Publications by authors named "Yuuki Iida"

28 Publications

  • Page 1 of 1

Intervention Strategies to Reduce Surgical Site Infection Rates in Patients Undergoing Rectal Cancer Surgery.

In Vivo 2022 Jan-Feb;36(1):439-445

Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.

Background/aim: This study aimed to determine the effectiveness of surgical site infection (SSI) prevention approaches in rectal cancer surgery.

Patients And Methods: A total of 1,408 patients who underwent elective rectal cancer surgery between 1995 and 2017 were reviewed. Patients were divided into three groups: control group (group A, n=245), SSI prevention intervention group (group B, n=516), and laparoscopic or robotic surgery group (group C, n=647). The groups were compared in terms of SSI and anastomotic leakage (AL) incidences, and risk factors for SSI were investigated.

Results: The overall SSI and AL rates were 19.4% and 3.6%, respectively. These rates were significantly lower in Group C (9.3%, 1.7%), compared to Groups A (40.0%, 6.1%) and B (22.5%, 3.5%). Abdominoperineal resection, open surgery, operation time, intraoperative bleeding, lack of absorbable sutures, lack of mechanical bowel preparation, and lack of oral antibiotics were independently associated with SSI.

Conclusion: SSI reduction after rectal cancer surgery was achieved through various intervention strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/invivo.12722DOI Listing
January 2022

Acetylated DNMT1 Downregulation and Related Regulatory Factors Influence Metastatic Melanoma Patients Survival.

Cancers (Basel) 2021 Sep 18;13(18). Epub 2021 Sep 18.

Department of Translational Molecular Medicine, Saint John's Cancer Institute (SJCI), Providence Saint John's Health Center (SJHC), Santa Monica, CA 90404, USA.

The role of post-translational modifications (PTM) of the key epigenetic factor DNMT1 protein has not been well explored in cutaneous metastatic melanoma progression. The acetylated DNMT1 (ac-DNMT1) protein level was assessed using an anti-acetylated lysine antibody in a clinically annotated melanoma patient tumor specimen cohort. In this study, we showed that surgically resected tumors have significantly higher DNMT1 protein expression in metastatic melanoma (stage III metastasis = 17, = 0.0009; stage IV metastasis = 164, = 0.003) compared to normal organ tissues ( = 19). Additionally, reduced ac-DNMT1 protein levels were associated with melanoma progression. There was a significant inverse correlation between ac-DNMT1 and DNMT1 protein levels in stage IV metastatic melanoma ( = -0.18, = 0.02, = 164). Additionally, ac-DNMT1 protein levels were also significantly positively correlated with TIP60 ( = 0.6, < 0.0001) and USP7 ( = 0.74, < 0.0001) protein levels in stage IV metastatic melanoma ( = 164). Protein analysis in metastatic melanoma tumor tissues showed that with high ac-DNMT1 ( = 0.006, = 59), or concurrent high ac-DNMT1 with low DNMT1 ( = 0.05, = 27), or high TIP60 ( = 0.007, = 41), or high USP7 ( = 0.01, = 48) consistently showed better 4-year melanoma-specific survival (MSS). Multivariate Cox proportional hazard analysis showed that ac-DNMT1 level is a significant independent factor associated with MSS (HR, 0.994; 95% confidential interval (CI), 0.990-0.998; = 0.002). These results demonstrated that low ac-DNMT1 levels may represent an important regulatory factor in controlling metastatic melanoma progression and a promising factor for stratifying aggressive stage IV metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13184691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471314PMC
September 2021

Long-term response on letrozole for gastric cancer: A case report.

Medicine (Baltimore) 2021 May;100(21):e26146

Department of Surgery, Yaizu City Hospital.

Rationale: Hormone therapies, particularly those targeting estrogen and its receptors, are a key treatment modality for patients with estrogen receptor (ER)-positive breast or ovarian cancer. Some gastric cancers (GCs) express ERs, and preclinical studies suggest the potential of estrogen-targeting hormone therapy on GC; however, the clinical relevance of this hormone therapy on GC treatment has not been well elucidated.

