STAT3in arsenic lung carcinogenicity

Abstract

We recently found that the chronic sterile inflammation contributes to arsenic lung tumorigenesis which is inhibited by autophagy. STAT3 regulates the interaction between inflammation and autophagy. STAT3 may also play a critical role in mediating the crosstalk between lung epithelial cells and their microenvironment, including immune cells, during arsenic lung carcinogenesis.Arsenic is a carcinogen and chronic arsenic exposure may cause lung cancer. The tumorigenic action of arsenic is complicated and varied among different cell type (e.g. non-immune vs. immune cells) and durations of arsenic exposure. Here, we explore a possible role of STAT3 in mediating intrinsic and extrinsic pathways that contribute to arsenic lung carcinogenicity.In our previous study, we have shown sub-chronic arsenic exposure induced lung epithelial cells transformation which was accompanied with oxidative stress and autophagy activation.1 Our data further indicate that autophagy acts as a cell selfprotective mechanism against oxidativestress-promoted cell transformation. Arsenic exposure causes sustained oxidative stress. But the activation of autophagy, after an initial boost by acute arsenic administration, decreased in response to prolonged arsenic exposure. Forced upregulation of autophagy ameliorates cell transformation. Our interpretation is that with the adequate protection of autophagy, short-term arsenic exposure does not cause cell transformation. Upon prolonged arsenic exposure, however, with decreased protection of autophagy, sustained oxidative stress induces gene mutation/genomic instability and eventually leads to cell transformation. Recently, we further uncovered the involvement of an STAT3-mediated autophagy and inflammation responses in this process. Chronic sterile inflammation caused by continuous carcinogen exposure has been linked to various steps of tumorigenesis. A pathogenic effect of pulmonary inflammation has been shown in several murine models of lung cancer. Over production of specific cytokines and abnormal activation of transcription factors are underlying the oncogenic action of chronic inflammation. Autophagy, on the other hand, has been proposed as a new immunological paradigm acting as a negative mediator of chronic inflammation. Defects in autophagy under the condition of chronic inflammation are generally in favor of oncogenesis since autophagy functions in cellular homeostasis. Failure to remove cellular garbage in autophagy-defective cells/tissues results in cell injury/death which certainly is an inflammatory stimulus and creates a cancer-prone microenvironment. However, previous work only shows an incomplete picture for the interaction between acute inflammation and autophagy. For instance, IL1b from acute inflammation activates autophagy while TH2 cell-associated cytokines, such as IL4 and IL13, inhibit autophagy.3 Conversely, autophagy has been shown to inhibit acute inflammatory response. So far little is known regarding the interaction between chronic inflammation and autophagy as well as h...

Arsenic promotes the COX2/PGE2–SOX2 axis to increase the malignant stemness properties of urothelial cells

“…However, our model showed the activation of EGFR, COX2, and transcription factors (NF-κB, p-STAT3, and HIF1α) for COX2/PGE2 expression, which were reported previously in other arsenic exposed models 9,17,46,47 . Furthermore, we assessed the expression status of SOX2 and COX2 using urine samples from arsenic-exposed non-cancer and UCB subjects.…”

“…However, our model showed the activation of EGFR, COX2 and transcription factors (NF-jB, p-STAT3 and HIF1a) for COX2/PGE2 expression, which was reported previously in other arsenic exposed models. 9,17,46,47 Furthermore, we assessed the expression status of SOX2 and COX2 using urine samples from arsenicexposed noncancer and UCB subjects. Undoubtedly, further studies are needed to determine whether our findings are generalizable to mechanisms of arsenic-induced urothelial carcinogenesis.…”

Taurine protects against As2O3-induced autophagy in livers of rat offsprings through PPARγ pathway

“…Furthermore, mice that received arsenic exposure in utero and throughout their life course developed more frequent and aggressive tumors at much lower doses compared with mice that only received arsenic exposure during the gestational period 4 . Inorganic arsenicals were converted to monomethylarsenic acid (MMA) and dimethylarsenicacid (DMA) in the body, predominantly in the liver 5 . Therefore, exposure to arsenic might induce hepatotoxicity.…”

STAT3 inhibition for cancer therapy: Cell-autonomous effects only?

“…4 Indeed, the inhibition of STAT3 in cancer cells is expected to limit the production of pro-inflammatory factors (such as IL-6), hence reducing local inflammatory reactions that may contribute to tumor progression. 4,[10][11][12] Moreover, the inhibition of STAT3 allows malignant cells to secrete high amounts of Type I interferon and other products of so-called interferon response genes (IRGs), including chemokine (C-X-C motif) ligand 9 (CXCL9) and CXCL10. 13,14 By virtue of this mechanism, STAT3 inhibition stimulates the recruitment of immune effectors into the tumor bed and improves immunosurveillance, especially in the context of ongoing anticancer immune responses.…”