Leptin in hepatocellular carcinoma

Wang, Shen‐Nien; Lee, King Teh; Ker, Chen‐Guo

doi:10.3748/wjg.v16.i46.5801

Cited by 59 publications

(53 citation statements)

References 94 publications

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“…1B). This finding is consistent with the observation that mutations in the leptin receptor are frequently found in cirrhotic livers and are linked to HCC in human (26,27). The db/db mice, which carry a genetic defect in the leptin receptor (28), provide a clinically relevant genetic context for evaluating candidate HCC-promoting genes.…”

Section: Resultssupporting

confidence: 78%

Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19

et al. 2014

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Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related death, develops from premalignant lesions in chronically damaged livers. Although it is well established that FGF19 acts through the receptor complex FGFR4-b-Klotho (KLB) to regulate bile acid metabolism, FGF19 is also implicated in the development of HCC. In humans, FGF19 is amplified in HCC and its expression is induced in the liver under cholestatic and cirrhotic conditions. In mice, ectopic overexpression of FGF19 drives HCC development in a process that requires FGFR4. In this study, we describe an engineered FGF19 (M70) that fully retains bile acid regulatory activity but does not promote HCC formation, demonstrating that regulating bile acid metabolism is distinct and separable from tumorpromoting activity. Mechanistically, we show that FGF19 stimulates tumor progression by activating the STAT3 pathway, an activity eliminated by M70. Furthermore, M70 inhibits FGF19-dependent tumor growth in a rodent model. Our results suggest that selectively targeting the FGF19-FGFR4 pathway may offer a tractable approach to improve the treatment of chronic liver disease and cancer. Cancer Res; 74(12); 3306-16. Ó2014 AACR.

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Section: Resultssupporting

confidence: 78%

Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19

et al. 2014

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“…45, 46 In addition, angiogenesis dysregulation induced by the adipose tissue through leptin expression has been suggested. 47 Siegel and colleagues showed that obesity is associated with microvascular invasion, resulting in poor HCC survival. 48 In our study, vascular invasion was observed more frequently in overweight and obese patients than in normal-weight patients, but the differences were not statistically significant.…”

Section: Discussionmentioning

confidence: 99%

Obesity Early in Adulthood Increases Risk but Does Not Affect Outcomes of Hepatocellular Carcinoma

et al. 2015

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BACKGROUND & AIMS Despite the significant association between obesity and several cancers, it has been difficult to establish an association between obesity and hepatocellular carcinoma (HCC). Patients with HCC often have ascites, making it a challenge to accurately determine body mass index (BMI), and many factors contribute to the development of HCC. We performed a case–control study to investigate whether obesity early in adulthood affects risk, age of onset, or outcomes of patients with HCC. METHODS We interviewed 622 patients newly diagnosed with HCC from January 2004 through December 2013, along with 660 healthy controls (frequency-matched by age and sex) to determine weights, heights, and body sizes (self-reported) at various ages before HCC development or enrollment as controls. Multivariable logistic and Cox regression analyses were performed to determine the independent effects of early obesity on risk for HCC and patient outcomes, respectively. BMI was calculated, and patients with a BMI ≥30 kg/m2 were considered obese. RESULTS Obesity in early adulthood (age, mid-20s to mid-40s) is a significant risk factor for HCC. The estimated odds ratios (OR) and 95% confidence intervals (CI) were 2.6 (1.4–4.4), 2.3 (1.2–4.4), and 3.6 (1.5–8.9) for the entire population, men, and women, respectively. Each unit increase in BMI at early adulthood was associated with a 3.89-month decrease in age at HCC diagnosis (P<.001). Moreover, there is a synergistic interaction between obesity and hepatitis virus infection. However, we found no effect of obesity on the overall survival of patients with HCC. CONCLUSION Early adulthood obesity is associated with increased risk of developing HCC at a young age in the absence of major HCC risk factors, with no effect on outcomes of patients with HCC.

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“…In light of the increasing reported role of leptin in several types of cancer [24–28], in this review we wish to focus on the role of leptin in breast cancer, highlighting the leptin-mediated signaling pathways and its potential as a drug target. Additionally, we will review and discuss recently identified molecular mechanisms of leptin in breast cancer, including its potential role in breast cancer stem cells (BCSC), tumor angiogenesis, as well as its crosstalk with other oncogenic signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells

Guo

Liu

Wang

et al. 2012

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

105

157

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Significant correlations between obesity and incidence of various cancers have been reported. Obesity, considered a mild inflammatory process, is characterized by a high level of secretion of several cytokines from adipose tissue. These molecules have disparate effects, which could be relevant to cancer development. Among the inflammatory molecules, leptin, mainly produced by adipose tissue and overexpressed with its receptor (Ob-R) in cancer cells is the most studied adipokine. Mutations of leptin or Ob-R genes associated with obesity or cancer are rarely found. However, leptin is an anti-apoptotic molecule in many cell types, and its central roles in obesity-related cancers are based on its pro-angiogenic, pro-inflammatory and mitogenic actions. Notably, these leptin actions are commonly reinforced through entangled crosstalk with multiple oncogenes, cytokines and growth factors. Leptin-induced signals comprise several pathways commonly triggered by many cytokines (i.e, canonical: JAK2/STAT; MAPK/ERK1/2 and PI-3K/AKT1 and, non-canonical signaling pathways: PKC, JNK and p38 MAP kinase). Each of these leptin-induced signals is essential to its biological effects on food intake, energy balance, adiposity, immune and endocrine systems, as well as oncogenesis. This review is mainly focused on the current knowledge of the oncogenic role of leptin in breast cancer. Additionally, leptin pro-angiogenic molecular mechanisms and its potential role in breast cancer stem cells will be reviewed. Strict biunivocal binding-affinity and activation of leptin/Ob-R complex makes it a unique molecular target for prevention and treatment of breast cancer, particularly in obesity contexts.

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Leptin in hepatocellular carcinoma

Cited by 59 publications

References 94 publications

Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19

Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19

Obesity Early in Adulthood Increases Risk but Does Not Affect Outcomes of Hepatocellular Carcinoma

Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells

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