Leptin enhances migration of human papillary thyroid cancer cells through the PI3K/AKT and MEK/ERK signaling pathways

Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan, ROC.
Oncology Reports (Impact Factor: 2.3). 07/2011; 26(5):1265-71. DOI: 10.3892/or.2011.1388
Source: PubMed


The incidence of thyroid cancer has remarkably increased in recent years. Epidemiologic data suggest that obesity is associated with an increased incidence of several types of malignancies, including thyroid cancer. Leptin, an adipocyte-derived cytokine, has been shown to be involved in cancer development and progression. We previously demonstrated that papillary thyroid cancer expressing leptin receptor and/or leptin has a higher incidence of lymph node metastasis. In this study, we investigated the effects of leptin on cell migration in K1 and B-CPAP papillary thyroid cancer cells. Expression of leptin receptor was observed in both cell lines. Leptin enhanced the migratory activity significantly in a dose-dependent manner. We showed that leptin induced AKT and extracellular signal-regulated kinase (ERK) phosphorylation. Inhibition of phosphatidylinositol 3-kinase and ERK activation using pharmacological inhibitors effectively blocked leptin-induced migration of K1 and B-CPAP cells. Taken together, this study provides new mechanistic evidence for a role of leptin in the regulation of papillary thyroid cancer progression by stimulating tumor cell migration.

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    • "Although trends were demonstrated between leptin levels and each of tumor size (p = 0.079), malignant lymph node involvement (p = 0.48), and multifocal disease (p = 0.064), the differences did not reach statistical significance. Cheng et al. [29, 30] observed a strong association between leptin tissue expression and both tumor size and metastatic lymph nodes in their clinicopathological study, with further work showing the role of leptin in tumor cell migration in PTC. "
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    ABSTRACT: Background There is a proven relationship between obesity and several cancers including breast, endometrium, colorectal, and esophagus. With the increasing incidence of both obesity and thyroid cancer, we designed the present study to investigate a causal relationship between leptin, which is one of the well known adipokines, and well-differentiated thyroid cancer (WDTC). Methods Serum leptin levels were measured in 30 patients with WDTC and compared to 30 healthy control subjects before and 1 month after surgery. Other parameters studied included age, sex, body mass index, menopausal status in women, lymph node status, tumor size, and disease multifocality. Results There were no differences between the two groups regarding age and sex. Preoperative leptin levels were higher in the WDTC patients when compared to the control patients [19.25 (1.50–109.60) vs 0.90 (0.50–11.80) ng/ml, p < 0.001, group 1 vs group 2, respectively]. A significant drop in leptin levels 1 month after surgery occurred in the WDTC group, falling from 19.25 (1.50–109.60) to 0.90 (0.60–8.90) ng/ml (p < 0.001). This did not occur in the control group (p = 0.274). Lymph node involvement, tumor size, and multifocality had no effect on leptin levels, although trends were observed (p = 0.48, 0.079, and 0.064), respectively. Conclusions Serum leptin levels were significantly higher in WDTC patients when compared to control group patients, with a significant drop after surgery. Leptin may play a role in diagnosis of WDTC; however, its prognostic value is still undetermined.
    European Journal of Surgical Oncology 05/2014; 38(10). DOI:10.1007/s00268-014-2634-8 · 3.01 Impact Factor
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    • "Cell viability assay was performed in triplicate for each experiment as previously described [46]. Briefly, 8505C and K1 cells were seeded into 96-well plates one day before lidocaine and bupivacaine (individually or in combinations) was added at the indicated concentrations. "
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    ABSTRACT: Local anesthetics are frequently used in fine-needle aspiration of thyroid lesions and locoregional control of persistent or recurrent thyroid cancer. Recent evidence suggests that local anesthetics have a broad spectrum of effects including inhibition of cell proliferation and induction of apoptosis in neuronal and other types of cells. In this study, we demonstrated that treatment with lidocaine and bupivacaine resulted in decreased cell viability and colony formation of both 8505C and K1 cells in a dose-dependent manner. Lidocaine and bupivacaine induced apoptosis, and necrosis in high concentrations, as determined by flow cytometry. Lidocaine and bupivacaine caused disruption of mitochondrial membrane potential and release of cytochrome c, accompanied by activation of caspase 3 and 7, PARP cleavage, and induction of a higher ratio of Bax/Bcl-2. Based on microarray and pathway analysis, apoptosis is the prominent transcriptional change common to lidocaine and bupivacaine treatment. Furthermore, lidocaine and bupivacaine attenuated extracellular signal-regulated kinase 1/2 (ERK1/2) activity and induced activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase. Pharmacological inhibitors of MAPK/ERK kinase and p38 MAPK suppressed caspase 3 activation and PARP cleavage. Taken together, our results for the first time demonstrate the cytotoxic effects of local anesthetics on thyroid cancer cells and implicate the MAPK pathways as an important mechanism. Our findings have potential clinical relevance in that the use of local anesthetics may confer previously unrecognized benefits in the management of patients with thyroid cancer.
    PLoS ONE 02/2014; 9(2):e89563. DOI:10.1371/journal.pone.0089563 · 3.23 Impact Factor
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    • "In the present study, leptin and OBR expression levels were found to be associated with PTC tumor size, which is similar to the observations of two previous studies (23,24). This result is to be expected, considering that leptin, through OBRs, has been shown to promote proliferation and inhibit apoptosis in numerous types of cancer (16) and PTC cell lines (23,31,32). "
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    ABSTRACT: The role of leptin and its receptors (OBRs) in the pathogenesis of various primary human malignancies has been demonstrated. However, their expression and clinicopathological significance in papillary thyroid cancer (PTC) is not fully understood. In this study, we examined the expression of leptin and OBRs in 76 PTC samples using immunohistochemistry, and their associations with clinicopathological parameters were evaluated. The expression of OBRs was observed in the tumor cell membrane and/or cytoplasm, with a positive rate of 73.7% (56/76), while leptin was expressed in the tumor cell cytoplasm in 55 of 76 cases (72.4%). The expression of either protein was associated with greater tumor size (P=0.016 for leptin and P=0.002 for OBRs). In addition, the expression levels of leptin and OBRs were associated with each other. Neither leptin nor OBR expression levels were associated with other parameters, including age, body weight, postmenopausal state, multifocality and lymph node metastasis. These data suggest that the expression of leptin and/or OBRs in PTC is associated with tumor size and may be a potential target in PTC.
    Oncology letters 03/2013; 5(3):797-800. DOI:10.3892/ol.2013.1125 · 1.55 Impact Factor
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