Masanobu Nakajima

MiR‐150 is associated with poor prognosis in esophageal squamous cell carcinoma via targeting the EMT inducer ZEB1

The association of microRNAs (miRs) with cancer progression has been established in many cancers including esophageal squamous cell carcinoma (ESCC). A public microarray database showed that the expression of miR‐150 was lower in ESCC than in normal esophageal mucosa. Here, we focused on ZEB1, epithelial‐mesenchymal‐transition (EMT)‐inducer, as a target gene of miR‐150 based on in silico predictions. The purpose of this study was to clarify the clinicopathological significance of miR‐150 in ESCC, and to investigate miR‐150′s EMT‐regulatory ability. Quantitative RT‐PCR was used to evaluate miR‐150 expression in 108 curative resected ESCC samples to determine the clinicopathological significance. Moreover, we examined the in vitro and in vivo function of miR‐150 via degradation of ZEB1. MiR‐150 expression was significantly lower in cancer tissues compared to adjacent non‐cancerous tissues (P < 0.001). Low expression of miR‐150 in ESCC contributed to malignant potential, such as tumor depth, lymph node metastasis, lymphatic invasion, venous invasion, clinical staging, and poor prognosis (P < 0.05). In vitro assays showed that EMT‐inducer‐ZEB1 is a new direct target of miR‐150. Moreover, miR‐150 induced MET‐like changes in TE‐8 cells through ZEB1 degradation (e.g., E‐cadherin expression, vimentin repression, epithelial morphology, and suppression of migration ability), and significantly inhibited tumorigenicity and tumor growth in a mouse xenograft model. Analysis of the regulation of ZEB1 by miR‐150 could provide new insights into preventing metastasis and also suggests novel targeted therapeutic strategies in ESCC. (Cancer Sci 2013; 104: 48–54)

CD47 expression regulated by the miR-133a tumor suppressor is a novel prognostic marker in esophageal squamous cell carcinoma

CD47 inhibits phagocytosis and its overexpression is correlated with poor prognosis in patients with several types of cancer. It has also been reported that CD47 expression in multiple sclerosis is regulated by microRNAs. However, the regulatory mechanism of CD47 in cancer tissues has not been yet clarified. Re-analysis of a public microarray database revealed that miR-133a is downregulated in esophageal squamous cell carcinoma (ESCC). Moreover, inxa0silico algorithms predicted that miR-133a is a regulator of CD47. The purpose of this study was to clarify the clinical significance of CD47 and its regulatory mechanism by miR-133a in ESCC. Quantitative real-time RT-PCR was used to evaluate CD47 and miR-133a expression in 102 cases of curative resected ESCC and adjacent non-cancerous tissue. The regulation of CD47 by miR-133a was examined with precursor miR-133a-transfected cells. A mouse xenograft model was used to investigate the ability of miR-133a to suppress tumor progression. High expression levels of CD47 were associated with lymph node metastasis (P=0.049). Multivariate analysis showed that CD47 expression was an independent prognostic factor (P=0.045). miR-133a expression was significantly lower in cancer tissues compared to adjacent non-cancerous tissues (P<0.001). Inxa0vitro assays showed that miR-133a is a direct regulator of CD47. miR‑133a significantly inhibited tumorigenesis and growth inxa0vivo. CD47 expression is a novel prognostic marker in ESCC that is directly inhibited by the miR-133a tumor suppressor. This correlation could provide new insight into the mechanism of cancer progression and a promising candidate for target therapy in ESCC.

Treatments for esophageal cancer: a review.

Esophageal cancer is the eighth most common form of cancer worldwide. The treatments for esophageal cancer depend on its etiology. For mucosal cancer, endoscopic mucosal resection and endoscopic submucosal dissection are standard, while for locally advanced cancer, esophagectomy remains the mainstay. The three most common techniques for thoracic esophagectomy are the transhiatal approach, the Ivor Lewis esophagectomy (right thoracotomy and laparotomy), and the McKeown technique (right thoracotomy followed by laparotomy and neck incision with cervical anastomosis). Surgery for carcinoma of the cervical esophagus requires an extensive procedure with laryngectomy in many cases. When the tumor is more advanced, neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy is added. The theoretical advantages of adding chemotherapy to the treatment of esophageal cancer are potential tumor down-staging prior to surgery, as well as targeting micrometastases and, thus, decreasing the risk of distant metastasis. Cisplatin- and 5-fluorouracil-based regimes are used worldwide. Chemoradiotherapy is the standard for unresectable esophageal cancer and could also be considered as an option for resectable tumors. For patients who are medically or technically inoperable, concurrent chemoradiotherapy should be the standard of care. Although neoadjuvant chemoradiotherapy followed by surgery or salvage surgery after definitive chemoradiotherapy is a practical treatment; judicious patient selection is crucial. It is important to have a thorough understanding of these therapeutic modalities to assist in this endeavor.

