Shinji Furuya

Interleukin 17A plays a role in lipopolysaccharide/D-galactosamine-induced fulminant hepatic injury in mice.

BACKGROUND Lipopolysaccharide/d-galactosamine (LPS/GalN)-induced hepatic injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor alpha (TNF-α) plays a pivotal role. Moreover, it was reported from our laboratory that interleukin (IL) 17A enhanced production of TNF-α by the Kupffer cell. OBJECTIVE The purpose of this study was to determine the role of IL-17A in LPS/GalN-induced hepatic injury in mice. METHODS LPS/GalN was injected into three mouse models: wild-type (WT) mice, IL-17A knockout (KO) mice, or IL-17A KO mice treated with recombinant mouse (rm) IL-17A homodimer (KO + rmIL-17A). Survival was assessed for 24 h after LPS/GalN injection, and histopathologic findings were evaluated at various time points after LPS/GalN injection for neutrophil and apoptosis markers. After LPS/GalN injection, expression of the inflammatory mediators TNF-α, IL-6, monocyte chemotactic protein 1, IL-17A, high-mobility group box 1, and soluble intercellular adhesion molecule 1 was assessed in serum by enzyme-linked immunosorbent assay. RESULTS Survival was higher in KO mice compared with WT mice after LPS/GalN injection. However, in KO + rmIL-17A mice, mortality was not significantly different compared to the other groups. Neutrophil infiltration and apoptosis were significantly greater in WT mice than KO mice. Furthermore, serum alanine aminotransferase, serum TNF-α, monocyte chemotactic protein 1, IL-17A, high-mobility group box 1, and soluble intercellular adhesion molecule 1 levels were also significantly greater in WT mice than KO mice. In KO + rmIL-17A mice, these levels were similar to those in WT mice. CONCLUSIONS IL-17A is a key regulator in hepatic injury caused by neutrophil-induced inflammatory responses after LPS/GalN injection.

The platelet-activating receptor C-type lectin receptor-2 plays an essential role in liver regeneration after partial hepatectomy in mice

Essentials Regeneration role of C‐type lectin receptor‐2 (CLEC‐2) after 70% hepatectomy (HPx) was investigated. Wild‐type or CLEC‐2 deleted from platelets of chimeric mice (flKO) underwent HPx. The liver/body weight ratio was significantly lower in the flKO than in the wild‐type. CLEC‐2 plays an essential role in liver regeneration after HPx.

Macrophage colony-stimulating factor plays a pivotal role in chemically induced hepatocellular carcinoma in mice

The specific purpose of this study was to investigate the role of macrophage colony‐stimulating factor (M‐CSF) in initiation and progression of hepatocellular carcinoma using M‐CSF‐deficient mice.

Interleukin-17A plays a pivotal role after partial hepatectomy in mice.

BACKGROUND Liver regeneration after partial hepatectomy (PH) is regulated by tumor necrosis factor (TNF)-α derived from the Kupffer cell. Furthermore, it was reported from our laboratory that interleukin (IL)-17A enhances the production of TNF-α by the Kupffer cell, suggesting that IL-17A may play a role in liver regeneration. OBJECTIVE The purpose was to determine the role of IL-17A and the spleen in liver regeneration after PH. METHODS Two mouse models including the wild-type (WT) mice or the IL-17A knockout (KO) mice underwent PH. Animals were killed at the designated time points; liver tissues were harvested for further investigation. Proliferation of hepatocytes was evaluated. Furthermore, the messenger RNA and protein expression of TNF-α and IL-6 were measured in the liver. In another set of experiments, the two animal models underwent splenectomy before PH. In an in vitro study, CD4-positive lymphocytes in the spleen were isolated from mice, and the number of IL-17A-positive cells was investigated. RESULTS Liver regeneration was significantly impaired in the KO mice compared with the WT mice. This was associated with suppression of cell proliferation assessed by cell proliferation markers in the KO mice. In the WT mice that underwent splenectomy, liver regeneration was significantly delayed compared with animals without splenectomy. In contrast, splenectomy did not affect liver regeneration in the KO mice. IL-17A-positive lymphocytes increased significantly in the spleen in the WT mice after PH. CONCLUSIONS These results indicate that IL-17A derived from CD4-positive lymphocytes in the spleen is a key regulator in liver regeneration after PH.