Patient Concerns: An 80-year-old female was admitted to our department with hypogastric pain and vomiting. Computed tomography demonstrated small bowel obstruction, and laparotomy after bowel decompression revealed peritoneal dissemination consisting of a poorly-differentiated adenocarcinoma. Intestinal bypass between the ileum and transverse colon was performed.

Diagnoses: The tumor was ER- and mammaglobin-positive, indicating that it originated from a breast cancer. Diagnostic imaging revealed no evidence of breast cancer; however, right axillary ER- and mammaglobin-positive lymphadenopathy was found.

Interventions: The patient received hormone therapy using letrozole based on a clinical diagnosis of occult breast cancer with peritoneal dissemination and right axillary lymph node metastasis.

Outcomes: The patient remained disease free until 37 months but deceased at 53 months from the onset of disease. An autopsy revealed no tumor cells in the right breast tissue; however, there was a massive invasion of cancer cells in the stomach.

Lessons: A patient with ER positive GC with peritoneal dissemination and right axillary lymph node metastasis presented remarkable response to letrozole. The long-term survival obtained using letrozole for a patient with GC with distant metastasis suggests the potential of estrogen targeting hormone therapies for GC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000026146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154479PMC
May 2021

Risk factors of mFOLFOX6-induced hyperammonemia in patients with colorectal cancer: an observational study.

Int J Clin Oncol 2021 Aug 15;26(8):1477-1484. Epub 2021 May 15.

Department of Surgical Oncology, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: FOLFOX therapy, a standard treatment for colorectal cancer (CRC), causes a rare, but serious adverse event, hyperammonemia. However, the risk factors of hyperammonemia remain unknown.

Methods: We examined 74 patients who received mFOLFOX6 therapy with or without biologics for CRC between April 2013 and March 2018 in Yaizu City Hospital. Clinicopathological factors were retrospectively reviewed in association with hyperammonemia, and risk factors of hyperammonemia during mFOLFOX6 therapy were analyzed in 32 patients with the available data.

Results: Seven patients developed hyperammonemia, with onset exclusively on day 2 or 3 in the first cycle of therapy. They were treated with branched chain amino acid administration and hydration; however, one patient with stage G4 chronic kidney disease (CKD) died. By multivariate analysis, estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m was independently associated with hyperammonemia during FOLFOX therapy (odds ratio: 9.0, p = 0.040).

Conclusions: Reduced eGFR is considered a risk factor of developing hyperammonemia during FOLFOX therapy. Serum ammonia levels should be monitored especially during the first cycle of FOLFOX therapy in patients with CKD stage G3 or higher.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10147-021-01932-wDOI Listing
August 2021

Therapeutic effects and limitations of chemoradiotherapy in advanced lower rectal cancer focusing on T4b.

Int J Colorectal Dis 2021 Jul 3;36(7):1525-1534. Epub 2021 May 3.

Department of Surgical Oncology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Purpose: This study aimed to elucidate the benefits and limitations of preoperative chemoradiotherapy (CRT) in rectal cancer treatment, specifically in T4b rectal cancer.

Methods: This retrospective cohort study reviewed 1014 consecutive patients with clinical T3/4a/T4b adenocarcinomas of the lower rectum, who underwent total mesorectal excision at the Department of Surgical Oncology of the University of Tokyo Hospital and 22 referral institutions affiliated with the Japanese Study Group for Postoperative Follow-up of Colorectal Cancer. Patients were divided into two cohorts: cohort 1 comprised 298 consecutive patients who underwent CRT followed by radical surgery and cohort 2 comprised 716 consecutive patients who underwent curative surgery without preoperative therapy. We assessed the prognostic differences between the two cohorts, focusing particularly on T stages.

