A novel method in order to evaluate the efficacies and the safeties of new drugs for hepatocellular carcinoma with loss of transforming growth factor-β signaling
Authors: Hisashi Moriguchi
Journal: Hepatology (2009)

I read with interest the article by Mazzocca et al.1 in which they showed the rationale for targeting transforming growth factor-beta (TGF-β) signaling in patients with hepatocellular carcinoma (HCC).1 At least 40% of HCC is clonal, potentially arising from signal transducer and activator of transcription 3 (STAT3)-positive, NANOG-positive, and octamer-binding protein 3/4 (OCT3/4)-positive liver progenitor/stem cell transformation, along with inactivation of TGF-β signaling.2 Considering this point, Lin et al. conclude that inhibiting interleukin-6 (IL-6)/STAT3 in HCC with inactivation of the TGF-β/β2SP pathway is an effective approach in management of HCC.2 Furthermore, they show the STAT3 inhibitor NSC 74859 is effective in HCC with disrupted TGF-β signaling. On the other hand, pitavastatin at a low dose (0.1 μM) inhibits nuclear factor-kappaB activation and decreases IL-6 production.3 In fact, statin use is associated with a significant reduction in the risk of HCC among patients with diabetes.4 Though Odds ratios as estimates of the relative risk for HCC associated with statin use and 95% confidence intervals were obtained, the adjusted odds ratio for any statin prescription was 0.74 (95% confidence interval, 0.64-0.87). Thus, the STAT3-specific drug NSC 74859 or statins would be effective in HCC with loss of TGF-β signaling. The toxicities for these drugs should be evaluated appropriately in order to conduct clinical trials for these drugs. As for this point, human-induced pluripotent stem (iPS) cells can be efficiently induced to differentiate into hepatocyte-like cells.5 This suggests that human iPS cells derived from patients with HCC with loss of TGF-β signaling can differentiate into hepatocyte-like cells. By using the patient-specific hepatocyte-like cells, the patient-specific toxicities for NSC 74859 or statins could be evaluated in the near future. I investigated the relative ratio for gene expression of Oct3/4 and sex-determining region Y box 2 (Sox2) as human iPS cell–associated genes between human cancer cell lines and human normal tissues by using a comprehensive gene expression database (RefEXA) of human cancer cell lines and human normal tissues with GeneChip HG-U133A (http://www.lsbm.org/site_e/database/index.html). As a result, the relative ratio for Oct3/4 and Sox2 of human cancer cell lines compared to human normal tissues was 2:1 in the case of HepG2 as a human hepatoma cell line and human normal liver tissue, and 2:1 in the case of Capan-1 as a human pancreatic adenocarcinoma cell line and human normal pancreatic tissue, generally. Thus, the gene expression levels of Oct3/4 in the abovementioned human cancer cell lines were in excess compared to the cases of human normal tissues. Therefore, if we can identify molecules that cause relative ratio to become 1:1 as much as possible, these molecules would be novel drugs for human HCC or human pancreatic cancer. For example, investigation whether NSC 74859 or statins can decrease gene expression levels of Oct3/4 and improve the relative ratio of Oct3/4 and Sox2 is rational in the case of HCC with loss of TGF-β signaling. In conclusion, I show a method to evaluate the efficacies and the safeties of NSC 74859 or statins for HCC with loss of TGF-β signaling. I am grateful to Ms. Satoko Iioka for helpful discussions. Hisashi Moriguchi*, * Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.