Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis

Dipali Sharma, Jason Wang, Ping P. Fu, Shvetank Sharma, Arumugam Nagalingam, Jamie Mells, Jeffrey Handy, Andrew J. Page, Cynthia Cohen, Frank A. Anania, Neeraj K. Saxena

Research output: Contribution to journalArticle

Abstract

Obesity is rapidly becoming a pandemic and is associated with increased carcinogenesis. Obese populations have higher circulating levels of leptin in contrast to low concentrations of adiponectin. Hence, it is important to evaluate the dynamic role between adiponectin and leptin in obesity-related carcinogenesis. Recently, we reported the oncogenic role of leptin including its potential to increase tumor invasiveness and migration of hepatocellular carcinoma (HCC) cells. In the present study we investigated whether adiponectin could antagonize the oncogenic actions of leptin in HCC. We employed HCC cell lines HepG2 and Huh7, the nude mice-xenograft model of HCC, and immunohistochemistry data from tissue-microarray to demonstrate the antagonistic role of adiponectin on the oncogenic actions of leptin. Adiponectin treatment inhibited leptin-induced cell proliferation of HCC cells. Using scratch-migration and electric cell-substrate impedance-sensing-based migration assays, we found that adiponectin inhibited leptin-induced migration of HCC cells. Adiponectin treatment effectively blocked leptin-induced invasion of HCC cells in Matrigel invasion assays. Although leptin inhibited apoptosis in HCC cells, we found that adiponectin treatment induced apoptosis even in the presence of leptin. Analysis of the underlying molecular mechanisms revealed that adiponectin treatment reduced leptin-induced Stat3 and Akt phosphorylation. Adiponectin also increased suppressor of cytokine signaling (SOCS3), a physiologic negative regulator of leptin signal transduction. Importantly, adiponectin significantly reduced leptin-induced tumor burden in nude mice. In HCC samples, leptin expression significantly correlated with HCC proliferation as evaluated by Ki-67, whereas adiponectin expression correlated significantly with increased disease-free survival and inversely with tumor size and local recurrence. Conclusion: Collectively, these data demonstrate that adiponectin has the molecular potential to inhibit the oncogenic actions of leptin by blocking downstream effector molecules.

Original languageEnglish (US)
Pages (from-to)1713-1722
Number of pages10
JournalHepatology
Volume52
Issue number5
DOIs
StatePublished - Nov 2010
Externally publishedYes

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Adiponectin
Leptin
Carcinogenesis
Hepatocellular Carcinoma
Nude Mice
Obesity
Apoptosis
Pandemics
Therapeutics
Tumor Burden
Electric Impedance
Heterografts
Disease-Free Survival
Cell Movement
Signal Transduction

ASJC Scopus subject areas

  • Hepatology

Cite this

Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis. / Sharma, Dipali; Wang, Jason; Fu, Ping P.; Sharma, Shvetank; Nagalingam, Arumugam; Mells, Jamie; Handy, Jeffrey; Page, Andrew J.; Cohen, Cynthia; Anania, Frank A.; Saxena, Neeraj K.

In: Hepatology, Vol. 52, No. 5, 11.2010, p. 1713-1722.

Research output: Contribution to journalArticle

Sharma, D, Wang, J, Fu, PP, Sharma, S, Nagalingam, A, Mells, J, Handy, J, Page, AJ, Cohen, C, Anania, FA & Saxena, NK 2010, 'Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis', Hepatology, vol. 52, no. 5, pp. 1713-1722. https://doi.org/10.1002/hep.23892
Sharma, Dipali ; Wang, Jason ; Fu, Ping P. ; Sharma, Shvetank ; Nagalingam, Arumugam ; Mells, Jamie ; Handy, Jeffrey ; Page, Andrew J. ; Cohen, Cynthia ; Anania, Frank A. ; Saxena, Neeraj K. / Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis. In: Hepatology. 2010 ; Vol. 52, No. 5. pp. 1713-1722.
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AB - Obesity is rapidly becoming a pandemic and is associated with increased carcinogenesis. Obese populations have higher circulating levels of leptin in contrast to low concentrations of adiponectin. Hence, it is important to evaluate the dynamic role between adiponectin and leptin in obesity-related carcinogenesis. Recently, we reported the oncogenic role of leptin including its potential to increase tumor invasiveness and migration of hepatocellular carcinoma (HCC) cells. In the present study we investigated whether adiponectin could antagonize the oncogenic actions of leptin in HCC. We employed HCC cell lines HepG2 and Huh7, the nude mice-xenograft model of HCC, and immunohistochemistry data from tissue-microarray to demonstrate the antagonistic role of adiponectin on the oncogenic actions of leptin. Adiponectin treatment inhibited leptin-induced cell proliferation of HCC cells. Using scratch-migration and electric cell-substrate impedance-sensing-based migration assays, we found that adiponectin inhibited leptin-induced migration of HCC cells. Adiponectin treatment effectively blocked leptin-induced invasion of HCC cells in Matrigel invasion assays. Although leptin inhibited apoptosis in HCC cells, we found that adiponectin treatment induced apoptosis even in the presence of leptin. Analysis of the underlying molecular mechanisms revealed that adiponectin treatment reduced leptin-induced Stat3 and Akt phosphorylation. Adiponectin also increased suppressor of cytokine signaling (SOCS3), a physiologic negative regulator of leptin signal transduction. Importantly, adiponectin significantly reduced leptin-induced tumor burden in nude mice. In HCC samples, leptin expression significantly correlated with HCC proliferation as evaluated by Ki-67, whereas adiponectin expression correlated significantly with increased disease-free survival and inversely with tumor size and local recurrence. Conclusion: Collectively, these data demonstrate that adiponectin has the molecular potential to inhibit the oncogenic actions of leptin by blocking downstream effector molecules.

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