Suppression of hepatocellular carcinoma growth in mice via leptin, is associated with inhibition of tumor cell growth and natural killer cell activation.
OBJECTIVE
Leptin exerts potent immune modulatory properties. The aim of this study was to determine leptin's anti-tumor effect in a murine model of hepatocellular carcinoma (HCC).


METHODS
In vivo, athymic nude mice were transplanted with Hep3B cells, followed by daily leptin administration for 6 weeks.


RESULTS
Leptin administration induced a significant reduction in tumor size, improved survival rate, and was associated with a significant increase in peripheral natural killer (NK) cell number. Splenocytes from leptin-treated mice featured decreased expression of CIS mRNA. SCID mice featured a similar leptin-associated tumor suppression. In contrast, NK-deficient SCID-beige mice developed larger tumors which were unresponsive to leptin. NK cells incubated in vitro with increasing doses of leptin demonstrated increased cytotoxicity and proliferation. Incubation of leptin with hepatoma cells induced a dose-dependent reduction in proliferation, suggesting a direct anti-tumor effect. Leptin induced increased mRNA expression of STAT2 and SOCS1 on HCC cell lines.


CONCLUSIONS
Leptin administration induces a significant suppression of human HCC. This effect is mediated by induction of natural killer cell proliferation and activation, along with direct inhibition of tumor growth. Decreased NK expression of inhibitory CIS and over-expression of the antiproliferative STAT2 and SOCS1 proteins in HCC lines may underline the anti-cancerous effects of leptin.
Elinav
Eran
E
Liver Unit, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
Abd-Elnabi
Asad
A
Pappo
Orit
O
Bernstein
Itamar
I
Klein
Athalia
A
Engelhardt
Dean
D
Rabbani
Elazar
E
Ilan
Yaron
Y
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D020738:Leptin / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D012334:RNA, Neoplasm / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D012334:RNA, Neoplasm; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins