Cutaneous acantholytic dyskeratotic acanthoma accompanying syringofibroadenomatous hyperplasia with proliferation of mature sebocytes: A case report.

Acantholytic dyskeratotic acanthoma is a rare variant of epidermal acanthoma. It has a flat, plaque-like structure and is characterized microscopically by acantholysis and dyskeratosis. Eccrine syringofibroadenomatous hyperplasia is benign and likely reactive. It has recently been considered as a hyperplastic process affecting the eccrine ducts rather than the neoplasm because of its pathological heterogeneity and wide clinical associations. In this article, we present the case of 97-year-old Japanese women with a 10-mm wide, painful acantholytic dyskeratotic acanthoma accompanied by syringofibroadenomatous hyperplasia in the right femoral region. Although syringofibroadenomatous hyperplasia is known to occur as a reactive process with various dermatoses and cutaneous tumors, to date, there have been no reports of cases of acantholytic dyskeratotic acanthoma accompanying syringofibroadenomatous hyperplasia. Moreover, this case also includes the unusual finding of an increase in the mature sebocytes in the area of the syringofibroadenomatous hyperplasia.

Fibroblast growth factor-2-mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma.

In esophageal squamous cell carcinoma (ESCC), a subset of cells defined by high expression of CD44 and low expression of CD24 has been reported to possess characteristics of cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. Although fibroblast growth factor-2 (FGF-2) expression correlates with recurrence and poor survival in ESCC patients, the role of FGF-2 in regulation of ESCC CSCs has yet to be elucidated. We report that FGF-2 is significantly upregulated in CSCs and significantly increases CSC content in ESCC cell lines by inducing epithelial-mesenchymal transition (EMT). Conversely, the FGFR inhibitor, AZD4547, sharply diminishes CSCs via induction of mesenchymal-epithelial transition. Further experiments revealed that MAPK/Erk kinase (Mek)/extracellular signal-regulated kinases (Erk) pathway is crucial for FGF-2-mediated CSC regulation. Pharmacological inhibition of FGF receptor (FGFR)-mediated signaling via AZD4547 did not affect CSCs in Ras mutated cells, implying that Mek/Erk pathway, downstream of FGFR signaling, might be an important regulator of CSCs. Indeed, the Mek inhibitor, trametinib, efficiently suppressed ESCC CSCs even in the context of Ras mutation. Consistent with these findings in vitro, xenotransplantation studies demonstrated that inhibition of FGF-2-mediated FGFR/Erk signaling significantly delayed tumor growth. Taken together, these findings indicate that FGF-2 is an essential factor regulating CSCs via Mek/Erk signaling in ESCC. Additionally, inhibition of FGFR and/or Mek signaling represents a potential novel therapeutic option for targeting CSCs in ESCC.

Podocalyxin-like protein, linked to poor prognosis of pancreatic cancers, promotes cell invasion by binding to gelsolin.

The cell-adhesion glycoprotein PODXL is associated with an aggressive tumor phenotype in several forms of cancer. Here, we report that high PODXL expression was an independent predictor of worse overall survival of pancreatic cancer patients, and that PODXL promoted pancreatic cancer cell motility and invasion by physically binding to the cytoskeletal protein gelsolin. Suppression of PODXL or gelsolin decreased membrane protrusions with abundant peripheral actin structures, and in turn inhibited cell motility and invasion. Transfection of a PODXL-rescue construct renewed the expression of gelsolin bound to peripheral actin structures in cell protrusions, and abrogated the decreased cell protrusions caused by the knockdown of PODXL. Furthermore, transfection of a PODXL-rescue construct into pancreatic cancer cells in which both PODXL and gelsolin were suppressed failed to increase the formation of the protrusions. Thus, PODXL enhances motility and invasiveness through an increase in gelsolin-actin interactions in cell protrusions.

Vav3 is linked to poor prognosis of pancreatic cancers and promotes the motility and invasiveness of pancreatic cancer cells.

BACKGROUND/OBJECTIVES: The aim of this study was to investigate the role of the guanine nucleotide exchange factor Vav3 in the motility and invasiveness of pancreatic ductal adenocarcinoma (PDAC) cells. METHODS: Immunohistochemistry was used to determine whether high Vav3 expression in human PDAC tissues is correlated with poor prognosis. Immunocytochemistry was used to determine the association and intracellular distribution of Vav3, Rac1 and Akt in PDAC cells. Phosphoprotein array analysis was performed to determine the Vav3-associated intracellular signaling pathways. Immunocytochemistry and Matrigel invasion assays were used to examine the effects of Vav3 on the formation of cell protrusions and PDAC cell invasion. RESULTS: Expression of Vav3 in PDAC tissue was significantly correlated with overall survival. Vav3 was localized in cell protrusions of migrating PDAC cells. Knockdown of Vav3 inhibited the motility and invasiveness of PDAC cells through a decrease in cell protrusions. The levels of active Rac1 or active Akt were not associated with the concentration of Vav3 in cell protrusions. The Vav3-dependent promotion of motility and invasiveness was not modulated by Rac1 or Akt. Additionally, knockdown of Vav3 increased phosphorylated WNK1 in PDAC cells, and knockdown of WNK1 inhibited the motility and invasiveness. This study suggests that Vav3 can be a useful marker for predicting the outcome of patients with PDAC and that Vav3 can promote PDAC cell motility and invasion through association with dephosphorylation of WNK1. CONCLUSIONS: Vav3 was accumulated in cell protrusions, contributed to the formation of membrane protrusions, and thereby increased the motility and invasiveness of PDAC cells.

Expression of microRNAs associated with Gleason grading system in prostate cancer: miR-182-5p is a useful marker for high grade prostate cancer.

BACKGROUND: Expression profiles of some microRNAs (miRNAs) were associated with clinicopathological findings in human prostate cancer (PC), but the relative expression of miRNAs among Gleason patterns (GPs) remains unclear. In this study, we investigated the expression of several known microRNAs in each GP of PC. METHODS: Formalin-fixed, paraffin embedded (FFPE) tissue samples were obtained from radical prostatectomy (RP) (patient set 1, n = 43, including (GP 3) n = 22, (GP 4) n = 35, and (GP 5) n = 12) and needle biopsy (patient set 2, n = 10, (GP 4) n = 10). Cancer tissues from each GP and adjacent normal counterparts were separately collected using laser-captured microdissection (LCM). Real-time RT-PCR was performed to determine the relative expression of miRNAs, including miR-31-5p, -34c-5p, -96-5p, -182-5p, -183-5p, -205-5p, -221-3p, and -222-3p, which were currently reported to be involved in PC progression. RESULTS: In radical prostatectomy samples, relative expression of miR-31-5p, miR-34c-5p, and miR-205-5p in any GP was significantly decreased compared to normal counterpart. However, no significant difference was detected among GP 3, GP 4, and GP 5. Meanwhile, in the same GP4, expression of miR-31-5p miR-182-5p, and miR-205-5p in cancer tissues obtained from high grade cancer was significantly higher than those obtained from intermediate grade cancer. Validation study using biopsy samples revealed that the relative expression of miR-182-5p was statistically higher in high grade cancer even in same GP4. CONCLUSIONS: We confirmed the expression of miR-182-5p depended on the cancer grade even in same GP 4. Expression of miRNA associated with Gleason grading system may contribute to more accurate preoperative cancer risk evaluation.

Hypoxia induces IGFBP3 in esophageal squamous cancer cells through HIF-1α-mediated mRNA transcription and continuous protein synthesis.

Insulin-like growth factor binding protein (IGFBP)-3 regulates cell proliferation and apoptosis in esophageal squamous cell carcinoma (ESCC) cells. We have investigated how the hypoxic tumor microenvironment in ESCC fosters the induction of IGFBP3. RNA interference experiments revealed that hypoxia-inducible factor (HIF)-1α, but not HIF-2α, regulates IGFBP3 mRNA induction. By chromatin immunoprecipitation and transfection assays, HIF-1α was found to transactivate IGFBP3 through a novel hypoxia responsive element (HRE) located at 57 kb upstream from the transcription start site. Metabolic labeling experiments demonstrated hypoxia-mediated inhibition of global protein synthesis. 7-Methyl GTP-cap binding assays suggested that hypoxia suppresses cap-dependent translation. Experiments using pharmacological inhibitors for mammalian target of rapamycin (mTOR) suggested that a relatively weak mTOR activity may be sufficient for cap-dependent translation of IGFBP3 under hypoxic conditions. Bicistronic RNA reporter transfection assays did not validate the possibility of an internal ribosome entry site as a potential mechanism for cap-independent translation for IGFBP3 mRNA. Finally, IGFBP3 mRNA was found enriched to the polysomes. In aggregate, our study establishes IGFBP3 as a direct HIF-1α target gene and that polysome enrichment of IGFBP3 mRNA may permit continuous translation under hypoxic conditions.

