岸本 充

Keratins are intermediate filament proteins in epithelial cells, and they are important for cytoskeletal organization. Keratin 6A (KRT6A), classified as a type II keratin, is normally expressed in stratified squamous epithelium and squamous cell carcinomas. Little is known about the expression and role of KRT6A in adenocarcinomas. We investigated the clinicopathological and molecular biological significance of KRT6A in colorectal adenocarcinoma. Immunostaining of our institution's colorectal adenocarcinoma cases demonstrated that KRT6A showed significantly stronger expression at the invasive front than the tumor center (p < 0.0001). The high-KRT6A-expression cases (n = 47) tended to have a high budding grade associated with significantly worse prognoses. A multivariate analysis revealed that the KRT6A expression status was an independent prognostic factor for overall survival (p = 0.0004), disease-specific survival (p = 0.0097) and progression-free survival (p = 0.0033). The correlation between KRT6A and patient prognoses was also validated in an external cohort from a published dataset. To determine the function of KRT6A in vitro, KRT6A was over-expressed in three colon cancer cell lines, DLD-1, SW620, and HCT 116. KRT6A overexpression increased migration and invasion in DLD-1, but did not in SW620 and HCT116. In three-dimensional sphere-forming culture, KRT6A expression enhanced the irregular protrusion around the spheroid in DLD-1. Our findings in the present study indicated that KRT6A expression is a valuable prognostic marker of colorectal cancer and KRT6A may be involved the molecular mechanism in the progression of invasive areas of colorectal cancer.

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis. Neoadjuvant chemotherapy is an effective PDAC treatment option, but chemotherapy causes unfavorable side effects. Glucocorticoids (e.g., dexamethasone [DEX]) are administered to reduce side effects of chemotherapy for solid tumors, including pancreatic cancer. Glucocorticoids have both beneficial and detrimental effects, however. We investigated the functional changes and gene-expression profile alterations induced by DEX in PDAC cells. PDAC cells were treated with DEX, and the cell proliferation, migration, invasion, and chemosensitivity to gemcitabine (GEM) were evaluated. The results demonstrated decreased cell proliferative capacity, increased cell migration and invasion, and decreased sensitivity to GEM. A comprehensive genetic analysis revealed marked increases in ECM1 and KRT6A in DEX-treated PDAC cells. We evaluated the effects of ECM1 and KRT6A expression by using PDAC cells transfected with those genes. Neither ECM1 nor KRT6A changed the cells' proliferation, but each enhanced cell migration and invasion. ECM1 decreased sensitivity to GEM. We also assessed the clinicopathological significance of the expressions of ECM1 and KRT6A in 130 cases of PDAC. An immunohistochemical analysis showed that KRT6A expression dominated the poorly differentiated areas. High expressions of these two proteins in PDAC were associated with a poorer prognosis. Our results thus demonstrated that DEX treatment changed PDAC cells' functions, resulting in decreased cell proliferation, increased cell migration and invasion, and decreased sensitivity to GEM. The molecular mechanisms of these changes involve ECM1 and KRT6A, whose expressions are induced by DEX.

OBJECTIVE: Hepatic fibrosis has recently been evaluated using ultrasonography or magnetic resonance elastography. Although the shear wave velocity (SWV) obtained using point shear wave elastography (pSWE) provides a valuable measure of fibrosis, underlying steatosis may affect its measurement. METHODS: Using hepatic fibrosis samples, this study evaluated the effect of steatosis on the shear wave velocity of pSWE (Vs) and viscoelastic properties (assessed by dynamic mechanical analysis) of rat liver. Fifty rats with various grades of steatosis and fibrosis underwent open abdominal in vivo Vs measurements using a commercial ultrasound scanner. The mechanical properties of hepatic tissue were also characterized under ex vivo conditions using dynamic mechanical analysis and the Zener model of viscoelasticity. RESULTS: Fibrosis and steatosis progression influenced Vs and elasticity. The SWV computed using the Zener model and Vs showed a substantial correlation (r > 0.8). Fibrosis progression increased SWV. Steatosis was also related to SWV. Steatosis progression obscured the SWV change associated with fibrosis progression. CONCLUSION: We conclude that steatosis progression affects the evaluation of fibrosis progression. This finding could aid discrimination of non-alcoholic steatohepatitis from non-alcoholic fatty liver disease using SWV.