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We surveyed proteins capable of binding to the cytoplasmic domain of Na(+)/H(+) exchanger (NHE)1 in a rat brain cDNA library with the yeast two-hybrid system. One clone obtained coded for a protein reported previously as a human calcineurin homologous protein (CHP). Since CHP is homologous to the regulatory subunit B of calcineurin, we expected a possible interacting partner of CHP like the catalytic subunit of calcineurin (calcineurin A), and surveyed this putative partner again with the yeast two-hybrid system. A clone thus obtained coded for a kinase, which is basically the same as that reported for human DRAK2. Overexpression of the rat homologue of DRAK2 caused apoptosis-like cell death of NIH3T3 cells, which was dependent on the kinase activity, confirming the previous result for DRAK2. The purified CHP and rat DRAK2 proteins synthesized in Escherichia coli could bind in vitro. CHP and rat DRAK2 expressed in COS-7 cells were found to be localized in the Golgi apparatus and nucleus, respectively. Some of them was also found in the membrane peripheral region. When they were co-expressed in the same cells, most of CHP moved to the nucleus where rat DRAK2 is located, suggesting in vivo interaction of these proteins. However, minor but significant fractions of both proteins were also found in the membrane peripheral region. Rat DRAK2 is expressed highly in thymus, spleen, and testis, where the apoptosis plays an important role in physiology.

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Aberrant expression of regulators for epigenetics is involved in tumorigenesis. There is an urgent need to identify and characterize regulators concerned with epigenetics in the early stages of hepatocarcinogenesis. In the present study, we found that the expression of coactivator-associated arginine methyltransferase 1 (CARM1), a histone methyltransferase that functions as a cofactor for nuclear hormone receptors and several transcription factors, was elevated in adenomas and aberrant in carcinomas during hepatocellular carcinogenesis. In addition to RNA expression, immunohistochemical staining of liver sections revealed that CARM1 was highly expressed in the nucleus of tumor marker glutathione S-transferase placental form (GST-P)-positive foci. Neoplastic transformation of GST-P-positive foci guides the formation of hepatocellular carcinomas. CARM1 expression was not elevated in GST-P-negative regions. Furthermore, a luciferase reporter analysis revealed that CARM1 activated the Gst-p promoter in H4IIE, a hepatocellular carcinoma cell line. This activation was mediated by the enhancer element responsible for the carcinogenic-specific expression of Gst-p and nuclear factor E2-related factor 2. Knockdown of Carm1 by shRNA in H4IIE cells inhibited cell proliferation. These findings suggest that aberrantly expressed CARM1 in tumor marker-positive cells promotes tumorigenesis in the early stages of hepatocarcinogenesis.

Background: Division of intersegmental planes is one of the important practical issues for segmentectomy to obtain feasible outcomes without relapse for clinical stage I non-small cell lung cancer. Almost all surgeons perform this procedure using a stapler. However, division of intersegmental planes for segmentectomy can also be performed by electrocautery. In this article, we demonstrate the merits and drawbacks of division of the intersegmental plane by electrocautery for segmentectomy. Methods: Of those 125 patients who underwent segmentectomy with clinical stage I primary lung cancer, we compared cautery cases (n=50) with stapler cases (n=75). The cautery group included 29 cases (58.0%) with partial use of a staple at the end of division. Results: Operative time was significantly longer in cautery cases (281±72 min) than stapler in cases (235±86 min; P=0.003). No difference in the duration of chest tube placement was evident between cautery (3.0±3.0 days) and stapler groups (2.8±1.7 days; P=0.613). However, delayed air leakage occurred significantly more frequently in cautery cases (14.0%) than in stapler cases (4.0%; P=0.048). Five-year overall survival (OS) in clinical stage I was 94.7% in cautery cases and 80.5% in stapler cases (log-rank P=0.047). Five-year disease-free survival (DFS) was 80.0% and 71.3%, respectively (log-rank P=0.075). Conclusions: The merits of cautery division include the ability to achieve meticulous division of the intersegmental plane and good preservation of the shape of residual segments. Conversely, the drawbacks include prolonged air leakage. Pleural suture or closure of residual segments may be useful to prevent delayed air leakage.