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Subcellular localization of the NS2 and NS3 proteins of hepatitis C virus was analyzed. In stable Ltk transfectants inducibly expressing an NS2-NS3 polyprotein (amino acids [aa] 810 to 1463), processed full-size NS2 (aa 810 to 1026) was detected exclusively in a cytoplasmic membrane fraction. On the other hand, the other processed product, carboxy-truncated NS3 (NS3⌬C1463; aa 1027 to 1463), was present in both cytoplasmic and nuclear fractions. To further analyze subcellular localization of NS3, NS3⌬C1459 (aa 1027 to 1459), full-size NS3 (NS3F; aa 1027 to 1657), and both amino-and carboxy-truncated NS3 (NS3⌬N⌬C; aa 1201 to 1459) were expressed in HeLa cells by using a vaccinia virus-T7 hybrid expression system. NS3⌬C1459 and NS3F accumulated in the nucleus as well as in the cytoplasm, exhibiting a dot-like staining pattern. On the other hand, NS3⌬N⌬C was localized predominantly in the cytoplasm, suggesting the presence of a nuclear localization signal(s) in the amino-terminal sequence of NS3. NS4A, a viral cofactor for the NS3 protease, inhibited nuclear transport of NS3⌬C1459 and NS3F, with the latter inhibited to a lesser extent than was the former. Interestingly, wild-type p53 tumor suppressor augmented nuclear localization of NS3⌬C1459 and NS3F, whereas mutant-type p53 inhibited nuclear localization and augmented cytoplasmic localization of NS3⌬C1459. However, subcellular localization of NS3⌬N⌬C was not affected by either type of p53. Wild-type p53-mediated nuclear accumulation of NS3⌬C1459 and NS3F was inhibited partially, but not completely, by coexpressed NS4A, with NS3F again affected less prominently than was NS3⌬C1459.

To diagnose early gallbladder carcinoma is difficult but essential to improve the survival of the patients with this cancer. Fifty-three early gallbladder cancers were macroscopically divided into protruding and flat types. The diagnostic devises [ultrasonography (US), computed tomography (CT), and drip infusion cholangiography (DIC)] were compared for their ability of early detection. The specimens were examined cytologically for diagnosis during operation and the p53 protein was investigated. Thirty-three cases were of the protruding type, eighteen of the flat type, and two unclassified. Carcinoma tended to be missed when gallstones were present. Preoperative diagnosis of the flat type was difficult. Tumor location did not always correlate with the preoperative diagnosis. Of the misdiagnosed cases of the protruding type, half were missed with US and CT and were not visualized clearly by DIC. Among the flat type cancers, only three had no abnormal findings by diagnostic imaging. Cytologic examination was effective, and p53 was expressed only in early carcinoma, not in adenoma or dysplasia. Even in the presence of gallstones or cholecystitis, any abnormal findings should make one suspicious of gallbladder cancer. Cytology and p53 expression may be useful for the intraoperative diagnosis, and a combination of diagnostic methods is important.

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