Establishment of a mouse model of pancreatic cancer using human pancreatic cancer cell line S2-013-derived organoid.

A well-established preclinical model of pancreatic cancer needs to be established to facilitate research on new therapeutic targets. Recently established animal models of pancreatic cancer, including patient-derived tumor models and organoid models, are used for pre-clinical drug testing and biomarker discovery. These models have useful characteristics over conventional xenograft mouse models based on cell lines in preclinical studies, but still cannot accurately predict the clinical outcomes of new treatments and have not yet been broadly implemented in research. We employed pancreatic cancer organoid culture methods using the pancreatic cancer cell line S2-013, and performed pathological and immunohistochemical analyses to characterize tumor xenografts obtained from a mouse model implanted with S2-013 cell line-derived organoids. Serum levels of the pancreatic cancer tumor marker CA19-9 were measured by ELISA. We generated human pancreatic cancer organoids using a co-culture of S2-013 cells, human endothelial cells derived from human umbilical vein endothelial cells, and human mesenchymal stem cells, and established a mouse model with subcutaneously transplanted human pancreatic cancer organoids (S2-013-organoid model). Although blood clotting crater-like formation developed in the middle of subcutaneous xenografts in the S2-013-conventional model, created by subcutaneously injecting S2-013 cells into the right flank of nude mice, the size of xenografts in the S2-013-organoid model gradually increased without crater-like formation. Importantly, tumor xenografts obtained from the S2-013-organoid model exhibited a clinical human pancreatic cancer tissue-like cellular morphology, tissue architecture, and polarity, and actively formed cancer stroma containing mature blood vessels with the high expression of the vascular tight junction marker CD31. In subcutaneous xenografts of S2-013-conventional mice, no blood vessel density or widely expanding areas of necrotic regions were present. Consequently, serum levels of CA19-9 in the S2-013-organoid model correlated with tumor volumes. In addition, epithelial-mesenchymal transition, the conversion of epithelial cells to the mesenchymal phenotype, was observed in tumor xenografts of the S2-013-organoid model. The S2-013-organoid model provides tumor xenografts consisting of clinical human pancreatic cancer-like tissue formation with the effective development of vascularized stroma, and may be valuable for facilitating studies on pre-clinical drug testing and biomarker discovery.

Upregulation of PODXL and ITGB1 in pancreatic cancer tissues preoperatively obtained by EUS-FNAB correlates with unfavorable prognosis of postoperative pancreatic cancer patients.

The upregulation of PODXL and ITGB1 in surgically resected pancreatic cancer tissues is correlated with an unfavorable postoperative prognosis. The aim of this study was to investigate whether PODXL and ITGB1 are useful preoperative markers for the prognosis of postoperative pancreatic cancer patients in comparison with the TNM staging system. Immunohistochemistry was performed using anti-PODXL and anti-ITGB1 antibodies on 24 pancreatic cancer tissue samples preoperatively obtained by endoscopic ultrasound-guided fine-needle aspiration biopsy. Cox proportional hazards regression analysis was performed to investigate if the UICC TNM stage and upregulation of PODXL and ITGB1 were correlated with postoperative overall survival rates. Univariate analysis revealed that PODXL, TNM stage, lymphatic invasion and the combination of PODXL with ITGB1 are correlated with postoperative survival. Multivariate analysis demonstrated TNM stage and the combination of PODXL with ITGB1 to be correlated with postoperative survival, and the combination of PODXL with ITGB1 most accurately predicted the postoperative outcomes of pancreatic cancer patients before resection. Therefore, upregulation of PODXL and ITGB1 may indicate preoperative neoadjuvant therapy for pancreatic cancer patients by accurately predicting the postoperative prognosis.

Regulation of microRNA expression by hepatocyte growth factor in human head and neck squamous cell carcinoma.

