Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice.

BACKGROUND & AIM: Hydrogen peroxide-inducible clone-5 (Hic-5), also named as transforming growth factor beta-1-induced transcript 1 protein (Tgfb1i1), was found to be induced by TGF-ß. Previous studies have shown that TGF-ß is a principal mediator of hepatic stellate cell (HSC) activation in liver fibrosis. However, this process remains elusive. In this study, we aimed to define the role of Hic-5 in HSC activation and liver fibrosis. METHODS: We examined the expression levels of Hic-5 during HSCs activation and in fibrotic liver tissues by quantitative real-time reverse transcriptase polymerase chain reaction, Western blot and immunohistochemistry. Hic-5 knockout (KO) and wild-type (WT) mice were subjected to bile duct ligation (BDL) or carbon tetrachloride (CCl4) injection to induce liver fibrosis. RESULTS: Hic-5 expression was strongly upregulated in activated HSCs of the human fibrotic liver tissue and BDL or CCl4-induced mouse liver fibrosis. Hic-5 deficiency significantly attenuated mouse liver fibrosis and HSC activation. Furthermore, Hic-5 knockdown by siRNA in vivo repressed CCl4-induced liver fibrosis in mice. Mechanistically, the absence of Hic-5 significantly inhibited the TGF-ß/Smad2 signaling pathway, proved by increasing Smad7 expression, resulting in reduced collagen production and α-smooth muscle actin expression in the activated HSCs. CONCLUSION: Hic-5 deficiency attenuates the activation of HSCs and liver fibrosis though reducing the TGF-ß/Smad2 signaling by upregulation of Smad7. Thus, Hic-5 can be regarded as a potential therapeutic target for liver fibrosis.

Malignant peritoneal mesothelioma with lymph node metastasis that originated in the transverse colon.

BACKGROUND: We report an extremely rare case of resection of localized biphasic malignant peritoneal mesothelioma of the transverse colon. CASE REPORT: Computed tomography and magnetic resonance imaging in a 72-year-old man showed a tumor with enhanced borders consistent with the transverse colon. Colonoscopy showed ulcerative lesions in the transverse colon, but histological examination showed no malignancy. A gastrointestinal stromal tumor was strongly suspected, so an extended right hemicolectomy was performed. Histopathological examination showed that the tumor was a localized malignant peritoneal mesothelioma of the transverse colon. The patient did not receive postoperative chemotherapy and died 18 months after surgery. CONCLUSIONS: The number of patients with malignant mesotheliomas is predicted to increase in the future both in Japan and in western countries. We report this case due to its probable usefulness in future studies pertaining to the diagnosis and treatment of malignant mesotheliomas.

[A case of severe enteritis induced by adjuvant chemotherapy for colon cancer].

A 77-year-old man underwent surgery for sigmoid colon cancer. He was diagnosed with Stage IIIa colon cancer; there- fore, we initiated oral administration of adjuvant chemotherapy comprising uracil/tegafur(UFT)plus Leucovorin(LV). However, chemotherapy was stopped after 21 days because of fatigue and diarrhea. He recovered after 3 weeks, and we administered the same regimen with a dose reduction. However, he again experienced fatigue and diarrhea after 20 days; therefore, chemotherapy was discontinued. Subsequently, he was hospitalized 8 times for conditions such as diarrhea, hypoalbuminemia, and fever. Computed tomography revealed thickening of the transverse colonic wall and colonoscopy revealed colitis, which we believe was induced by UFT plus LV. Twelve months after the last chemotherapy session, he was diagnosed with Clostridium difficile colitis. Therefore, we initiated the oral administration of vancomycin, which resulted in rapid recovery from colitis. However, he developed liver metastasis and died 29 months after the initiation of chemotherapy. We believe that this severe case of intractable colitis was caused by UFT plus LV. Therefore, we report this case with a review of the literature on enteritis induced by fluorouracil-based anticancer agents in Japan.

[A case of cecal cancer with abdominal wall abscess].

A 63-year-old woman was admitted to our hospital for a palpable mass and abdominal pain. Abdominal CT showed an abscess in the abdominal wall and a contiguous mass in the intraperitoneal cavity. After drainage of the abscess was performed, we conducted a colonoscopy to investigate the cause of the mass. It revealed a type 2 tumor and a whole-circumferential stenosis in the cecum. It required preoperative chemotherapy with CPT-11 and S-1 to achieve radical cure characteristics with the operation. Because there was tumor reduction, right hemicolectomy and resection of the abdominal wall were performed. The patient was discharged 15 days after the operation with an eventful clinical course. Although 5 years have passed since the operation, she is alive and has had no recurrence. This patient accepted tumor reduction by chemotherapy , and the abdominal wall deficit that resulted from excision did not have it was it with a small range, and to rebuild the abdominal wall. The utility of preoperative chemotherapy is recommended in colon cancer which invades other organs.

Hic-5 is required for activation of pancreatic stellate cells and development of pancreatic fibrosis in chronic pancreatitis.

Accumulated evidence suggests that activated pancreatic stellate cells (PSCs) serve as the main source of the extracellular matrix proteins accumulated under the pathological conditions leading to pancreatic fibrosis in chronic pancreatitis (CP). However, little is known about the mechanisms of PSC activation. PSCs have morphologic and functional similarities to hepatic stellate cells, which are activated by hydrogen peroxide-inducible clone-5 (Hic-5), a TGF-ß1-induced protein. In this study, we investigated whether Hic-5 activates PSCs, which promote pancreatic fibrosis development in CP. Hic-5-knockout and wild type mice were subjected to caerulein injection to induce CP. Hic-5 expression was strongly upregulated in activated PSCs from human CP tissue and from mouse pancreatic fibrosis in caerulein-induced CP. Hic-5 deficiency significantly attenuated mouse pancreatic fibrosis and PSC activation in the experimental murine CP model. Mechanistically, Hic-5 knock down significantly inhibited the TGF-ß/Smad2 signaling pathway, resulting in reduced collagen production and α-smooth muscle actin expression in the activated PSCs. Taken together, we propose Hic-5 as a potential marker of activated PSCs and a novel therapeutic target in CP treatment.

