TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway

Abstract

Toll-like receptors (TLR) are conserved immune sensors mediating antimicrobial and antitumoral responses, but recent evidence implicates them in promoting carcinogenesis in certain cancers. Kaposi’s sarcoma (KS) is caused by infection of Kaposi’s sarcoma-associated herpesvirus (KSHV) and is characterized by uncontrolled neoangiogenesis and inflammation. Here we show that TLR4 is upregulated in KSHV-infected spindle tumor cells in human KS lesions. In a model of KSHV-induced cellular transformation, KSHV upregulated expression of TLR4, its adaptor MyD88, and coreceptors CD14 and MD2. KSHV induction of TLR4 was mediated by multiple viral microRNAs. Importantly, the TLR4 pathway was activated constitutively in KSHV-transformed cells resulting in chronic induction of IL-6, IL-1β and IL-18. Accordingly, IL-6 mediated constitutive activation of the STAT3 pathway, an essential event for uncontrolled cellular proliferation and transformation. TLR4 stimulation with lipopolysaccharides or live bacteria enhanced tumorigenesis while TLR4 antagonist CLI095 inhibited it. These results highlight an essential role of the TLR4 pathway and chronic inflammation in KSHV-induced tumorigenesis, which helps explain why HIV-infected patients, who frequently suffer from opportunistic bacterial infections and metabolic complications, frequently develop KS.

Signatures of oral microbiome in HIV-infected individuals with oral Kaposi's sarcoma and cell-associated KSHV DNA

“…Altered oral microbiota has been observed in several diseases including diabetes, bacteremia, endocarditis, cancer and autoimmune disease, and in some cases can influence disease progression [27] or tumor response to immunotherapy [28]. Furthermore, we previously demonstrated that TLR4 stimulation with LPS from either E. coli strain K12 or C25 promoted KSHVinduced cellular transformation and tumorigenesis in a KS-like animal model [20]. Therefore, the purpose of this study was to investigate whether oral KS was associated with an alteration of the bacterial microbiota in the oral cavity.…”

“…Some enterotoxic Escherichia coli (E. coli) strains are associated with tumorigenesis in mouse models of colorectal cancers [19]. We have recently shown that E. coli C25 strain could promote KSHV-induced tumorigenesis in a KSlike mouse model [20].…”

“…Interestingly, HIV-infected individuals display a higher rate of periodontal disease [23], which has been proposed to promote oral KS development by inducing proinflammatory cytokines or releasing SCFA. We previously showed that E. coli infection or bacterial ligands such as LPS can promote KSHV-induced tumorigenesis in mice through the activation of TLR4 and pro-inflammatory pathways [20].…”

Melatonin Synergizes with Sorafenib to Suppress Pancreatic Cancer via Melatonin Receptor and PDGFR-β/STAT3 Pathway

“…Notably, PDGFR-β is known to induce STAT3 phosphorylation, and activated STAT3 leads to cell transformation [47,48]. Consequently, elevated STAT3 signaling inhibits apoptosis and supports cancer survival, producing a phenotype similar to chemo-resistance [49].…”

Dietary iodine intake, thyroid diseases and the prevalence of papillary carcinoma (PTC)

“…Oncogenic receptor ALK belongs to an insulin receptor (IR) or oncogenic receptor IGF-1R family [127]. TLR4 stimulation with its ligand lipopolysaccharides promotes KSHV-induced cellular transformation and tumorigenesis by activating the STAT3 pathway [128] TLR4 mediated tumorigenesis while TLR4 antagonist CL1095 inhibite it. Toll-like receptor (TLR4) induced pro-oncogenic or also protumoral function in head and neck carcinoma [129].…”