Prognostic significance of CD151 expression in esophageal squamous cell carcinoma with aggressive cell proliferation and invasiveness.

BackgroundCD151 is a member of the tetraspanins and has recently been reported as a promoter of the malignant progression of cancer. The purpose of this study was to clarify the clinicopathological outcome and prognostic significance of the immunohistochemical expression of CD151 in esophageal squamous cell carcinoma (ESCC).MethodsWe evaluated the significance of CD151 expression by immunohistochemistry in 138 surgically resected ESCC and the association of CD151 expression with clinicopathological features.ResultsSeventy-five (51.7%) ESCC showed a positive expression of CD151, which indicated a significant association with tumor depth (Pxa0=xa00.004), lymph node metastasis (Pxa0=xa00.002), distant metastasis (Pxa0=xa00.025), and lymphatic invasion (Pxa0=xa00.046), as well as the Ki-67 labeling index (Pxa0=xa00.011). The 5-year survival rate of ESCC patients with CD151-positive expression was significantly lower than with CD151-negative expression (positive, 43.1%; negative, 63.8%; Pxa0=xa00.003). Multivariate analysis showed that positive CD151 expression was not an independent factor for poor survival (Pxa0=xa00.096).ConclusionsCD151 expression is associated with tumor proliferation and invasiveness in ESCC.

Treatment options for esophageal squamous cell carcinoma

Introduction: The treatment for esophageal squamous cell carcinoma (SCC) depends on its etiology. For mucosal cancer, endoscopic resection is standard; while for locally advanced cancer, esophagectomy is the main treatment. When the tumor is more advanced, neoadjuvant or adjuvant therapy is added. For unresectable cancer, concurrent chemoradiotherapy is the standard therapy. Areas covered: The standard chemotherapy for esophageal SCC is a cisplatin- and 5-fluorouracil (CF)-based regimen. Chemoradiotherapy (CRT) is the standard treatment for unresectable esophageal SCC and is also an option for resectable tumors. For patients who are inoperable, concurrent CRT should be the standard of care. Docetaxel, cisplatin and 5-fluorouracil (DCF) therapy is a promising candidate for chemotherapy with or without radiotherapy because an excellent local control rate and pathological remission rate have been reported. Although salvage surgery after definitive CRT is a practical treatment, judicious patient selection is crucial. Expert opinion: Presently, the standard regimen for esophageal SCC is CF. DCF is expected to be the next standard regimen. In the near future, some new therapeutic options, such as molecular targeted therapy or particle beam therapy, may confer further advantages. A thorough understanding of these therapeutic modalities is important to achieve this endeavor.

MUTYH-associated colorectal cancer and adenomatous polyposis

MUTYH-associated polyposis (MAP) was first described in 2002. MUTYH is a component of a base excision repair system that protects the genomic information from oxidative damage. When the MUTYH gene product is impaired by bi-allelic germline mutation, it leads to the mutation of cancer-related genes, such as the APC and/or the KRAS genes, via G to T transversion. MAP is a hereditary colorectal cancer syndrome inherited in an autosomal-recessive fashion. The clinical features of MAP include the presence of 10–100 adenomatous polyps in the colon, and early onset of colorectal cancer. Ethnic and geographical differences in the pattern of the MUTYH gene mutations have been suggested. In Caucasian patients, c.536A>G (Y179C) and c.1187G>A (G396D) mutations are frequently detected. In the Asian population, Y179C and G396D are uncommon, whereas other variants are suggested to be the major causes of MAP. We herein review the literature on MUTYH-associated colorectal cancer and adenomatous polyposis.

Esophageal granular cell tumor successfully resected by endoscopic submucosal dissection

Granular cell tumors of the esophagus are rare neoplasms and their diagnosis is mainly based on histopathologic examination of endoscopic biopsies. With the development of endoscopic techniques, there has been a marked increase in local treatment modalities for early esophageal neoplasms. In this case report, we describe the removal of a granular cell tumor by the endoscopic submucosal dissection technique, and briefly discuss the literature on clinicopathologic aspects and management of granular cell tumors.