Results: In T3/4a patients, cohort 1 showed a significantly lower local recurrence rate than cohort 2 (4.8% vs. 9.4%, p=0.024), but not in T4b patients (23.5% vs. 16.0%, p=0.383). In contrast, no significant differences in survival were observed between T3/4a and T4b patients. T4b classification was found to be an independent predictive factor of local recurrence in cohort 1, but not in cohort 2.

Conclusion: In T4b rectal cancer, preoperative CRT demonstrated a limited benefit for local control and survival. In cases of suspected T4b rectal tumors, additional therapies such as induction chemotherapy to conventional CRT may contribute to better outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00384-021-03936-4DOI Listing
July 2021

Extended Left Colectomy with Coloanal Anastomosis by Indocyanine Green-guided Deloyers Procedure: A Case Report.

J Anus Rectum Colon 2021 28;5(2):202-206. Epub 2021 Apr 28.

Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.

The Deloyers procedure is performed after extended left colectomy, enabling the reach of the proximal colon to the rectum for anastomosis while preserving sufficient blood supply. We report a case of the Deloyers procedure performed safely under indocyanine green (ICG) fluorescence guidance. A 50-year-old man with obesity (body mass index, 35.7 kg/m) and a history of diabetes underwent an extended left hemicolectomy and ultralow anterior resection of the rectum as radical resection for transverse and sigmoid colon cancers and a lower rectal neuroendocrine tumor. Reconstruction was performed by the Deloyers procedure. A necessary length of the transverse colon with reduced blood flow was additionally resected under ICG fluorescence guidance, and a transanal hand-sewn coloanal anastomosis was performed. This is the first report in which the Deloyers procedure was performed successfully with the ICG fluorescence method. ICG fluorescence may be useful when combined with the Deloyers procedure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.23922/jarc.2020-097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084531PMC
April 2021

Risk factors for non-reaching of ileal pouch to the anus in laparoscopic restorative proctocolectomy with handsewn anastomosis for ulcerative colitis.

Intest Res 2021 Mar 12. Epub 2021 Mar 12.

Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.

Background/aims: Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis and handsewn anastomosis for ulcerative colitis requires pulling down of the ileal pouch into the pelvis, which can be technically challenging. We examined risk factors for the pouch not reaching the anus.

Methods: Clinical records of 62 consecutive patients who were scheduled to undergo RPC with handsewn anastomosis at the University of Tokyo Hospital during 1989-2019 were reviewed. Risk factors for non-reaching were analyzed in patients in whom hand sewing was abandoned for stapled anastomosis because of nonreaching. Risk factors for non-reaching in laparoscopic RPC were separately analyzed. Anatomical indicators obtained from presurgical computed tomography (CT) were also evaluated.

Results: Thirty-seven of 62 cases underwent laparoscopic procedures. In 6 cases (9.7%), handsewn anastomosis was changed to stapled anastomosis because of non-reaching. Male sex and a laparoscopic approach were independent risk factors of non-reaching. Distance between the terminal of the superior mesenteric artery (SMA) ileal branch and the anus > 11 cm was a risk factor for non-reaching.

Conclusions: Laparoscopic RPC with handsewn anastomosis may limit extension and induction of the ileal pouch into the anus. Preoperative CT measurement from the terminal SMA to the anus may be useful for predicting non-reaching.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5217/ir.2020.00158DOI Listing
March 2021

Establishing a novel method for assessing elasticity of internal anal sphincter using ultrasonic real-time tissue elastography.

ANZ J Surg 2021 06 12;91(6):E360-E366. Epub 2021 Apr 12.

Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Evaluating anorectal function using real-time tissue elastography (RTE) has not been reported. A previous study reported that in the internal anal sphincter (IAS) of surgical specimens of patients with rectal cancer who underwent abdominoperineal resection, there was an increased fibrosis trend in those who underwent pre-operative chemoradiotherapy (CRT) compared with non-CRT. We speculated that CRT might have induced sclerosis of the IAS because of fibrosis. Therefore, we aimed to establish a method of quantitating the degree of IAS hardness using RTE on endoanal ultrasonography.

