scholarly journals Diet-Induced Obesity Increases Tumor Growth and Promotes Anaplastic Change in Thyroid Cancer in a Mouse Model

Endocrinology ◽  
2013 ◽  
Vol 154 (8) ◽  
pp. 2936-2947 ◽  
Author(s):  
Won Gu Kim ◽  
Jeong Won Park ◽  
Mark C. Willingham ◽  
Sheue-yann Cheng
Keyword(s):  
Thyroid Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
Thyroid Tumor ◽  
Janus Kinase ◽  
Histopathological Analysis ◽  
Diet Induced Obesity ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Recent epidemiological studies provide strong evidence suggesting obesity is a risk factor in several cancers, including thyroid cancer. However, the molecular mechanisms by which obesity increases the risk of thyroid cancer are poorly understood. In this study, we evaluated the effect of diet-induced obesity on thyroid carcinogenesis in a mouse model that spontaneously develops thyroid cancer (ThrbPV/PVPten+/− mice). These mice harbor a mutated thyroid hormone receptor-β (denoted as PV) and haplodeficiency of the Pten gene. A high-fat diet (HFD) efficiently induced the obese phenotype in ThrbPV/PVPten+/− mice after 15 weeks. Thyroid tumor growth was markedly greater and survival was significantly lower in ThrbPV/PVPten+/− mice fed an HFD than in controls fed a low-fat diet (LFD). The HFD increased thyroid tumor cell proliferation by increasing the protein levels of cyclin D1 and phosphorylated retinoblastoma protein to propel cell cycle progression. Histopathological analysis showed that the frequency of anaplasia of thyroid cancer was significantly greater (2.6-fold) in the HFD group than the LFD group. The HFD treatment led to an increase in parametrial/epididymal fat pad and elevated serum leptin levels in ThrbPV/PVPten+/− mice. Further molecular analyses indicated that the HFD induced more aggressive pathological changes that were mediated by increased activation of the Janus kinase 2-signaling transducer and activator of transcription 3 (STAT3) signaling pathway and induction of STAT3 target gene expression. Our findings demonstrate that diet-induced obesity exacerbates thyroid cancer progression in ThrbPV/PVPten+/− mice and suggest that the STAT3 signaling pathway could be tested as a potential target for the treatment of thyroid cancer.

scholarly journals Curcumin-Mediated Apoptotic Cell Death in Papillary Thyroid Cancer and Cancer Stem-Like Cells through Targeting of the JAK/STAT3 Signaling Pathway

2020 ◽  
Vol 21 (2) ◽  
pp. 438 ◽  
Author(s):  
Abdul Q. Khan ◽  
Eiman I. Ahmed ◽  
Noor Elareer ◽  
Hamna Fathima ◽  
Kirti S. Prabhu ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Signaling Pathway ◽  
Papillary Thyroid Cancer ◽  
Cell Lines ◽  
Janus Kinase ◽  
Dependent Manner ◽  
Papillary Thyroid ◽  
Cytotoxic Effects ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

The constitutive activation of Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signal transduction is well elucidated in STAT3-mediated oncogenesis related to thyroid cancer and is considered to be a plausible therapeutic target. Hence, we investigated whether curcumin, a natural compound, can target the JAK/STAT3 signaling pathway to induce cytotoxic effects in papillary thyroid cancer (PTC) cell lines (BCPAP and TPC-1) and derived thyroid cancer stem-like cells (thyrospheres). Curcumin suppressed PTC cell survival in a dose-dependent manner via the induction of caspase-mediated apoptosis and caused the attenuation of constitutively active STAT3 (the dephosphorylation of Tyr705–STAT3) without affecting STAT3. Gene silencing with STAT3-specific siRNA showed the modulation of genes associated with cell growth and proliferation. The cotreatment of PTC cell lines with curcumin and cisplatin synergistically potentiated cytotoxic effects via the suppression of JAK/STAT3 activity along with the inhibition of antiapoptotic genes and the induction of proapoptotic genes, and it also suppressed the migration of PTC cells by downregulating matrix metalloproteinases and the inhibition of colony formation. Finally, thyrospheres treated with curcumin and cisplatin showed suppressed STAT3 phosphorylation, a reduced formation of thyrospheres, and the downregulated expression of stemness markers, in addition to apoptosis. The current study’s findings suggest that curcumin synergistically enhances the anticancer activity of cisplatin in PTC cells as well as in cancer stem-like cells by targeting STAT3, which suggests that curcumin combined with chemotherapeutic agents may provide better therapeutic outcomes.

