Hirokazu Uyama

Hepatoma-Derived Growth Factor Is a Novel Prognostic Factor for Patients with Pancreatic Cancer

Purpose: Hepatoma-derived growth factor (HDGF) is a nucleus-targeted growth factor playing an important role in the development and progression of cancers. This study investigated the correlation of HDGF expression and prognosis in patients with pancreatic ductal carcinoma. Patients and Methods: HDGF expression in pancreatic cancer cell lines was analyzed by Western blotting. HDGF expression was analyzed by immunohistochemistry for 50 patients with primary ductal carcinoma of the pancreas (33 male and 17 female) ranging in age from 48 to 80 years (median, 65 years) receiving surgical treatment. Cancer cells showing stronger staining than the noncancerous ducts were regarded as positive. Cases showing positive staining in <90% and >90% of tumor cells were regarded as HDGF labeling index (LI) levels 1 and 2, respectively. HDGF LI was determined separately for the nucleus and the cytoplasm. Results: Western blotting showed HDGF expression in pancreatic cancer cells similar to that of hepatic cell lines. Twenty-three (46%) and 27 (54%) cases and 22 (44%) and 28 (56%) cases showed HDGF LI levels 1 and 2 for the nucleus and the cytoplasm, respectively. Patients with nuclear HDGF LI level 1 showed a significantly better 5-year survival rate (37.0%) than those with level 2 (6.8%; P = 0.023). No significant difference was observed in the cytoplasmic HDGF LI classification. Multivariate analysis revealed nuclear HDGF LI to be an independent prognosticator. Conclusions: These findings suggest that HDGF could be a novel prognostic factor for pancreatic ductal carcinoma.

Hepatoma-derived growth factor induces tumorigenesis in vivo through both direct angiogenic activity and induction of vascular endothelial growth factor

Hepatoma‐derived growth factor (HDGF) is highly expressed in tumor cells, and stimulates their proliferation. In the present study, we investigated the role of HDGF in tumorigenesis and elucidated the mechanism of action. Stable transfectants of NIH3T3 cells overexpressing HDGF did not show significant anchorage‐independent growth in soft agar assay. However, these stable transfectants overexpressing HDGF generated sarcomatous tumors in nude mice. These tumors were red‐colored macroscopically, and histologically showed a rich vascularity. Immunohistochemical analysis using CD31 antibody showed new vessel formation. Recombinant HDGF stimulated proliferation of human umbilical vein endothelial cells in a dose‐dependent manner, and stimulated tubule formation. Furthermore, vascular endothelial growth factor (VEGF) was detected immunohistochemically in the tumor tissues. Transient expression of HDGF induced both VEGF gene and protein expression as demonstrated by a reporter assay using VEGF gene promoter. The administration of anti‐VEGF neutralizing antibody significantly suppressed, but did not block, the tumor growth of HDGF‐overexpressing cells in nude mice. Thus, these findings suggested that HDGF‐induced tumor formation in vivo involves induction of VEGF as well as direct angiogenic activity.

Hepatoma-Derived Growth Factor Is a Novel Prognostic Factor for Hepatocellular Carcinoma

BackgroundHepatoma-derived growth factor (HDGF) is involved in hepatocarcinogenesis, as well as in liver development and regeneration. This study investigated the correlation of HDGF expression with differentiation and prognosis of hepatocellular carcinoma (HCC).MethodsHDGF expression in 100 patients with HCC (81 men and 19 women) with ages ranging from 34 to 81 years (median, 61 years) receiving surgical treatment was analyzed by immunohistochemistry. HDGF messenger RNA expression was evaluated in 10 cases by reverse transcription-polymerase chain reaction. The immunostaining pattern in HCCs was categorized as a positive HDGF index (showing positive staining in >90% of tumor cells in both nucleus and cytoplasm) or a negative HDGF index (all others).ResultsTwenty-seven cases (27%) showed a positive and 73 (73%) showed a negative HDGF index. HDGF messenger RNA expression was significantly higher in four cases with a positive HDGF index than in six with a negative index. Cases with well-differentiated histological characteristics showed a higher rate of positive HDGF index than those with a poorly differentiated subtype. Univariate and multivariate analysis revealed significantly poorer disease-free and overall survivals in patients with a positive HDGF index compared with patients with a negative index.ConclusionsThese findings suggest the potential utility of HDGF immunohistochemistry in determining the prognosis of HCC.

