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Abstract.We have previously shown that expression of SIAH1 is frequently down-regulated in HCCs and associated with their advanced stages. It has been shown that SIAH1 functions in the phosphorylation-independent degradation of ß-catenin and induces apoptosis and growth arrest. To examine if the effects of SIAH1 overexpression depend on the altered ß-catenin signaling pathway, we transferred the SIAH1 gene into three hepatoma cell lines with different genetic backgrounds: HepG2 (mutant ß-catenin), SNU475 (mutant AXIN1), and Huh7 cells (wild type ß-catenin and AXIN1). SIAH1 significantly decreased aberrant ß-catenin signal in HepG2 and SNU475 cells and induced growth arrest and apoptosis. However, SIAH1 also induced apoptosis in Huh7 cells, which retained a normal membranous distribution pattern of ß-catenin. Immunoblotting study demonstrated that SIAH1 also reduces the amount of PEG10 protein, which is known to be frequently overexpressed in HCC and to promote cell proliferation. These data suggest that PEG10 is another target protein of SIAH1 to induce apoptosis in hepatoma cells. Our results should lead to a better understanding of the relationship between deregulation of ß-catenin signals and hepatocarcinogenesis. Further investigations into the mechanisms by which SIAH1 promotes apoptosis and suppresses cell growth should also allow for the discovery of new therapeutic strategies. IntroductionHepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Epidemiological studies have revealed that major causes of HCC are exposure to carcinogens such as aflatoxin B1, cirrhosis of any etiology, or chronic infection to hepatitis B or C. Molecular approaches have disclosed involvement of several genetic alterations in hepatocellular carcinogenesis, including mutation of TP53, ß-catenin and AXIN1 (1-3). Among these, mutation of ß-catenin or AXIN1 has been shown to result in nuclear accumulation of ß-catenin protein. Accumulated ß-catenin is known to associate with the Tcf/Lef family of transcriptional factors thereby activating target genes, such as c-myc and cyclin D1. Immunohistochemical analysis revealed that ß-catenin is aberrantly accumulated in nearly 50% of HCCs (3,4), suggesting that alteration of the ß-catenin signaling pathway is one of the most common and major mechanisms of the development of HCC.We previously performed a fine deletion mapping of chromosome 16 to search for a novel tumor suppressor gene for HCC and identified SIAH1, which is located at a commonly deleted region 16q12.1 (5). Although we did not find any somatic mutation of SIAH1, its expression was markedly down-regulated, especially in cases harboring loss of heterozygosity (LOH) at the SIAH1 locus. Moreover, decreased expression of SIAH1 was associated with the advanced stage of HCCs, suggesting that inactivation of SIAH1 plays an important role in HCC progression (5). SIAH1 is a human homolog of the Drosophila seven in absentia (sina), required for formation of the R7 photoreceptor cells during eye developmen...

BackgroundRegorafenib is an oral multikinase inhibitor that has been demonstrated as clinically effective in patients with metastatic colorectal cancer in phase III studies. Although disease control was achieved in 40% of the pretreated patients with metastatic colorectal cancer in the pivotal studies, radiological response has rarely been reported. Severe adverse events associated with regorafenib are known to occur during the first and second courses of treatment. We present a case of a 62-year-old Japanese patient whose metastatic colorectal cancer has been responding to treatment with regorafenib for 2 years.Case presentationA 54-year-old Japanese man visited our institute exhibiting general malaise, and he was diagnosed with ascending colon cancer in April 2006. He underwent right hemicolectomy, and the final staging was T3N0M0, stage II. After 19 months, pulmonary metastasis and anastomotic recurrences were detected, and a series of operations were performed to resect both metastatic lesions. After that, liver metastasis, a duodenal metastasis with right renal invasion, right adrenal metastasis, and para-aortic lymph node metastases were observed during follow-up, and chemotherapy and resection were performed. The patient had metastatic para-aortic lymph nodes after the fifth tumor resection and underwent multiple lines of chemotherapy in April 2014. Regorafenib monotherapy was started at 80 mg/day. Then, regorafenib was increased to 120 mg/day in the second cycle. Regorafenib monotherapy led to 60% tumor shrinkage within the initial 2 months, and the tumor further decreased in size over 4 months until it became unrecognizable on imaging studies. The clinical effects of regorafenib monotherapy have shown a partial response according to Response Evaluation Criteria in Solid Tumors criteria. No severe adverse events were observed, except for mild fatigue and hand-foot syndrome. The patient has received 24 courses of regorafenib over 2 years without exhibiting tumor progression.ConclusionsTo the best of our knowledge, this is the longest treatment with regorafenib without tumor progression ever reported. A reduced dosage of regorafenib at induction may ameliorate the cutaneous and hepatic toxicity associated with its use.

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