CD24 expression is associated with progression of gastric cancer.

BACKGROUND/AIMSnMortality rates due to gastric cancer are high in Japan. To improve patient prognosis, new biomarkers for diagnosis and treatment are urgently required. In this study we investigated the role of CD24, a cell adhesion glycoprotein implicated in tumor cell proliferation, which is used as a prognostic marker in various cancers.nnnMETHODOLOGYnWe analyzed CD24 expression in 173 gastric adenocarcinomas by immunohistochemistry and compared the data with clinicopathological parameters and patient overall survival. Furthermore, we performed Western blotting analysis of CD24 in six human gastric adenocarcinoma cell lines, Kato III, MKN1, MKN28, MKN45, MKN74, and HGC-27.nnnRESULTSnCD24 up-regulation was significantly correlated with depth of invasion (p=0.005) and pathological high stages (p=0.043). We observed a relationship between high CD24 expression and lymph node metastasis, venous invasion and lymphatic invasion. CD24 expression tended to be higher in cell lines derived from differentiated gastric carcinoma, including those derived from lymph node metastasis.nnnCONCLUSIONSnOur study suggests that gastric cancer patients with high CD24 expression should be closely monitored for recurrence following resections. CD24 expression is a potential biomarker for gastric cancer prognosis and provides a new molecular target for therapeutic strategies.

Ghrelin level and body weight loss after esophagectomy for esophageal cancer.

BACKGROUNDnGhrelin is a peptide hormone predominantly produced by endocrine cells in the oxyntic mucosa of the stomach and is an endogenous ligand for the growth hormone secretagogue receptor. Ghrelin plays an important role in regulating appetite, food intake, and energy metabolism. We investigated the correlation between clinicopathologic factors and plasma ghrelin concentration before and after esophagectomy with gastric tube reconstruction for esophageal cancer treatment.nnnMETHODSnThe study group comprised 25 patients (22 men, three women, age range 46-78 y) with esophageal cancer who underwent esophagectomy with gastric tube reconstruction between 1999 and 2007. Blood samples were collected before and three times after the operation. Plasma concentrations of ghrelin were determined using a sandwich-type enzyme immunoassay kit.nnnRESULTSnPlasma ghrelin concentrations were significantly decreased to 38.7% of the preoperative concentration at postoperative d 7. Plasma ghrelin concentrations recovered slightly over 6-24 mo postoperatively. After 36 mo or longer, ghrelin concentrations had returned to preoperative levels. There was no relationship between ghrelin concentrations and gender, location of tumor, tumor stage, operative procedure, and reconstruction route at each time point. There was a significant relationship between the decrease in body mass index and decrease in plasma ghrelin in patients at 6-24 mo after esophagectomy (P < 0.01).nnnCONCLUSIONSnPlasma ghrelin concentrations decrease on a temporary basis after esophagectomy with gastric tube reconstruction and are associated with body weight loss after surgery.

Significance of Lymph Node Capsular Invasion in Esophageal Squamous Cell Carcinoma

BackgroundExtranodal invasion (ENI) has been reported to be associated with a poor prognosis in several malignancies. However, previous studies have included perinodal fat tissue tumor deposits in their definitions of ENI. To investigate the precise nature of ENI in esophageal squamous cell carcinoma (ESCC), we excluded these tumor deposits from our definition of ENI and defined tumor cell invasion through the lymph node capsule and into the perinodal tissues as lymph node capsular invasion (LNCI). The aim of the current study was to elucidate the significance of LNCI in ESCC.MethodsWe investigated the associations between LNCI and other clinicopathologic features in 139 surgically resected ESCC. We also investigated the prognostic significance of LNCI in ESCC.ResultsLNCI was detected in 35 (25.2%) of 139 patients. The overall survival rate of the ESCC patients with LNCI was significantly lower than that of the ESCC patients with lymph node metastasis who were negative for LNCI. The survival difference between the patients with 1–3 lymph node metastases without LNCI and those with no lymph node metastasis was not significant. LNCI was significantly associated with distant organ recurrence. LNCI was also found to be an independent predictor of overall survival in addition to the number of lymph node metastases.ConclusionsLNCI in ESCC patients is an indicator of distant organ recurrence and a worse prognosis. LNCI could be used as a candidate marker for designing more precise staging and therapeutic strategies for ESCC.