Concurrent Overexpression of Two Hyaluronidases, KIAA1199 and TMEM2, Strongly Predicts Shorter Survival After Resection in Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is characterized by accelerated hyaluronan metabolism. Our previous studies have shown increased expression of 2 newly identified hyaluronidases, KIAA1199 and transmembrane protein 2 (TMEM2), in PDAC. However, the relationship between these 2 hyaluronidases is unknown. In the present study, we investigated the correlation between KIAA1199 and TMEM2 expression in PDAC. METHODS: Using quantitative real-time reverse transcription polymerase chain reaction, we analyzed KIAA1199 and TMEM2 mRNA expression in 11 PDAC cell lines and frozen tissues from 12 patients with PDAC. We used immunohistochemistry to investigate expression patterns of KIAA1199 and TMEM2 in archival tissues obtained from 92 patients with PDAC who underwent surgical resection. We compared survival between 4 groups according to expression patterns of KIAA1199 and TMEM2. RESULTS: We found a significantly positive correlation between KIAA1199 and TMEM2 mRNA in PDAC cell lines and tissues. Immunohistochemical analysis found that median overall survival was 30.2 months in patients with low expression of KIAA1199 and TMEM2 and 12.5 months in those with high expression of both. Patients with high expression of KIAA1199 and TMEM2 had significantly shorter survival than other patient groups. CONCLUSIONS: Concurrent overexpression of these 2 hyaluronidases could be a strong prognostic marker in PDAC.

Prognostic and functional role of hyaluronan-binding protein 1 in pancreatic ductal adenocarcinoma.

Hyaluronan-binding protein 1 (HABP1) is among the molecules known to bind to hyaluronan and is involved in a variety of cellular processes, including cell proliferation and migration. HABP1 has been implicated in the progression of various cancers; however, there have been (to the best of our knowledge) few studies on the expression and function of HABP1 in pancreatic ductal adenocarcinoma (PDAC), a topic that is examined in the present study. Immunohistochemical analysis of HABP1 protein was conducted in archival tissues from 105 patients with PDAC. Furthermore, the functional effect of HABP1 on proliferation, colony formation, and migration in PDAC cells was examined by knockdown of HABP1. It was revealed that HABP1 was overexpressed in 49 (46.2%) out of 105 patients with PDAC. Overall survival was significantly shorter in patients with high HABP1 expression than in those with low HABP1 expression (median survival time of 12.8 months vs. 28.5 months; log-rank test, P=0.004). Knockdown of HABP1 expression in PDAC cells resulted in decreased cell proliferation, colony formation, and cell migration activity. Thus, HABP1 may serve as a prognostic factor in PDAC and may be of use as a novel therapeutic target.

Hypoxia increases KIAA1199/CEMIP expression and enhances cell migration in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterised by dense desmoplasia and hypoxic microenvironment. Our previous reports demonstrated that hyaluronan (HA), especially low-molecular-weight HA, provides a favourable microenvironment for PDAC progression. However, the effect of hypoxia on HA metabolism remains unknown. Using quantitative real-time RT-PCR and western blot analysis, we analysed the changes in the expression of HA-synthesizing enzymes (HAS2 and HAS3) and HA-degrading enzymes (HYAL1, KIAA1199/CEMIP) in PDAC cell lines under hypoxic conditions. Hypoxia increased the mRNA and protein expression of KIAA1199, whereas it decreased HYAL1 expression. The expression of HAS3 was increased and HAS2 remained unchanged in response to hypoxia. The effect of KIAA1199 on hypoxia-induced cell migration was determined using a transwell migration assay and small-interfering RNA (siRNA). Hypoxia enhanced the migratory ability of PDAC cells, which was inhibited by KIAA1199 knockdown. We also used immunohistochemistry to analyse the protein expression of hypoxia inducible factor (HIF) 1α and KIAA1199 in PDAC tissues. There was a significant immunohistochemically positive correlation between KIAA1199 and HIF1α. These findings suggest that hypoxia-induced KIAA1199 expression may contribute to enhanced motility in PDAC.

