Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma

Porta, Camillo; Amici, Mara De; Quaglini, Silvana; Paglino, Chiara; Tagliani, Federica; Boncimino, A.; Moratti, Remigio; Corazza, Gino Roberto

doi:10.1093/annonc/mdm448

Cited by 151 publications

(144 citation statements)

References 37 publications

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“…As in the gp130-deleted animals, no STAT3 DNA binding was found, and activation is likely to be mediated through a gp130-dependent cytokine while in IL-6 null animals, no STAT3 activation was found [63]. IL-6 levels in liver cancer patients are 25-fold higher than in healthy adults [64]. Subsequent studies showed that the levels of IL-6 in SNU-387 and SNU-449 liver cancer cell lines were much higher than those in human hepatocytes [65].…”

Section: Inflammationmentioning

confidence: 81%

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

Subramaniam

Shanmugam

Perumal

et al. 2013

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

203

229

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a b s t r a c t a r t i c l e i n f oHepatocellular carcinoma (HCC) is one of the most lethal malignancies, and is also the fourth most common cancer worldwide with around 700,000 new cases each year. Currently, first line chemotherapeutic drugs used for HCC include fluorouracil, cisplatin, doxorubicin, paclitaxel and mitomycin, but most of these are non-selective cytotoxic molecules with significant side effects. Sorafenib is the only approved targeted therapy by the U.S. Food and Drug Administration for HCC treatment, but patients suffer from various kinds of adverse effects, including hypertension. The signal-transducer-and-activator-of-transcription 3 (STAT3) protein, one of the members of STATs transcription factor family, has been implicated in signal transduction by different cytokines, growth factors and oncogenes. In normal cells, STAT3 activation is tightly controlled to prevent dysregulated gene transcription, whereas constitutively activated STAT3 plays an important role in tumorigenesis through the upregulation of genes involved in anti-apoptosis, proliferation and angiogenesis. Thus, pharmacologically safe and effective agents that can block STAT3 activation have the potential both for the prevention and treatment of HCC. In the present review, we discuss the possible role of STAT3 signaling cascade and its interacting partners in the initiation of HCC and also analyze the role of various STAT3 regulated genes in HCC progression, inflammation, survival, invasion and angiogenesis.

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Section: Inflammationmentioning

confidence: 81%

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

Subramaniam

Shanmugam

Perumal

et al. 2013

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

203

229

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“…At a threshold of 7.9 pg/mL, inter leukin-6 (IL-6) has a sensitivity of 0.83, a specificity of 0.83, and an AUC of 0.810 [62] . Higher Creactive protein and IL6 levels correlated well with larger tumour sizes, poorer ChildPugh functions, shorter survival times and more predictable outcomes in patients with HCC receiving locoregional therapy [63] .…”

Section: Interleukin-6mentioning

confidence: 99%

Role of biomarkers in the prediction and diagnosis of hepatocellular carcinoma

Khattab

Fouad

Ahmed

2015

WJH

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The prevalence of hepatocellular carcinoma (HCC) has progressively increased in recent years and is now the fifth and the second most common cancer in the World and in Egypt, respectively. Much work has focused in the development of assays for detecting hepatic carcinogensis before the observance of hepatic focal lesions. Particular attention has been directed towards HCC-specific biomarkers for use in the early diagnosis of HCC and in the confirmation of radiological studies. Although a number of biomarkers have been identified, none have been considered reliable indicators of early HCC lesions. This review presents a few of the most relevant HCC biomarkers and suggests improvements to the accuracy of diagnostic assays through their combined use. Furthermore, we present an algorithm for the biomarker-based diagnosis of HCC and highlight its important role in the early prediction of HCC. Core tip: Alpha-fetoprotein (AFP) has been widely used as a reference biomarker to validate the diagnosis of hepatocellular carcinoma (HCC). However, normal physiological-levels of AFP are observed in approximately one third of HCC cases. Furthermore, a number of HCC positive patients have AFP levels less than the threshold value of 400 ng/mL. These factors make an AFP-based diagnosis of HCC far from reliable. However, high diagnostic accuracy indices have been reported when AFP is combined with other biomarkers such as midkine, golgi protein 73, des-γ-carboxyprothrombin, glypican-3, and gamma-glutamyl transferase.Khattab M, Fouad M, Ahmed E. Role of biomarkers in the prediction and diagnosis of hepatocellular carcinoma. World J Hepatol 2015; 7(23): 24742481 Available from:

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“…Hep3B and SNU-398 cells were cultured in serumfree medium overnight and then were pre-treated with different concentrations of FLLL32 for 4 hours followed by 25 HCC patients than in healthy controls, whereas IL-6 receptor levels do not show much change. 9,10 Moreover, high serum IL-6 may promote HCC development in hepatitis B patients. 11 Thus, IL-6 could be considered a HCC biomarker and high risk factor for HCC.…”

Section: Flll32 Inhibits Il-6-induced Stat3mentioning

confidence: 99%

IL-6, a risk factor for hepatocellular carcinoma: FLLL32 inhibits IL-6-Induced STAT3 phosphorylation in human hepatocellular cancer cells

Liu¹,

Fuchs²,

Li³

et al. 2010

Cell Cycle

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H epatocellular carcinoma (HCC) isone of the most common human cancers, and the patients' five-year survival rate is very low. Growing evidence indicates that interleukin-6 (IL-6) is a risk factor for HCC. High serum IL-6 may promote HCC development in hepatitis B patients. Therefore, IL-6 could be considered a HCC biomarker and blockade of IL-6 pathway may be a promising therapeutic alternative for HCC. STAT3 is a major pathway to mediate signal from IL-6 to the nucleus, where different genes associated with proliferation and apoptosis are regulated. We previously reported that IL-6 induces cell survival upon drug treatment in HCC cells and that inhibition of IL-6/ STAT3 pathway using anti-IL-6 antibody or STAT3 small-molecule inhibitor LLL12 reduces this effect. Here we summarized the recent studies of IL-6 in HCC and showed another STAT3 smallmolecule inhibitor FLLL32 also blocked IL-6-induced STAT3 activation in HCC cells. FLLL32 is a novel curcumin analog, which has been described to suppress the constitutive activation of STAT3 in pancreatic and breast cancer cells in vitro and vivo. We demonstrated that FLLL32 blocked IL-6-induced STAT3 phosphorylation and nuclear translocation.

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Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma

Abstract: IL-6 could be considered a promising tumor marker for HCC. In particular, the diagnostic value of the test is significantly increased when combined with A(1)FP.

Cited by 151 publications

References 37 publications

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

Role of biomarkers in the prediction and diagnosis of hepatocellular carcinoma

IL-6, a risk factor for hepatocellular carcinoma: FLLL32 inhibits IL-6-Induced STAT3 phosphorylation in human hepatocellular cancer cells

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