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A polymorphism at position -174 of the IL-6 promoter region is reportedly associated with systemic onset juvenile idiopathic arthritis (Fishman et al. 1998) and susceptibility to RA in Europeans (Lee et al. 2012). Stimulation with lipopolysaccharide (LPS) and IL-1 did not evoke any response in a reporter assay using -174 C construct. A -174 G construct, on the other hand, was found to promote transcription of the reporter gene, suggesting that a genetic background of excess IL-6 production constitutes a risk factor for juvenile idiopathic arthritis and RA.
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As reported by previous studies, mouse γδ T cells can be divided into Vγ1, Vγ4, Vγ5, Vγ6, Vγ7 γδ T cell subsets, which are defined according to TCR V gene utilization17. Several previous reports have suggested that Vγ4 and Vγ6 γδ T cells are the major IL-17A-producing γδ T cell subsets in mouse tumour models18,19,20,21. However, several groups have reported that Vγ1 γδ T cells are also capable of producing IL-17A, and in one such study, Vγ1 γδ T cells were actually shown to be the dominant source of IL-17A in the lungs of mice during pulmonary aspergillosis infection17,52. Vγ1 γδ T cells have also been reported to play critical roles in multiple processes, including tumourigenesis, anti-bacterial host defence and airway hyperresponsiveness55,64,65,66. Interestingly, a previous study utilizing a syngeneic mouse tumour model reported that depletion of Vγ1 γδ T cells had a therapeutic anti-tumour effect, which was mediated by suppression of Vγ4 γδ T cell acitivity55. This study is consistent with our finding that the Vγ1 γδ T cell subset has a tumour-promoting effect. In the current study, we found that Vγ1 γδ T cells are the major IL-17A-producing cells in the TME, which differs from prior reports that Vγ4- and Vγ6-restricted cells constitute the dominant γδT17 cell population in tumours. One possible explanation for this discrepancy may be due to differences in mouse tumour models, as we mainly employed heterotopic implantation and intravenous delivery of syngeneic tumour, while the other groups primarily utilized spontaneous mouse tumour models18,19,21,67. Nevertheless, our data from multiple mouse syngeneic tumour models consistently demonstrated a critical role for Vγ1 γδ T cells in tumour progression. Although the precise mechanism by which Vγ1 γδ T cells exert this pro-tumour effect was outside the scope of the present study, we believe that this question merits additional investigation.
Triple-negative breast cancer (TNBC) is a poor prognostic breast cancer with the highest mutations and limited therapeutic choices. Cytokine networking between cancer cells and the tumor microenvironment (TME) maintains the self-renewing subpopulation of breast cancer stem cells (BCSCs) that mediate tumor heterogeneity, resistance and recurrence. Immunotherapy of those factors combined with targeted therapy or chemoagents may advantage TNBC treatment.
We found that the oncogene Multiple Copies in T-cell Malignancy 1 (MCT-1/MCTS1) expression is a new poor-prognosis marker in patients with aggressive breast cancers. Overexpressing MCT-1 perturbed the oncogenic breast epithelial acini morphogenesis and stimulated epithelial-mesenchymal transition and matrix metalloproteinase activation in invasive TNBC cells, which were repressed after MCT-1 gene silencing. As mammary tumor progression was promoted by oncogenic MCT-1 activation, tumor-promoting M2 macrophages were enriched in TME, whereas M2 macrophages were decreased and tumor-suppressive M1 macrophages were increased as the tumor was repressed via MCT-1 knockdown. MCT-1 stimulated interleukin-6 (IL-6) secretion that promoted monocytic THP-1 polarization into M2-like macrophages to increase TNBC cell invasiveness. In addition, MCT-1 elevated the soluble IL-6 receptor levels, and thus, IL-6R antibodies antagonized the effect of MCT-1 on promoting M2-like polarization and cancer cell invasion. Notably, MCT-1 increased the features of BCSCs, which were further advanced by IL-6 but prevented by tocilizumab, a humanized IL-6R antibody, thus MCT-1 knockdown and tocilizumab synergistically inhibited TNBC stemness. Tumor suppressor miR-34a was induced upon MCT-1 knockdown that inhibited IL-6R expression and activated M1 polarization.
Cancer cell-intrinsic mechanisms and cell-extrinsic factors determine tumor development and aggressiveness [1]. Epithelial-mesenchymal transition (EMT) induces epithelial cells transforming into mesenchymal cells [2], cancer cell movement, cancer progression, metastasis and stemness. Tumor-associated macrophages (TAMs) derived from peripheral blood monocytes are recruited to microenvironment and polarized into M1 or M2 macrophages in response to secreted factors from cancer cells or microenvironmental cells [3]. M1 macrophages highly express inducible nitric oxide synthase (iNOS) and Tumor Necrosis Factor (TNF)-α and promote pro-inflammatory and immune responses that prevent oncogenic effects [4], while M2 macrophages express Arginase 1 (ARG1) and highly produce cytokines, growth factors and protease that are crucial for pro-tumorigenic processes. Furthermore, M2 macrophages stimulate tumor angiogenesis [5, 6], cancer cell migration/invasion, immunosuppression and marix remodeling.