A natural product phillygenin suppresses osteosarcoma growth and metastasis by regulating the SHP-1/JAK2/STAT3 signaling

2021 ◽  
Vol 85 (2) ◽  
pp. 307-314
Author(s):  
Xiaomin Ding ◽  
Danqing Lu ◽  
Jianbo Fan
Keyword(s):  
Cell Growth ◽  
Signaling Pathway ◽  
Janus Kinase ◽  
Potential Candidate ◽  
Osteosarcoma Cell ◽  
Cancer Cell Growth ◽  
Functional Roles ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

ABSTRACT Osteosarcoma represents one of the most devastating cancers due to its high metastatic potency and fatality. Osteosarcoma is insensitive to traditional chemotherapy. Identification of a small molecule that blocks osteosarcoma progression has been a challenge in drug development. Phillygenin, a plant-derived tetrahydrofurofuran lignin, has shown to suppress cancer cell growth and inflammatory response. However, how phillygenin plays functional roles in osteosarcoma has remained unveiled. In this study, we showed that phillygenin inhibited osteosarcoma cell growth and motility in vitro. Further mechanistic studies indicated that phillygenin blocked STAT3 signaling pathway. Phillygenin led to significant downregulation of Janus kinase 2 and upregulation of Src homology region 2 domain-containing phosphatase 1. Gene products of STAT3 regulating cell survival and invasion were also inhibited by phillygenin. Therefore, our studies provided the first evidence that phillygenin repressed osteosarcoma progression by interfering STAT3 signaling pathway. Phillygenin is a potential candidate in osteosarcoma therapy.

scholarly journals Jak1/Stat3 Activation Alters Phosphate Metabolism Independently of Sex and Extracellular Phosphate Levels

2021 ◽  
pp. 1-9
Author(s):  
Nicole Gehring ◽  
Carla Bettoni ◽  
Carsten A. Wagner ◽  
Isabel Rubio-Aliaga
Keyword(s):  
Signaling Pathway ◽  
Mineral Metabolism ◽  
Janus Kinase ◽  
Phosphate Metabolism ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
The Impact

<b><i>Introduction:</i></b> Phosphate homeostasis is regulated by a complex network involving the parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and calcitriol acting on several organs including the kidney, intestine, bone, and parathyroid gland. Previously, we showed that activation of the Janus kinase 1 (Jak1)-signal transducer and activator of transcription 3 (Stat3) signaling pathway leads to altered mineral metabolism with higher FGF23 levels, lower PTH, and higher calcitriol levels. Here, we investigated if there are sex differences in the role of Jak1/Stat3 signaling pathway on phosphate metabolism and if this pathway is sensitive to extracellular phosphate alterations. <b><i>Methods:</i></b> We used a mouse model (<i>Jak1</i><sup>S645P+/−</sup>) that resembles a constitutive activating mutation of the Jak1/Stat3 signaling pathway in humans and analyzed the impact of sex on mineral metabolism parameters. Furthermore, we challenged <i>Jak1</i><sup>S645P+/−</sup> male and female mice with a high (1.2% w/w) and low (0.1% w/w) phosphate diet and a diet with phosphate with organic origin with lower bioavailability. <b><i>Results:</i></b> Female mice, as male mice, showed higher intact FGF23 levels but no phosphaturia, and higher calcitriol and lower PTH levels in plasma. A phosphate challenge did not alter the effect of Jak1/Stat3 activation on phosphate metabolism for both genders. However, under a low phosphate diet or a diet with lower phosphate availability, the animals showed a tendency to develop hypophosphatemia. Moreover, male and female mice showed similar phosphate metabolism parameters. The only exception was higher PTH levels in male mice than those in females. <b><i>Discussion/Conclusion:</i></b> Sex and extracellular phosphate levels do not affect the impact of Jak1/Stat3 activation on phosphate metabolism.

scholarly journals Da-Cheng-Qi Decoction Alleviates Intestinal Injury in Rats with Severe Acute Pancreatitis by Inhibiting the JAK2-STAT3 Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Wenyin Jin ◽  
Yinfeng Shen
Keyword(s):  
Acute Pancreatitis ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Severe Acute Pancreatitis ◽  
Terminal Ileum ◽  
Intestinal Injury ◽  
Janus Kinase ◽  
Jak2 Inhibitor ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Objective. To investigate the effect of Da-Cheng-Qi decoction (DCQD) on treating intestinal injury in rats with severe acute pancreatitis (SAP), based on the Janus kinase 2 (JAK2)/signal transducers and transcription 3 (STAT3) signaling pathway. Methods. Rats were randomly divided into the SAP group, SAP + ruxolitinib (JAK2 inhibitor) group, SAP + Stattic (STAT3 inhibitor) group, SAP + DCQD group, and sham operation group. They were further divided into 3-hour, 6-hour, 12-hour, and 18-hour subgroups. Levels of amylase and the inflammatory cytokines tumor necrosis factor-α, interleukin 6, interleukin 10, and interleukin 4 in plasma were tested. The messenger ribonucleic acid (mRNA) expression of JAK2 and STAT3 and the protein expression of phosphorylated JAK2 (p-JAK2) and phosphorylated STAT3 (p-STAT3) in the pancreas and terminal ileum tissues were examined. Results. Rats with SAP had severe changes in plasma levels of amylase and inflammatory cytokines and showed an overexpression of JAK2 mRNA, STAT3 mRNA, p-JAK2 protein, and p-STAT3 protein in the pancreas and terminal ileum. The events could be downregulated by treatment with DCQD, JAK2 inhibitor, and STAT3 inhibitor. Conclusions. In rats with SAP, DCQD ameliorated inflammatory cytokines and intestinal injury, which may be closely associated with the inhibition of the JAK2/STAT3 signaling pathway.

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