Hepatocyte growth factor (HGF) is a multifunctional molecule that acts as mitogen, motogen, and/or morphogen in a variety of cells. MET, a specific receptor tyrosine kinase for HGF, is upregulated in various tumors including squamous cell carcinoma of the human head and neck (HNSCC), but how HGF affects the expression of downstream functional genes has not yet been elucidated in detail. In the present study, we examined the expression of microRNA (miRNA), non-coding small RNA that regulate cell proliferation and functions by interfering with the translation of target mRNA, with or without HGF stimulation in HNSCC cell line HSC3. Among several miRNAs, in which the expression was altered after HGF stimulation, we focused on miR-200c and miR-27b, both of which were drastically downregulated after HGF stimulation. Expression of ZEB1, a target mRNA for miR-200c, was upregulated 3 and 6 h after HGF stimulation, and that of E-cadherin, a downstream molecule of ZEB1, was downregulated 12 h after HGF stimulation. Expression of ST14/matriptase, an enzyme for extracellular matrix (ECM) degradation and HGF activation and a target mRNA for miR-27b, was drastically upregulated in the protein level after HGF stimulation, although it was not statistically altered in the mRNA level. These results suggest that miR-200c and miR-27b downregulated by HGF might play an important role in epithelial-mesenchymal transition mediated by ZEB1/E-cadherin and ECM degradation and HGF autoactivation mediated by ST14/matriptase, respectively. Altered expression of miRNA directly regulated by HGF might contribute enhanced progressive and invasive characteristics of HNSCC by regulating the translation of HGF-induced functional molecules.

Ruptured mucinous cystic neoplasm with an associated invasive carcinoma of pancreatic head in a pregnant woman: report of a case and review of literature.

Mucinous cystic neoplasm (MCN) of the pancreas is characterized by mucin-producing columnar epithelium and an ovarian-type stroma. It occurs almost exclusively in women and is almost always located in the pancreatic body or tail. Here, we report a case of large MCN located in the pancreatic head but not in the body nor tail in a 32-year-old pregnant woman, which was thought to have grown rapidly during pregnancy. It was ruptured at 34 weeks of gestation and the patient was admitted to the emergency department of the University of Fukui Hospital with an acute abdomen. Emergency cesarean section followed by pancreaticoduodenectomy was performed. The tumor consisted of many small cysts lined by a single-layer of mucinous epithelium with papillary growth and partial solid parts showing invasive growth and sarcomatoid changes, indicating mucinous cystic neoplasm with an associated invasive carcinoma (previously referred as mucinous cystadenocarcinoma). Thickened septa revealed ovarian-type stroma strongly positive for α-inhibin and partly positive for progesterone receptor immunohistochemically. We also review and discuss previous reports of MCNs including those with an associated invasive carcinoma in pregnant patients.

FGFR2 maintains cancer cell differentiation via AKT signaling in esophageal squamous cell carcinoma.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are important for signaling to maintain cancer stem-like cells (CSCs) in esophageal squamous cell carcinoma (ESCC). However, which FGF receptor, 1, 2, 3, 4, and L1, is essential or whether FGFRs have distinct different roles in ESCC-CSCs is still in question. This study shows that FGFR2, particularly the IIIb isoform, is highly expressed in non-CSCs. Non-CSCs have an epithelial phenotype, and such cells are more differentiated in ESCC. Further, FGFR2 induces keratinocyte differentiation through AKT but not MAPK signaling and diminishes CSC populations. Conversely, knockdown of FGFR2 induces epithelial-mesenchymal transition (EMT) and enriches CSC populations in ESCC. Finally, data analysis using The Cancer Genome Atlas (TCGA) dataset shows that expression of FGFR2 significantly correlated with cancer cell differentiation in clinical ESCC samples. The present study shows that each FGFR has a distinct role and FGFR2-AKT signaling is a key driver of keratinocyte differentiation in ESCC. Activation of FGFR2-AKT signaling could be a future therapeutic option targeting CSC in ESCC.

Murine remote ischemic preconditioning suppresses diabetic ketoacidosis by enhancing glycolysis and entry into tricarboxylic acid cycle in the liver.