MCT-1 is a ribosome binding protein encoded by MCTS1 gene [13, 14], which orchestrates ribosomal recycling, translation reinitiation and tissue growth. Density regulated protein and the MCT-1 heterodimer bind to the 40S ribosomal subunit and, with the recruitment of tRNA, cooperatively regulate noncanonical translation initiation [15, 16]. Moreover, MCT-1 affects mitotic progression via interacting with γ-tubulin molecule and Src/p190B complex [17, 18]. MCT-1 destabilizes p53 and PTEN in a ubiquitin-dependent proteasome pathway [18, 19]. Consequently, MCT-1 expression advances the p53-null or PTEN-null cancer cell progression and chromosomal/nuclear aberrations [17, 18, 20, 21]. Importantly, targeting MCT-1 suppresses genomic instability and tumorigenicity [18, 22]. MCT-1 overexpression also induces ROS generation [23], leading to YY-1/EGFR/MnSOD signaling amplification and cancer cell invasion. Here, we first demonstrate that MCT-1 induces IL-6/IL-6R/Stat3 pathway, M2 macrophage polarization, TNBC progression and stemness.
Abundant IL-6 released from aggressive cancer cells stimulates angiogenesis and tumor evasion from immune surveillance [43]. Nevertheless, IL-6 promotes antitumor effect by boosting T-cell immunity and by trafficking antitumor T cells to lymph nodes and tumor sites, executing the cytotoxic effects. It is unclear whether MCT-1 also influences Th1-Th2 polarization. Reflecting the Th1-Th2 polarization of T cells [44], the activation of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages are functionally modified by Th1 and Th2 cytokines. Th1 cytokines such as IFN-γ and GM-CSF induce M1 polarization, which produces pro-inflammatory cytokines (IL-1β, IL-6, IL-12, IL-23 and TNF-α). Th2 cytokines such as IL-4 and IL-13 promote M2 polarization, which produces anti-inflammatory cytokines (IL-10 and TGF-β).
YY1 transcriptionally activates IL-6 gene expression [45], and the EGFR signaling triggers IL-6 production via NF-kB activation [46]. Oncogenic MCT-1 activation promotes the expression of YY1 and EGFR [23], suggesting that MCT-1 may increase IL-6 expression via the YY1-EGFR signaling amplification. NOTCH activation through NO facilitates constitutive IL-6-dependent STAT3 activation [32], promoting breast cancer stemness. MCT-1 stimulated IL-6/Stat3 signaling (Fig. 2e), suggesting that MCT-1 may also stimulate the NO/NOTCH pathway to mediate breast cancer metastasis and recurrence. In addition, systematic administration of IL-6/IL-6R antagonist(s) with MCT-1 inhibitor(s) may promote immune cell infiltration to advance therapeutics against tumor heterogeneity and aggressiveness, with fewer adverse effect(s).
Supplementary Methods. Cell culture. Plasmid construction and transfection. Targeting MCT-1 gene. Targeting IL-6 gene. Antibodies (Abs) and protein analysis. MCF-10A acinar morphogenesis. Cell invasion and migration assays. Gelatin zymography assay. Cell fractionation. Quantitative RT-PCR analysis of cancer stemness markers. ALDEFLUOR assay. Immunohistochemistry study. Quantification of miR-34a levels. Statistical analysis. (PDF 227 kb)
The pathogenesis of NAFLD is hypothesized to begin with abnormal accumulation of lipids in the liver due to a stress condition such as obesity and imbalanced nutrition uptake. Mechanistically, the associated signaling pathways include the accumulation of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, increased ceramide synthesis in hepatic cells, and so on [4]. It was commonly accepted that most of the above pathways lead to hepatocellular apoptosis (programmed cell death) and necrosis (non-programmed cell death) [5]. But more recently, it has been revealed that other types of programmed cell death, such as pyroptosis, may play an important role in NAFLD. Meanwhile, many studies agree with the important role of inflammation in the development and progression of NAFLD. Therefore, we hypothesize that pyroptosis is an better inflammatory link between NAFLD and NASH.
The role of ER stress in the pathology of lipotoxicity is extensively discussed in a variety of diseases, including neurodegenerative diseases, diabetes and metabolic disorders, atherosclerosis, cancer, as well as renal and lung diseases [25,26,27,28]. Many cellular perturbations can lead to the accumulation of unfolded or misfolded proteins inside the ER. When the UPR is insufficient to handle the unfolded protein load, cells undergo apoptosis. The reported downstream molecular mechanisms include activation of CHOP, which is induced via PERK and ATF4 and plays a master role in cell stress induced cell damage [29]. An interesting molecule in PA triggered ER stress is BIP (also named GRP78), a famous ER chaperone. It is well known that ER stress is initiated by the dissociation of BIP from the ER transducers PERK, IRE1, and ATF6, resulting in their activation [30], so GPR78 is recognized as an important molecular marker when the activation of ER stress. In agreement with many previous reports, including our previous results, we demonstrated that ER stress were remarkably elicited by saturated fatty acids in either HepG2 cells or HFD rats, evidenced by facilitated expression of CHOP and GRP78 (Figs. 4 and 7), and OA or olive oil was able to effectively suppress both PA and chemical ER stressor (TM) induced expressions of ER stress markers. Based on literatures, the widely studied downstream signals of ER stress are related to apoptosis, particularly lipoapoptosis. The associated mechanisms include that CHOP represses the antioxidant genes and induces growth arrest and DNA damage-inducible protein (GADD34) expression, which promotes dephosphorylation of eIF2α and subsequently increases oxidative stress to activate cell death. Alternatively, IRE1α can trigger apoptosis via activation of caspase molecules and pathways of TNF receptor-associated factor 2 (TRAF2) and c-Jun N-terminal kinase (JNK) [31]. However, in the present study, we have not found significant cell apoptosis occurred in PA challenged HepG2 cells as well as liver samples of HFD rats (Figs. 2 and 7), which could not explain the link between the simulated ER stress and substantial deterioration of cell viability or cell function we observed in both in vitro and in vivo models. Taken that, we hypothesize that there is alternative pathways cross talking with ER stress and governing cell destiny. 2b1af7f3a8