Circulating interleukin-6 and cancer: A meta-analysis using Mendelian randomization

Abstract

Interleukin-6 (IL-6) plays a contributory role in the progression and severity of many forms of cancer; it however remains unclear whether the relevance between circulating IL-6 and cancer is causal. We therefore meta-analyzed published articles in this regard using IL-6 gene -174G/C variant as an instrument. Seventy-eight and six articles were eligible for the association of -174G/C variant with cancer and circulating IL-6, respectively. Overall analyses failed to identify any significance between -174G/C and cancer risk. In Asians, carriers of the -174CC genotype had an 1.95-fold increased cancer risk compared with the -174GG genotype carriers (P = 0.009). By cancer type, significance was only attained for liver cancer with the -174C allele conferring a reduced risk under allelic (odds ratio or OR = 0.74; P = 0.001), homozygous genotypic (OR = 0.59; P = 0.029) and dominant (OR = 0.67; P = 0.004) models. Carriers of the -174CC genotype (weighted mean difference or WMD = −4.23 pg/mL; P < 0.001) and -174C allele (WMD = −3.43 pg/mL; P < 0.001) had circulating IL-6 reduced significantly compared with the non-carriers. In further Mendelian randomization analysis, a reduction of 1 pg/mL in circulating IL-6 was significantly associated with an 12% reduced risk of liver cancer. Long-term genetically-reduced circulating IL-6 might be causally associated with a lower risk of liver cancer.

Bazedoxifene exhibits growth suppressive activity by targeting interleukin‐6/glycoprotein 130/signal transducer and activator of transcription 3 signaling in hepatocellular carcinoma

“…IL‐6 released from T cells can induce proliferation and differentiation of B cells, as well as stimulate antibody production. Recent studies have revealed that the expression of IL‐6 in primary liver cancer was dramatically elevated and is positively correlated with morbidity and progression . IL‐6 exerts its biological effects through binding to two subunits of signal transducing receptor GP130 and IL‐6R, resulting in dimerization of GP130 and IL‐6R and subsequently activation of the Janus kinases/STAT3 pathway.…”

Relevance of Interleukin-6 and D-Dimer for Serious Non-AIDS Morbidity and Death among HIV-Positive Adults on Suppressive Antiretroviral Therapy

“…First, in a panel of 6 plasma biomarkers measured in the INSIGHT SMART study, these 3 biomarkers were strongly associated with all-cause mortality, which motivated us to determine these markers also for the ESPRIT and SILCAAT trials, using stored baseline plasma specimens. [ 6 ] Second, higher levels of IL-6, hsCRP and D-dimer have been associated with increased risk of CVD, cancer, and all-cause mortality among people living with HIV [ 5 – 11 ], as well as in the general population [ 14 – 25 , 27 – 29 ]. Third, the biomarkers have high laboratory and biological reproducibility.…”

“…While ART decreases IL-6, D-dimer and hsCRP levels [ 10 , 12 ], these biomarkers remain elevated relative to the general population even when the plasma HIV RNA is suppressed [ 13 ]. Markers of inflammation and coagulation have been widely studied in the general population, and related to higher risk of CVD [ 14 – 22 ], cancer [ 23 – 25 ], kidney function decline [ 26 ] and all-cause mortality [ 27 – 29 ]. These data collectively suggest that chronic inflammation and/or hyper-coagulation contribute to the pathogenesis of these serious non-AIDS events during otherwise effective ART.…”

A novel small molecule STAT3 inhibitor, LY5, inhibits cell viability, colony formation, and migration of colon and liver cancer cells

“…Increased expression of IL-6 is thought to act as a link between chronic inflammation and tumor development [ 44 ]. IL-6 stimulates the progression of colon and liver cancers and elevated IL-6 levels are associated with poor prognosis in liver and colon cancers [ 45 – 47 ]. IL-6 stimulates STAT3 phosphorylation and nuclear translocation of STAT3 to promote oncogenesis by inhibiting apoptosis.…”