AIMS: Hindlimb ischemia-reperfusion (IR) was previously demonstrated by our group to decrease blood sugar levels by suppressing hepatic gluconeogenesis and enhancing glucose uptake using activation of the parasympathetic nervous system. While IR attenuated hyperglycemia in diabetic mice, it was unclear whether IR regulated energy metabolism in the liver. We investigated the mechanisms by which IR regulates energy metabolism in the liver from type1 diabetic mice. MAIN METHODS: Streptozotocin-induced diabetic male C57BL/6J mice were used to determine the effect of IR on the factors involved in energy metabolism in the liver (i.e., activation levels of AMP-activated protein kinase, aconitase and pyruvate dehydrogenase; adenosine triphosphate and fumarate concentrations; sirtuin (Sirt) 1 expression). These various signaling pathways and key enzyme activities were examined using western blot analysis and a biochemical technique including a colorimetric assay. KEY FINDINGS: Under feeding conditions (free access to normal murine chow and water), blood glucose levels and serum ketone body levels were significantly suppressed by IR, whereas phospho-AMP-activated protein kinase and its activity, pyruvate dehydrogenase, aconitase activity, and Sirt 1expression were upregulated. In contrast, peroxisome proliferator-activated receptor γ coactivator-1, which accelerated fatty acid use, was suppressed by IR. SIGNIFICANCE: These results indicated that in the IR-treated diabetic liver, energy production was promoted through acceleration of the tricarboxylic acid cycle linked with increased glucose preference rather than fatty acid under feeding conditions. Therefore, IR may be beneficial against diabetic hyperglycemia, but also ketoacidosis.

Superficial Angiomyxoma of the Nipple in a Japanese Woman: A Case Report and Review of Literature.

Superficial angiomyxoma is a rare, benign, multilobulated cutaneous tumor composed of stellate and spindle cells, a prominent myxoid matrix, and numerous blood vessels. Superficial angiomyxoma may be indistinguishable from cutaneous lesions of the Carney complex, although superficial angiomyxoma can occur independently of the complex. In this article, we present the case of a 39-year-old Japanese woman with a 40 × 30 mm, focally ulcerated, polypoid superficial angiomyxoma on the left nipple without any evidence of Carney complex. The development of superficial angiomyxoma on the nipples in a patient without the Carney complex is extremely rare. Indeed, only 3 cases of superficial angiomyxoma arising on the nipple have been reported to date, and this is the first such report in Japan. In such cases, the majority of superficial angiomyxoma of the nipples develop in premenopausal women. The possibility of superficial angiomyxoma should be considered for all polypoid nipple lesion, particularly in premenopausal women, and complete excision with follow-up observation should be performed.

[Effects of voriconazole and vascular lesions in invasion of aspergillosis into the central nerve system].

We report 2 patients showing invasion of aspergillosis into the central nerve system (CNS). Patient 1, an 81-year-old woman, underwent surgery for sphenoidal sinusitis. She developed cerebral infarction with unconsciousness on 12th postoperative day. CSF examination demonstrated pleocytosis with increased protein and aspergillus antigen. She was diagnosed as having invasion of aspergillosis into the CNS, and was treated with voriconazole. Her clinical manifestations and CSF findings markedly improved. However, the effects of voriconazole gradually attenuated and she demonstrated recurrence of the cerebral infarction. After 2 months, she died of systemic aspergillosis and sepsis. Autopsy studies. Severe atherosclerotic changes with calcification were demonstrated in the bilateral carotid and basilar arteries, and many aspergillus were clustered in the vessel walls. Granulomatous inflammatory lesions with aspergillus were also demonstrated in the area surrounding the chiasm. There were no massive infarcts or bleeding in the brain, but multiple small infarcts were present. Patinet 2, a 64-year-old man, showing bilateral visual loss, was receiving treatment with corticosteroids under a diagnosis of optic neuritis. Two weeks later, he developed cerebral infarction. CSF examination showed pleocytosis with increased protein and aspergillus antigen. He was diagnosed as having invasive aspergillosis from the sphenoidal sinusitis into the CNS. He was treated with voriconazole, and unconsciousness and CSF findings improved transiently. However, he developed a recurrence of the brain infarction and pneumonia and finally died 6 months later. Treatment by voriconazole was definitely effective in both patients, but both patients died of recurrent cerebral infarction, possibly due to resistance for voriconazole, or developing multicellular filamentous biofilms. Voriconazole is recommended as the first choice of antifungal agents for aspergillosis. Aspergillus infection is strongly invasive into arterial vessels. It is important to consider the possible occurrence of cerebrovascular disease when treating invasion of aspergillosis into the CNS.

