation requires multi-factorial analysis of many immune playmakers rather than a specific immune target.

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“…Improving immune cells function with cytokine thera- 15 Despite these conflicting data, IL-35 remains a potential and promising study target in HCC.…”

Section: Immune System In Hepatocellular Carcinomamentioning

confidence: 99%

Translational research for hepatocellular carcinoma: What’s new?

Pisconti¹,

Gnoni²,

Scarpati³

et al. 2017

Transl Med Rep

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Hepatocellular carcinoma (HCC) is a heterogeneous disease that usually develops within liver cirrhosis. Cancerogenesis in HCC is not a clear process and, at present, there is not a well-defined sequence of DNA mutations able to explain the entire process, from normal hepatocyte to HCC. Lately, the impact of some oncogenes on HCC development has been studied and some of these genes belong to the MAPKinases pathway, highlighting the importance of downstream effectors stimulated by the interaction between extracellular growth factors and tyrosine kinase receptors. Unfortunately, drugs able to interfere with the aforementioned pathway showed no positive results in clinical trials. A number of preclinical studies have focused the attention on epigenetic changes in HCC cells, focusing on the extensive DNA hypermetilation as a factor causing the knockout of several tumor suppressor genes. Cancerogenesis of HCC, at least at an early phase, could be sustained by epigenetic changes. Finally, some authors have tried to classify HCC on the basis of gene mutations found after performing an extensive genome sequencing, and interestingly, they have identified different classes of HCC on the basis of different clusters of mutated genes. HCC is not characterized by a unique driver mutation, as the case of EGFR mutations for lung cancer or K-Ras mutations for colorectal cancer, thus it is, at present, very difficult to identify a reliable target for antitumoral therapy. This review focuses on current translational research and molecular targets in the treatment of HCC.

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IL-35 expression in hepatocellular carcinoma cells is associated with tumor progression

Cited by 39 publications

References 33 publications

Interleukin-35 Expression in Non-Small Cell Lung Cancer is Associated with Tumor Progression

Interleukin-35 Expression in Non-Small Cell Lung Cancer is Associated with Tumor Progression

IL‐35, a hallmark of immune‐regulation in cancer progression, chronic infections and inflammatory diseases

Translational research for hepatocellular carcinoma: What’s new?

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