Leptin and Adiponectin Expression in Hepatocellular Carcinoma: Correlation with Proliferation and Prognostic Parameters
J Wang, A Page, D Lawson, C Cohen. Emory University, Atlanta, GA
Background: Obesity, a risk factor for hepatocellular carcinoma (HCC), results in increased serum leptin and decreased serum adiponectin. In vitro studies show that leptin, the key regulator of energy balance and body weight, increases proliferation and induces invasion of HCC cells via JAK/STAT, ERK, and PI3K/AKT signaling pathways, and is blocked by inhibitors of these pathways. This suggests that leptin plays a crucial role in the growth, invasion, and migration of HCC. Adiponectin, however, inhibits HCC growth with a decrease in proliferation and increase in apoptosis through AMPK-JNK and AMPK-mTOR signaling pathways.
Design: 140 HCCs in 3 tissue microarrays with 2 1mm cores of each tumor were assessed for leptin and adiponectin expression. Stains, scored as intensity 0-4+ and % (+) cells, were compared to proliferation (mitoses/10HPF, MIB-1 labeling index [LI], and phosphohistone-3 [PPH3] LI using the ACIS III Image Cytometer [Dako]) and prognostic parameters (size, grade, stage, vascular invasion, metastases, and focality).
Results: Of the 140 HCCs, 105 (75%) had 3-4+ leptin expression while 42 (30%) had 3-4+ adiponectin expression. Mean mitotic count was 3.7/10HPF, MIB-1 LI was 3.7%, and PPH-3 LI was 3.6%. Leptin expression correlated significantly with proliferation (MIB-1 [p=0.038] and PPH3 [p=0.01] LIs), and stage (p=0.02), and tended to correlate with metastases (p=0.062); no other correlation was found. Adiponectin expression correlated significantly and inversely only with tumor size (p<0.001).
|Size (mean)||6.3 +/- 4.6||4.0 +/- 2.5||<0.001|
|MIB-1 LI||4.7 +/- 3.9||3.4 +/- 3.1||0.038|
|PPH3 LI||5.0 +/- 4.3||3.1 +/- 3.3||0.01|
|Stage 1-2||21 (61.7%)||68 (64.8%)|
|Stage 3-4||11 (32.4%)||36 (34.3%)||0.02|
|Mets -||23 (67.6%)||75 (71.4%)|
|Mets +||3 (8.8%)||20 (19.0%)||0.062|