The impact of stromal Hic-5 on the tumorigenesis of colorectal cancer through lysyl oxidase induction and stromal remodeling.

Carcinoma-associated fibroblasts (CAFs) influence tumor initiation, progression, and metastasis within the tumor-associated stroma. This suggests that CAFs would be a potential target for tumor therapy. Here we found that Hydrogen peroxide-inducible clone-5 (Hic-5), also named transforming growth factor beta-1-induced transcript 1 protein (Tgfb1i1), was strongly induced in CAFs found in human colorectal cancer. To investigate the role of Hic-5 in CAFs, we isolated CAFs and the control counterpart normal fibroblasts (NFs) from human colorectal cancer and non-cancerous regions, respectively. Hic-5 was highly expressed in isolated human CAFs and strongly induced in NFs in culture by the supernatant from cultured colorectal cancer cells as well as cytokines such as TGF-ß, IL-1ß and stromal cell-derived factor 1 (SDF-1/CXCL12). Furthermore, tumor growth was inhibited in a co-culture assay with Hic-5 knockdown fibroblasts compared with control fibroblasts. To clarify the function and significance of Hic-5 in colorectal cancer in vivo, we utilized a mouse model of azoxymethane (AOM)-induced colorectal cancer using Hic-5-deficient mice. Lack of Hic-5 in CAFs completely prevented AOM-induced colorectal cancer development in the colon tissues of mice. Mechanistic investigation revealed that Hic-5 promoted the expression of lysyl oxidase and collagen I in human control counterpart fibroblasts. Taken together, these results demonstrate that Hic-5 in CAFs is responsible for orchestrating or generating a tumor-promoting stroma.

Comparison of Clinicopathological Characteristics in the Patients with Cardiac Cancer with or without Esophagogastric Junctional Invasion: A Single-Center Retrospective Cohort Study.

Background. This study addresses clinicopathological differences between patients with gastric cardia and subcardial cancer with and without esophagogastric junctional invasion. Methods. We performed a single-center, retrospective cohort study. We studied patients who underwent curative surgery for gastric cardia and subcardial cancers. Tumors centered in the proximal 5 cm of the stomach were classed into two types, according to whether they did (Ge) or did not (G) invade the esophagogastric junction. Results. A total of 80 patients were studied; 19 (73.1%) of 26 Ge tumors and 16 (29.6%) of 54 G tumors had lymph nodes metastases. Incidence of nodal metastasis in pT1 tumors was significantly higher in the Ge tumor group. No nodal metastasis in cervical lymph nodes was recognized. Only two patients with Ge tumors had mediastinal lymph node metastases. Incidence of perigastric lymph node metastasis was significantly higher in those with Ge tumors. Ge tumors tended to be staged as progressive disease using the esophageal cancer staging manual rather than the gastric cancer staging manual. Conclusion. Because there are some differences in clinicopathological characteristics, it is thought to be adequate to distinguish type Ge from type G tumor.

Prognostic impact of prophylactic splenectomy for upper-third gastric cancer: a cohort study.

AIM: The aim of this study was to investigate the effect of splenectomy on survival outcomes and recurrence in patients who underwent curative surgery for gastric cancer. PATIENTS AND METHODS: This is a retrospective study of 129 patients who underwent upper-third gastric cancer curative resection with lymphadenectomy. Forty-two patients (32%) also underwent splenectomy. RESULTS: The median follow-up period was 33 months. Approximately 40% of the patients had lymph node metastases; four of them had nodal involvement along the splenic artery and 5 had nodal involvement at the splenic hilum. No patients in the pT1-2 group with nodal metastases had involvement of the splenic hilar lymph nodes. There was no significant association between splenectomy and either overall or disease-free survival in the patients. CONCLUSION: Splenectomy should not be performed in patients with pT1-2 tumors for prophylactic lymphadenectomy.

Complete laparoscopic surgery for early colorectal cancer after endoscopic resection.

INTRODUCTION: Laparoscopic-assisted colorectal surgery requires a mini-laparotomy to extract the specimen and insert the anvil head of the circular stapler into the proximal colon. However, such a mini-laparotomy occasionally causes local pain and surgical-site infection. To avoid mini-laparotomy, we invented a new laparoscopic technique, complete laparoscopic surgery for colorectal cancer. MATERIALS AND SURGICAL TECHNIQUE: Sigmoid colon or rectal cancer patients who had undergone colonoscopic excision for T1 cancer and subsequently required bowel resection due to unfavorable histology were recruited. This new procedure used both the double stapling technique and the rectal-prolapsing technique, where the anvil was transanally inserted into the proximal colon and bowel resection was extracorporeally performed after pulling out the colon-rectum via the anus. DISCUSSION: This procedure was attempted in 17 patients and successfully achieved in 13 patients. Total laparoscopic colorectal surgery has some problems such as bacterial contamination or infection, as well as dissemination caused by intraluminal exfoliated cancer cells. This procedure is limited to post-endoscopic resection patients who are suited for reconstruction by double stapling technique, and it may be impossible in patients with thick mesentery or anal stenosis. Moreover, this method resolves issues of peritoneal contamination and dissemination. However, a new protection method for implantation of exfoliated cancer cells needs to be established, so that complete laparoscopic surgery can be employed in patients with small cancers.