Expression Level of Hepatoma-Derived Growth Factor Correlates with Tumor Recurrence of Esophageal Carcinoma

Hepatoma-derived growth factor (HDGF) is thought to play an important role in the development and progression of carcinomas. In the present study, association of HDGF expression with recurrence and prognosis of esophageal carcinoma (EC) was examined. HDGF expression in 111 patients with EC (101 men and 10 women) with ages ranging from 38 to 82 (median, 61) years was analyzed by immunohistochemistry. Samples in which >90% of tumor cells exhibited nuclear and cytoplasmic HDGF immunoreactivity at levels greater than or equal to what is observed in the endothelial cells were regarded as HDGF expression level 1, and others as HDGF expression level 0. Thirty-seven of 111 patients showed level 1 HDGF expression. There was no correlation between HDGF expression and other clinicopathologic factors. Patients with level 1 expression showed poorer disease-free and overall survival (P < .05 for both) compared with those with level 0 expression. HDGF expression was an independent prognostic factor for patients with early (pT1–2) stage of the disease, but not for those with advanced (pT3–4) stage. HDGF expression level was shown to be a prognostic factor for EC.

Expression of hepatoma-derived growth factor in hepatocarcinogenesis

Background and Aim:  The present study investigated the expression of hepatoma‐derived growth factor (HDGF) in human hepatocellular carcinoma (HCC) and in the liver during hepatocarcinogenesis in two rodent models.

Antibodies against hepatoma-derived growth factor and mucosal repair in ulcerative colitis

Ulcerative colitis is a chronic inflammatory disease of colonic mucosa in which the pathogenesis of any immunological disorders would likely be related. Various circulating autoantibodies have been reported in patients with ulcerative colitis, although their possible roles in this disease process have not yet been clarified. Autoantibody against hepatoma-derived growth factor (HDGF) was detected at high frequency in the serum of patients with ulcerative colitis, especially in patients with total colitis and left-sided colitis. In pursuit of the possible role of anti-HDGF autoantibody in the pathogenesis, we investigated HDGF expression in the intestinal mucosa by Western blotting and immunohis-tochemistry and the effects of recombinant proteins and antirecombinant HDGF antibody on the proliferation of the colonic epithelial cell-derived cell line, HT-29. HDGF was expressed in the nucleus of the colonic epithelial cells dominantly in the bottom of the crypts. Recombinant HDGF stimulated the proliferation of HT-29 cells significantly, although its effects were small, about 20% greater than the control at 100ng/ml. On the other hand, the polyclonal IgG antibody against recombinant HDGF generated by rabbits suppressed their proliferation almost completely at 250 μg/ml. These findings suggest that HDGF plays an important role in epithelial cell renewal of intestinal crypts as a growth and survival factor, and that autoantibody against HDGF may delay mucosal healing and repair by inhibiting the stimulatory effects of HDGF on epithelial cell proliferation, resulting in a chronic process of colonic mucosal injury.

New chemotherapy for patients with advanced hepatocellular carcinoma: Pilot study of β‐interferon and doxorubicin one‐shot intra‐arterial chemotherapy

Background:  Patients with advanced hepatocellular carcinoma (HCC) need an effective treatment modality because of the poor prognosis of the disease. From an in vitro study, β‐interferon (IFN‐β) has been reported to enhance the antiproliferative effects of doxorubicin on HCC cell lines. In the present study, we investigated the therapeutic effects of combined IFN‐β and doxorubicin intra‐arterial injection therapy on patients with advanced HCC.

Triple therapy of initial high-dose interferon with ribavirin and amantadine for patients with chronic hepatitis C

Aims:  We previously reported the potential effect of combination therapy of an initial high‐dose interferon (IFN) and amantadine on the eradication of HCV‐RNA in patients with chronic hepatitis C. The additive effects of amantadine on interferon and ribavirin combination therapy remain controversial. In this study we investigated the efficacy of initial high‐dose IFN with ribavirin and amantadine on the virological response in patients with chronic hepatitis C with a high viral load of genotype 1b.