Methods: RTE was performed with freehand manual compression under a defined pressure at the middle anal canal. Using the most compressive point in the strain graph, we traced the region of interest in the IAS. The strain histogram showed a frequency distribution of colours according to the degree of strain (numeric scan ranging from 0 to 255; smaller number indicated harder tissue). We defined the mean of the strain histogram as 'elasticity'. Ten patients with locally advanced rectal cancer who underwent pre-operative CRT were prospectively enrolled. We statistically evaluated the correlation between IAS elasticity and maximum resting pressure (MRP) values both at pre- and post-CRT. MRP was examined concurrently with the examination of IAS elasticity.

Results: Representativity of elasticity measurements was demonstrated. It revealed a trend: IAS elasticity had a moderate inverse correlation with MRP (r = 0.41, P = 0.07), regardless of whether measurements were made before or after CRT.

Conclusion: We established a completely novel method for the assessment of elasticity of the IAS, using RTE on endoanal ultrasonography.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ans.16760DOI Listing
June 2021

Use of catheter with 2-methacryloyloxyethyl phosphorylcholine polymer coating is associated with long-term availability of central venous port.

Sci Rep 2021 03 8;11(1):5385. Epub 2021 Mar 8.

Department of Surgery, Yaizu City Hospital, 1000 Dobara, Yaizu City, Shizuoka, 425-8505, Japan.

Central venous port (CVP) is a widely used totally implantable venous access device. Recognition of risks associated with CVP-related complications is clinically important for safe, reliable, and long-term intravenous access. We therefore investigated factors associated with CVP infection and evulsion, including the device type. A total of 308 consecutive patients with initial CVP implantation between January 2011 and December 2017 were retrospectively reviewed, and the association of clinical features with CVP-related complications were analyzed. Intraoperative and postoperative complications occurred in 11 (3.6%) and 39 (12.7%) patients, respectively. The overall rate of CVP availability at six months was 91.4%. Malignancy and 2-Methacryloyloxyethyl phosphorylcholine (MPC) polymer-coated catheter use were negatively associated with the incidence of CVP infections. Accordingly, malignancy and MPC polymer-coated catheter use were independent predictors for lower CVP evulsion rate (odds ratio, 0.23 and 0.18, respectively). Furthermore, both factors were significantly associated with longer CVP availability (hazard ratio, 0.24 and 0.27, respectively). This retrospective study identified factors associated with CVP-related complications and long-term CVP availability. Notably, MPC polymer-coated catheter use was significantly associated with a lower rate of CVP infection and longer CVP availability, suggesting the preventive effect of MPC coating on CVP infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-84885-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940397PMC
March 2021

Therapeutic significance of D3 dissection for low rectal cancer: a comparison of dissections between the lateral pelvic lymph nodes and the lymph nodes along the root of the inferior mesenteric artery in a multicenter retrospective cohort study.

Int J Colorectal Dis 2021 Jun 3;36(6):1263-1270. Epub 2021 Feb 3.

Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Purpose: D3 dissection is the standard treatment modality for locally advanced low rectal cancer in Japan. The benefit of lateral pelvic lymph node (LPLN) dissection (LPLND) and lymph nodes along the root of inferior mesenteric artery (253 LN) dissection (253 LND) for low rectal cancer has often been studied separately, and few studies have investigated their benefit in the same cohort. This study aimed to clarify the therapeutic significance of dissection of the LPLN in comparison to that of dissection of the 253 LN for low rectal cancer.

Methods: We retrospectively evaluated 3508 patients with treatment-naïve stage I-III low rectal cancer who underwent mesorectal excision between 1997 and 2012. They were identified from the Japanese Study Group for Postoperative Follow-Up of Colorectal Cancer database. The rates of metastasis, survival, and therapeutic value index (5-year overall survival (OS) rate multiplied by metastatic rate for lymph node metastasis) were compared between LPLN and 253 LN.