Overexpression of transmembrane protein 2 (TMEM2), a novel hyaluronidase, predicts poor prognosis in pancreatic ductal adenocarcinoma.

BACKGROUND: Abnormal metabolism of hyaluronan (HA), a major component of extracellular matrix, is a hallmark of cancer. Our previous studies have shown the importance of enzymes responsible for HA degradation in the aggressive phenotype of pancreatic ductal adenocarcinoma (PDAC). In the present study, we investigated the expression and function of transmembrane protein 2 (TMEM2), a recently identified HA-degrading enzyme, in PDAC. MATERIALS & METHODS: We used immunohistochemistry to investigate expression patterns of TMEM2 in archival tissues obtained from 100 patients with PDAC who underwent surgical resection from 1982 to 2012. The correlations between TMEM2 expression and clinicopathological variables, including survival, were determined using univariate and multivariate analyses. The effect of TMEM2 on proliferation and migratory ability (measured using transwell cell migration assay) of PDAC cells was determined by TMEM2 knockdown with small-interfering RNA (siRNA). RESULTS: Immunohistochemical analysis revealed high expression of TMEM2 in 22 (22%) of 100 patients. The overall survival was significantly shorter in patients with high TMEM2 expression than in those with low expression (P = 0.013). Multivariate analysis identified high TMEM2 expression as an independent factor predicting poor prognosis (P = 0.011). Unexpectedly, knockdown of TMEM2 resulted in increased migratory ability of PDAC cells, which was associated with increased expression of KIAA1199, a potent HA-degrading enzyme shown to enhance cell migration. CONCLUSION: TMEM2 overexpression is associated with poor prognosis in PDAC patients. Targeted disruption of this molecule, however, could enhance the aggressiveness of PDAC cells through a possible interaction with KIAA1199.

A Case of Retroperitoneal Paraganglioma.

We report a surgical case of retroperitoneal paraganglioma. A paraganglioma is a catecholamine-producing tumor originating in the chromaffin cells of the sympathetic ganglion. It is a kind of pheochromocytoma which occurs on the outside of the adrenal gland. The patient was a 72 year old male with a history of hypertension and a pacemaker implantation. A mass in the ventral side of the right iliopsoas muscle was detected during a routine contrasting computed tomography (CT) examination for checking his pacemaker. The mass was considered to be malignant, and a laparotomy and mass enucleation was performed. It was diagnosed as phaeochromocytoma, based on the pathology and immunestology of the excised specimen. The hypertension was cured soon after the surgery. Nine months after surgery, there is no evidence of any abnormality or recurrence. There is a previous report of a recurrence 25 years after surgery, so a careful follow-up of this patient will be necessary in the future.

Validity of the management strategy for intraductal papillary mucinous neoplasm advocated by the international consensus guidelines 2012: a retrospective review.

PURPOSE: The aim of this study was to investigate the validity of the management strategy for intraductal papillary mucinous neoplasms (IPMNs) advocated by the international consensus guidelines 2012 (ICG2012). METHODS: The medical records of 49 patients who underwent pancreatectomy for IPMN were retrospectively reviewed. RESULTS: According to preoperative imaging, 10 patients (20 %) had main-duct IPMNs, 20 (41 %) had mixed IPMNs, and 19 (39 %) had branch-duct IPMNs, with malignancy frequencies of 80, 15, and 37 %, respectively. Twenty-seven patients had high-risk stigmata and 21 had worrisome features, with malignancy frequencies of 59 and 10 %, respectively. The sensitivity, specificity, and positive and negative predictive values of high-risk stigmata for malignancy were 88, 65, 59, and 91 %, respectively. Lesions were malignant in 88 % of patients with an enhanced solid component, which was significantly correlated with the prevalence of malignancy (P < 0.01). However, of the 10 patients who underwent pancreatectomy solely due to a main pancreatic dilation of ≥10 mm, 9 (90 %) had benign IPMNs. CONCLUSIONS: Many mixed IPMNs defined according to ICG2012 are benign. Although the management strategy advocated by ICG2012 has been improved relative to the Sendai criteria, the different high-risk stigmata carry unequal weights. Consequently, ICG2012 remains suboptimal for predicting malignant IPMN.