6-OAP formed hydrogen bonds with Ser611/Ser613/Arg609 at the SH2 domain of STAT3 and inhibited the constitutive and interleukin-6-induced phosphorylated STAT3 (pSTAT3), leading to inhibitory effects on lung cancer cells and suppression of Skp2 transcription.
Interleukin-6 (IL-6) can activate downstream signaling pathways in lung cancer cells, such as the STAT3 pathway, and is reported to be produced by tumor cells with activating EGFR mutations.
A highly active interleukin 6 (IL-6)/glycoprotein 130 (gp130)/signal transducer and activator of transcription 3 (STAT3) pathway has been identified in a subset of primary lung cancer and closely correlated with tumor progression and poor prognosis.
Accumulating evidence has suggested that TERT could modulate the expression of numerous genes including interleukin 6 (IL-6), an important cytokine for the development of lung cancer.
Additionally, we found that an IL8 promoter polymorphism had a protective effect for lung cancer in female subjects, whereas an IL6 promoter polymorphism was only associated with risk of squamous cell carcinoma.
Baseline concentrations of hsCRP (median 6·0 mg/L vs 4·2 mg/L; p<0·0001) and interleukin 6 (3·2 vs 2·6 ng/L; p<0·0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer.
Body and muscle weight, grip strength, physical activity, muscle morphometry, apoptotic nuclei, troponin-I systemic levels, interleukin-6, proteolytic markers, and tyrosine release, and apoptosis markers were determined in diaphragm and gastrocnemius muscles of lung cancer (LP07 adenocarcinoma cells) mice (BALB/c) treated with monoclonal antibodies (mAbs), against immune check-points and pathways (CD-137, cytotoxic T-lymphocyte associated protein-4, programed cell death-1, and CD-19; N = 10/group).
Collectively, these preclinical findings identify trans-signalling via STAT3 as the signalling modality by which IL-6 promotes muscle wasting in lung cancer cachexia, and therefore support the clinical evaluation of the IL-6 trans-signalling/STAT3 axis as a therapeutic target in advanced lung cancer patients presenting with cachexia.
Comparably, luciferase reporter assays of A549 lung cancer cell lines transfected with the CC haplotype revealed that the two-SNP haplotype had significantly higher IL-6 transcriptional activity compared with cells transfected with the common haplotype.
Compared with the control, no significant association was revealed between TNF-α-308G/A (GG + GC vs. CC: OR = 1.10, 95% CI: 0.73 to 1.64; GG vs. GC + CC: OR = 1.02, 95% CI: 0.81 to 1.27; GC vs. CC: OR = 1.13, 95% CI: 0.73 to 1.77; GG vs. CC: OR = 1.04, 95% CI: 0.80 to 1.36; G vs. C: OR = 1.03, 95% CI: 0.90 to 1.18) or IL-6174G/C (GG + GC vs. CC: OR = 1.10, 95% CI: 0.73 to 1.64; GG vs. GC + CC: OR = 1.02, 95% CI: 0.81 to 1.27; GC vs. CC: OR = 1.13, 95% CI: 0.73 to 1.77; GG vs. CC: OR = 1.04, 95% CI: 0.80 to 1.36; G vs. C: OR = 1.03, 95% CI: 0.90 to 1.18) and lung cancer risk.
Constitutive production of granulocyte colony-stimulating factor and interleukin-6 by a human lung cancer cell line, KSNY: gene amplification and increased mRNA stability.
DEN-2 infection significantly increased the expression levels of IL-6 and RANTES in four of the six lung cancer cell lines, which is consistent with the high expression levels of these molecules in DHF/DSS patients.
Despite that ataxia-telangiectasia mutated (ATM) is involved in IL-6 promoted lung cancer chemotherapeutic resistance and metastasis, the exact role of ATM in tumor necrosis factor-alpha (TNF-α) increasing tumor migration is still elusive.
Finally, the potential role of the natural agents and synthetic derivatives of natural compounds with anti-cancer activity, e.g. curcumin, CDF, and BR-DIM is highlighted in overcoming therapeutic resistance, suggesting that the above mentioned agents could be important for better treatment of lung cancer in combination therapy.
Hence, ATM modulates vimentin expression to facilitate IL-6-induced epithelial-mesenchymal transition and metastasis in lung cancer, indicating that ATM and vimentin might be potential therapeutic targets for inflammation-associated lung cancer metastasis.
Higher level of interleukin-6 (IL-6) existed in lung cancer patients and mutant EGFR and TGFβ signal requires the upregulation of IL-6 through the gp130/JAK pathway to overactive STAT3, an oncogenic protein which has been considered as a potential target for cancer therapy.