Results: The rates of LPLN metastasis and 253 LN metastasis were 17.9% and 1.5%, respectively. The 5-year OS was significantly different between patients with and without LPLN metastasis (55.0% vs 85.5%, P < 0.0001) and between patients with and without 253 LN metastasis (36.2% vs 83.3%, P < 0.0001). The therapeutic value indexes of LPLN and 253 LN were 9.85 and 0.54, respectively.

Conclusions: LPLND may have more therapeutic value than 253 LND for patients with treatment-naïve low rectal cancer, although both the patients with LPLN metastasis and those with 253 LN metastasis remained to have poor prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00384-021-03858-1DOI Listing
June 2021

Epithelial-mesenchymal transition and metastatic ability of CD133 colorectal cancer stem-like cells under hypoxia.

Oncol Lett 2021 Jan 9;21(1):19. Epub 2020 Nov 9.

Department of Surgical Oncology, The University of Tokyo, Tokyo 113-8655, Japan.

Although CD133 is a representative cancer stem cell marker, its function in tumor aggressiveness under hypoxia remains unclear. Therefore, the present study aimed to investigate the associations between CD133, the epithelial-mesenchymal transition and distant metastasis in colorectal cancer. CD133 and CD133 cells were isolated from a single colorectal cancer cell line LoVo, and their adhesive and migratory properties were compared under hypoxic conditions. Immunostaining analysis was performed to determine CD133 expression in clinical samples of primary tumors, as well as liver and peritoneal metastases. Under hypoxia, the expression levels of hypoxia-inducible factor (HIF)-1α and the epithelial-mesenchymal transition markers N-cadherin and vimentin were significantly higher in the CD133 compared with those in the CD133 cells. Furthermore, the migratory ability of the CD133 cells was higher compared with that of the CD133 cells under hypoxia. By contrast, the expression levels of β1 integrin were significantly lower in the CD133 cells under hypoxia compared with those in the CD133 cells. Immunohistochemical analysis of clinical samples revealed that the levels of CD133 expression in metastatic tissues from the liver were significantly higher compared with those in the corresponding primary tumors, whereas CD133 expression levels in peritoneal metastatic tissues were significantly lower compared with those in the corresponding primary tumors. In conclusion, compared with the CD133 cells, the CD133 colorectal cancer cells exhibited enhanced levels of HIF-1α expression and tumor cell migration during hypoxia. This was associated with an increased ability of epithelial-mesenchymal transition, possibly leading to the acquisition of an increased hematogenous metastatic potential and eventually resulting in liver metastasis. High β1 integrin expression levels in the CD133 cells under hypoxia may serve a key role in cell adhesion to the peritoneum, resulting in peritoneal metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ol.2020.12280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681219PMC
January 2021

Change in skeletal muscle index and its prognostic significance in patients who underwent successful conversion therapy for initially unresectable colorectal cancer: observational study.

Therap Adv Gastroenterol 2020 12;13:1756284820971197. Epub 2020 Nov 12.

Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Systemic therapy can cause loss of skeletal muscle mass in colorectal cancer (CRC) patients in the neoadjuvant and palliative settings. However, it is unknown how the body composition is changed by chemotherapy rendering unresectable CRC to resectable disease or how it affects the prognosis. This study aimed at elucidating the effects of systemic therapy on skeletal muscles and survival in stage IV CRC patients who underwent conversion therapy.

Methods: We reviewed 98 stage IV CRC patients who received systemic therapy in our hospital. According to the treatment setting, patients were divided into the conversion, neoadjuvant chemotherapy (NAC), and palliation groups. The cross-sectional area of skeletal muscles at the third lumbar level and changes in the skeletal muscle index (SMI), defined as the area divided by height squared, during systemic therapy were compared among patient groups. The effects of these parameters on prognosis were analyzed in the conversion group.

Results: The mean SMI increased by 9.4% during systemic therapy in the conversion group ( = 38), whereas it decreased by 5.9% in the NAC group ( = 18) and 3.7% in the palliation group ( = 42,  < 0.0001). Moreover, patients with increased SMI during systemic therapy had a better overall survival (OS) than those whose SMI decreased in the conversion group ( = 0.025). The increase in SMI was an independent predictor of favorable OS on multivariate analysis (hazard ratio 0.25).