Overexpression of PODXL/ITGB1 and BCL7B/ITGB1 accurately predicts unfavorable prognosis compared to the TNM staging system in postoperative pancreatic cancer patients.

We previously reported that overexpression of PODXL, BCL7B, and ARHGEF4 in pancreatic cancer tissue is correlated with pancreatic cancer-related survival. The aim of this study was to investigate the use of PODXL, BCL7B, ARHGEF4, and the integrin family member ITGB1 as useful markers for the prognosis of postoperative pancreatic cancer patients in comparison with tumor size and the tumor node metastasis (TNM) staging system. Immunohistochemistry was performed using an anti-ITGB1 antibody on 102 samples of pancreatic cancer tissue surgically resected at the University of Kochi Medical School Hospital and the Matsuyama Shimin Hospital. Univariate Cox proportional hazards regression analysis showed that TNM stage and overexpression of PODXL, BCL7B, and ITGB1 were correlated with postoperative survival. However, tumor size was not significantly associated with postoperative prognosis of pancreatic cancer compared to these features. Multivariate Cox proportional hazards regression analysis showed that the overexpression of both PODXL and ITGB1 and overexpression of both BCL7B and ITGB1 increased the hazard ratio (6.27, 95% confidence interval [CI] 2.58-15.21; and 3.93, 95% CI 1.74-8.91, respectively) compared to that of TNM stage (IIA and IIB vs. III and IV; 3.05, 95% CI 1.25-7.42). These results imply that the combination of PODXL with ITGB1 and the combination of BCL7B with ITGB1 accurately predicted the postoperative outcomes of pancreatic cancer patients, and they were superior compared to the TNM staging system. The combination of PODXL with ITGB1 would be particularly useful, as it was the most highly correlated with postoperative outcomes. Importantly, the present results are useful to determine which adjuvant therapy should be selected.

Three-Dimensional Organoids Reveal Therapy Resistance of Esophageal and Oropharyngeal Squamous Cell Carcinoma Cells.

Background & Aims: Oropharyngeal and esophageal squamous cell carcinomas, especially the latter, are a lethal disease, featuring intratumoral cancer cell heterogeneity and therapy resistance. To facilitate cancer therapy in personalized medicine, three-dimensional (3D) organoids may be useful for functional characterization of cancer cells ex vivo. We investigated the feasibility and the utility of patient-derived 3D organoids of esophageal and oropharyngeal squamous cell carcinomas. Methods: We generated 3D organoids from paired biopsies representing tumors and adjacent normal mucosa from therapy-naïve patients and cell lines. We evaluated growth and structures of 3D organoids treated with 5-fluorouracil ex vivo. Results: Tumor-derived 3D organoids were grown successfully from 15 out of 21 patients (71.4%) and passaged with recapitulation of the histopathology of the original tumors. Successful formation of tumor-derived 3D organoids was associated significantly with poor response to presurgical neoadjuvant chemotherapy or chemoradiation therapy in informative patients (P = 0.0357, progressive and stable diseases, n = 10 vs. partial response, n = 6). The 3D organoid formation capability and 5-fluorouracil resistance were accounted for by cancer cells with high CD44 expression and autophagy, respectively. Such cancer cells were found to be enriched in patient-derived 3D organoids surviving 5-fluorouracil treatment. Conclusions: The single cell-based 3D organoid system may serve as a highly efficient platform to explore cancer therapeutics and therapy resistance mechanisms in conjunction with morphological and functional assays with implications for translation in personalized medicine.

Multiseptate gallbladder: report of a case.

A 53-year-old Japanese female was referred to Miyazaki University hospital for the surgical treatment of gastric cancer. She had no symptoms and the presence of the complex cystic gallbladder with multiple and linear hyperechogenic septa was incidentally found by ultrasonography. Multicystic lesion of gallbladder was also observed on DIC-CT and MRCP. Neither the bile duct nor the pancreatic duct was dilated. The papilla of the Vater was of normal appearance endoscopically. Pathological study of the biopsy specimen from the type 3 tumor of the stomach showed poorly differentiated adenocarcinoma. Distal partial gastrectomy and cholecystectomy were performed. The gross examination of the gallbladder confirmed the presence of multiple thin septa with honeycomb appearance. Cancer cells were not observed histologically and final diagnosis was the multiseptate gallbladder. The postoperative course was uneventful. We herein report a rare case of multiseptate gallbladder showing the findings on DIC-CT and MRCP.

