Compelling epidemiological evidence shows a strong positive correlation of obesity with thyroid cancer. In vivo studies have provided molecular evidence that high-fat-diet-induced obesity promotes thyroid cancer progression by aberrantly activating leptin-JAK2-STAT3 signaling in a mouse model of thyroid cancer (Thrb PV/PV Pten +/ − mice). The Thrb PV/PV Pten +/ − mouse expresses a dominantly negative thyroid hormone receptor β (denoted as PV) and a deletion of one single allele of the Pten gene. The Thrb PV/PV Pten +/ − mouse spontaneously develops follicular thyroid cancer, which allows its use as a preclinical mouse model to test potential therapeutics. We recently showed that inhibition of STAT3 activity by a specific inhibitor markedly delays thyroid cancer progression in high-fat-diet-induced obese Thrb PV/PV Pten +/ − mice (HFD-Thrb PV/PV Pten +/ − mice). Further, metformin, a widely used antidiabetic drug, blocks invasion and metastasis, but not thyroid tumor growth in HFD-Thrb PV/PV Pten +/ − mice. To improve efficacy in reducing thyroid tumor growth, we treated HFD-Thrb PV/PV Pten +/ − with JQ1, a potent inhibitor of the activity of bromodomain and extraterminal domain (BET) and with metformin. We found that the combined treatment synergistically suppressed thyroid tumor growth by attenuating STAT3 and ERK signaling, resulting in decreased anti-apoptotic key regulators such as Mcl-1, Bcl-2 and survivin and increased pro-apoptotic regulators such as Bim, BAD and cleave caspase 3. Furthermore, combined treatment of JQ1 and metformin reduced cMyc protein levels to suppress vascular invasion, anaplasia and lung metastasis. These findings indicate that combined treatment is more effective than metformin alone and suggest a novel treatment modality for obesity-activated thyroid cancer.
Sunmi Park, Mark C Willingham, Jun Qi and Sheue-Yann Cheng
Jing Nie, Guang-long Huang, Sheng-Ze Deng, Yun Bao, Ya-Wei Liu, Zhan-Peng Feng, Chao-Hu Wang, Ming Chen, Song-Tao Qi and Jun Pan
Craniopharyngiomas (CPs) are usually benign, non-metastasizing embryonic malformations originating from the sellar area. They are, however, locally invasive and generate adherent interfaces with the surrounding brain parenchyma. Previous studies have shown the tumor microenvironment is characterized by a local abundance of adenosine triphosphate (ATP), infiltration of leukocytes and elevated levels of pro-inflammatory cytokines that are thought to be responsible, at least in part, for the local invasion. Here, we examine whether ATP, via the P2X7R, participates in the regulation of cytokine expression in CPs. The expression of P2X7R and pro-inflammatory cytokines were measured at the RNA and protein levels both in tumor samples and in primary cultured tumor cells. Furthermore, cytokine modulation was measured after manipulating P2X7R in cultured tumor cells by siRNA-mediated knockdown, as well as pharmacologically by using selective agonists and antagonists. The following results were observed. A number of cytokines, in particular IL-6, IL-8 and MCP-1, were elevated in patient plasma, tumor tissue and cultured tumor cells. P2X7R was expressed in tumor tissue as well as in cultured tumor cells. RNA expression as measured in 48 resected tumors was positively correlated with the RNA levels of IL-6, IL-8 and MCP-1 in tumors. Furthermore, knockdown of P2X7R in primary tumor cultures reduced, and stimulation of P2XR7 by a specific agonist enhanced the expression of these cytokines. This latter stimulation involved a Ca2+-dependent mechanism and could be counteracted by the addition of an antagonist. In conclusion, the results suggest that P2X7R may promote IL-6, IL-8 and MCP-1 production and secretion and contribute to the invasion and adhesion of CPs to the surrounding tissue.