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Partial Hepatectomy Protects Against HCC Formation in Cyclin-D1 Transgenic Mice
Ketsia B. Pierre*1, Christopher M. Jones1, Christopher Anderson1, Janene Pierce1, Ian Nicoud1, Truman M. Earl1, Natasha Deane2, Jalal Hamaamen2, Robert D. Beauchamp2, Ravi Chari1
1Division of Hepatobiliary Surgery and Liver Transplant, Vanderbilt University Medical Center, Nashville, TN; 2Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN

Introduction: Surgery offers the best chance for cure in hepatocellular carcinoma (HCC), however, 45-70% undergoing resection recur. Regenerative stimuli are proposed to contribute to recurrence. Cyclin-D1 expression is increased in HCC. Cyclin D1 (CD1) transgenic mice exhibit hepatic dysplasia at 9 months of age with progression to HCC by 15 months. We hypothesized that in this genetic model of HCC, partial hepatectomy (hx) would shorten the time to malignant transformation.
Methods: CD1 or wild-type (WT) mice underwent sham operation or partial hepatectomy at 9 months of age. Animals were sacrificed at 3 and 6 months post hepatectomy; liver samples were examined for evidence of HCC. Real time PCR quantified the presence of the transgene. Statistical analysis: Fisher exact test and Mann-Whitney U with p<0.05 taken as significant.
Results: 1) All groups of mice regenerated completely. 2) All sham-CD1 mice developed HCC (n = 5). 3) None of the hx-CD1 mice developed tumor by 12 (n = 4) or 15 (n = 5) months. 4) No WT mice (sham or hx) developed dysplasia or HCC at any time point. 5) Silencing of the transgene was demonstrated in the hx-CD1 mice (Figure 1). This held true regardless of the time of sacrifice (12 or 15 months). 6) Transgene expression is maintained in the CD1 mice undergoing sham operation.
Conclusions: 1) Partial hepatectomy did not accelerate the development of HCC in this genetic mouse model of HCC. 2) Partial hepatectomy resulted in the loss of the transgene expression which may account for the lack of neoplasm formation. To our knowledge, this is the first demonstration of a surgical intervention that permanently alters transgene expression.

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