WAVE2 is associated with poor prognosis in pancreatic cancers and promotes cell motility and invasiveness via binding to ACTN4.

WAVE2 is a member of the WASP/WAVE family of actin cytoskeletal regulatory proteins; unfortunately, little is known about its function in pancreatic cancers. In this study, we report the role of WAVE2 in the motility and invasiveness of pancreatic cancer cells. High WAVE2 expression in human pancreatic cancer tissues was correlated with overall survival. WAVE2 accumulated in the cell protrusions of pancreatic cancer cell lines. Downregulation of WAVE2 by small interfering RNA decreased the cell protrusions and inhibited the motility and invasiveness of pancreatic cancer cells. WAVE2 promoted pancreatic cancer cell motility and invasion by forming a complex with the actin cytoskeletal protein alpha-actinin 4 (ACTN4). Downregulation of ACTN4 by small interfering RNA also inhibited the motility and invasiveness of the cells through a decrease in cell protrusions. Further investigation showed that WAVE2/ACTN4 signaling selectively stimulated p27 phosphorylation and thereby increased the motility and invasiveness of the cells. These results suggest that WAVE2 and ACTN4 stimulate p27 phosphorylation and provide evidence that WAVE2 promotes the motility and invasiveness of pancreatic cancer cells.

ARHGEF4 predicts poor prognosis and promotes cell invasion by influencing ERK1/2 and GSK-3α/ß signaling in pancreatic cancer.

Rho guanine nucleotide exchange factor 4 (ARHGEF4) is a guanine nucleotide exchange factor that is specific for Rac1 and Cdc42. The aim of the present study was to investigate the role of ARHGEF4 in the motility and invasiveness of pancreatic cancer cells. Evaluation of an immunohistochemical staining of 102 resected pancreatic cancer samples demonstrated that high ARHGEF4 expression was correlated with an independent predictor of worse overall survival in univariate and multivariate analyses. Immunofluorescence analyses and Matrigel invasion assays demonstrated that suppression of ARHGEF4 inhibited the formation of membrane protrusions, and in turn inhibited cell motility and invasion. A phosphoprotein array analysis demonstrated that knockdown of ARHGEF4 decreased phosphorylated extracellular signal-regulated kinase (ERK)1/2 and glycogen synthase kinase-3 (GSK-3)α/ß in pancreatic cancer cells, and ERK1/2 and GSK-3α/ß were associated with ARHGEF4-related motility and invasiveness through an increase in cell protrusions. These results suggested that ARHGEF4 stimulates ERK1/2 and GSK-3α/ß, and provided evidence that ARHGEF4 promotes cell motility and invasiveness. Inhibition of ARHGEF4 may be a novel approach to a targeted molecular therapy, as any such therapy would limit the motility and invasiveness of pancreatic cancer cells.

BCL7B, a predictor of poor prognosis of pancreatic cancers, promotes cell motility and invasion by influencing CREB signaling.

The functions of B-cell CLL/lymphoma 7B (BCL7B) are unknown and the protein lacks any known functional domains. The aim of this study was to investigate the role of BCL7B in the motility and invasiveness of pancreatic cancer cells. Immunohistochemistry was performed to determine whether high BCL7B expression in human pancreatic cancer tissues is correlated with poor prognosis. High BCL7B expression was an independent predictor of worse overall survival of pancreatic cancer patients. Immunocytochemistry showed that BCL7B was accumulated in cell protrusions of migrating pancreatic cancer cells. Knockdown of BCL7B inhibited the motility and invasiveness of pancreatic cancer cells through a decrease in cell protrusions. Phosphoprotein array analysis was performed to determine BCL7B-associated intracellular signaling pathways. Suppression of BCL7B increased phosphorylated CREB expression in pancreatic cancer cells, and knockdown of CREB promoted the motility and invasiveness by increasing cell protrusions. The combined data suggest that BCL7B promotes pancreatic cancer cell motility and invasion through a signaling pathway that involves dephosphorylation of CREB.