Macrophage colony-stimulating factor expressed in non-cancer tissues provides predictive powers for recurrence in hepatocellular carcinoma

AIM To investigate the role of macrophage colony-stimulating factor (M-CSF) in patients with hepatocellular carcinoma (HCC) after surgery. METHODS Expression of M-CSF, distribution of M2 macrophages (MΦs), and angiogenesis were assessed in the liver, including tumors and peritumoral liver tissues. The prognostic power of these factors was assessed. Mouse isolated hepatic MΦs or monocytes were cultured with media containing M-CSF. The concentration of vascular endothelial growth factor (VEGF) in media was assessed. Furthermore, the role of the M-CSF-matured hepatic MΦs on proliferation of the vascular endothelial cell (VEC) was investigated. RESULTS A strong correlation between the expressions of M-CSF and CD163 was observed in the peritumoral area. Also, groups with high density of M-CSF, CD163 or CD31 showed a significantly shorter time to recurrence (TTR) than low density groups. Multivariate analysis revealed the expression of M-CSF or hepatic M2MΦs in the peritumoral area as the most crucial factor responsible for shorter TTR. Moreover, the expression of M-CSF and hepatic M2MΦs in the peritumoral area had better predictable power of overall survival. Values of VEGF in culture media were significantly greater in the hepatic MΦs compared with the monocytes. Proliferation of the VEC was greatest in the cells co-cultured with hepatic MΦs when M-CSF was present in media. CONCLUSION M-CSF increases hepatocarcinogenesis, most likely by enhancing an angiogenic factor derived from hepatic MΦ and could be a useful target for therapy against HCC.

miR-122-5p as a novel biomarker for alpha-fetoprotein-producing gastric cancer

AIM To investigate the clinical utility of alpha-fetoprotein (AFP)-producing gastric cancer (AFPGC)-specific microRNA (miRNA) for monitoring and prognostic prediction of patients. METHODS We performed a comprehensive miRNA array-based approach to compare miRNA expression levels between AFP-positive and AFP-negative cells in three patients with primary AFPGC. We next examined the expression levels of the selected miRNAs in five AFPGC and ten non-AFPGC tissue samples by quantitative reverse transcription-polymerase chain reaction to validate their utility. We also investigated the expression levels of the selected miRNA not only in tissue but also in plasma samples. Moreover, we investigated the relationship between plasma AFP levels and plasma selected miRNA expression levels, and also investigated the correlation of the selected miRNA expression levels and malignant potential. RESULTS Among the five miRNAs selected from the miRNA array results, the expression levels of miR-122-5p were significantly higher in the AFPGC patients than in the non-AFPGC patients (P < 0.05). In tissue samples, miR-122-5p expression level tended to be lower in the non-AFPGC tissue than the normal gastric mucosa. Conversely, in the AFPGC tissue, miR-122-5p expression level was significantly higher in the AFPGC tissue than both the normal gastric mucosa and the non-AFPGC tissue samples (P < 0.05). Plasma miR-122-5p expression levels were also significantly higher in the AFPGC patients than the health volunteers and the non-AFPGC patients (P < 0.05) and were strongly correlated with plasma AFP levels (r = 0.7975, P < 0.0001). Moreover, the correlation of miR-122-5p expression in tissue samples with malignant potential was stronger than that of plasma AFP level in the AFPGC patients. In contrast, no correlation was found between miR-122-5p expression levels and liver metastasis in the non-AFPGC patients. CONCLUSION miR-122-5p might be a useful biomarker for early detection and disease monitoring in AFPGC.

Clinical Impact of Histological Heterogeneity in the Metastatic Lymph Nodes of Patients with Colorectal Cancer

Aim: The purpose of this study was to evaluate the clinical impact of histological heterogeneity in patients with node-positive colorectal cancer (CRC). Patients and Methods: One hundred and twenty-nine patients who underwent curative surgical resection for histological node-positive CRC were enrolled. Patients were divided according to the histological heterogeneity in the primary lesion into p-hetero and p-homo groups. The p-hetero group was further divided according to histological heterogeneity in the metastatic lymph nodes into n-hetero and n-homo groups. Results: There were no significant differences between p-homo and p-hetero groups and between n-homo and n-hetero groups in prognosis. However, the recurrence-free survival rate of the n-homo group was significantly lower than that of the n-hetero group in the N2 category. Conclusion: Histological heterogeneity in metastatic lymph nodes may be useful for predicting prognosis, and prognosis in those with histological heterogeneity in a metastatic lymph node is not necessarily poor, even in those of the N2 category.

A huge primary peritoneal papillary adenocarcinoma which demonstrated imaging findings similar to those of extrahepatic-growing type hepatic tumor: Report of a case

We herein report a 69-year-old woman who presented with a huge intra-abdominal tumor which demonstrated imaging findings similar to those of extrahepatic-growing type hepatic tumor, but turned out to be primary peritoneal papillary adenocarcinoma. Computed tomography showed a well-demarcated mass, measuring 12.0 cm in diameter, which came in contact with the lateral segment of the liver and invaded the diaphragm and abdominal wall. Distant lymph node metastasis was also detected. A fine-needle aspiration biopsy of the tumor showed poorly differentiated adenocarcinoma of unknown origin. After chemotherapy with 5-fluorouracil and cisplatin, the maximal diameter of the tumor decreased to 6.0 cm. The patient then underwent a tumorectomy together with a lateral segmentectomy of the liver, a splenectomy, a partial resection of the diaphragm and abdominal wall, and a left oophorectomy. Histological and immunohistochemical examinations demonstrated the tumor to be primary peritoneal papillary adenocarcinoma.