Conclusions: Stage IV CRC patients who underwent conversion to resection often had an increased SMI. On the other hand, a decrease in the SMI during systemic therapy was a negative prognostic factor in such patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1756284820971197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672750PMC
November 2020

Oncological Outcomes of Pathological T1 Lower Rectal Cancer Patients With or Without Preoperative Chemoradiotherapy.

In Vivo 2020 Nov-Dec;34(6):3559-3564

Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.

Background/aim: It remains unclear whether rectal cancers down-staged by preoperative chemoradiotherapy (CRT) have similar prognoses to those of the same stage without preoperative CRT. We compared prognoses of pT1 rectal cancer patients stratified by preoperative CRT.

Patients And Methods: We retrieved data of patients with pathological T1 rectal cancer between 2003 and 2020. Patients were divided into the "ypT1 group" who received preoperative CRT following surgery and the "pT1 group" who underwent surgery alone. Factors associated with relapse-free survival (RFS) were investigated.

Results: Among 86 patients, ypT1 and pT1 groups comprised 18 and 68 patients, respectively. There was no significant difference in RFS between the groups (p=0.19). Tumor location within 5 cm from the anal verge was associated with recurrence (hazard ratio: 0.13, p=0.034).

Conclusion: The prognosis of patients with ypT1 rectal cancer was similar to that of patients with pT1. Low tumor location was a poor prognostic factor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/invivo.12199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811633PMC
June 2021

Downregulation of the Ubiquitin-E3 Ligase RNF123 Promotes Upregulation of the NF-κB1 Target SerpinE1 in Aggressive Glioblastoma Tumors.

Cancers (Basel) 2020 Apr 27;12(5). Epub 2020 Apr 27.

Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI) at Providence Saint John's Health Center, Santa Monica, CA 90404, USA.

This study examined the role of the ubiquitin E3-ligase RNF123 in modulating downstream NF-κB1 targets in glioblastoma (GB) tumor progression. Our findings revealed an oncogenic pathway (miR-155-5p-RNF123-NF-κB1-p50-SerpinE1) that may represent a new therapeutic target pathway for GB patients with isocitrate dehydrogenase 1 and 2 () WT (wild type). Mechanistically, we demonstrated that is downregulated in WT GB patients and leads to the reduction of p50 levels. RNA-sequencing, reverse-phase protein arrays, and in vitro functional assays on WT GB cell lines with RNF123 overexpression showed that SerpinE1 was a downstream target that is negatively regulated by RNF123. knockdown reduced the proliferation and invasion of WT GB cell lines. Both SerpinE1 and miR-155-5p overexpression negatively modulated RNF123 expression. In clinical translational analysis, RNF123, SerpinE1, and miR-155-5p were all associated with poor outcomes in GB patients. Multivariable analysis in WT GB patients showed that concurrent low RNF123 and high SerpinE1 was an independent prognostic factor in predicting poor overall survival ( < 0.001, hazard ratio (HR) = 2.93, 95% confidence interval (CI) 1.7-5.05), and an increased risk of recurrence ( < 0.001, relative risk (RR) = 3.56, 95% CI 1.61-7.83).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12051081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281601PMC
April 2020

Predominance of triple wild-type and IGF2R mutations in mucosal melanomas.

BMC Cancer 2018 Oct 30;18(1):1054. Epub 2018 Oct 30.

Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, 90404, USA.

Background: Primary mucosal melanoma (MM) is a rare subtype of melanoma that arises from melanocytes in the mucosa. MM has not been well profiled for mutations and its etiology is not well understood, rendering current treatment strategies unsuccessful. Hence, we investigated mutational landscape for MM to understand its etiology and to clarify mutations that are potentially relevant for MM treatment.

Methods: Forty one MM and 48 cutaneous melanoma (CM) tissues were profiled for mutations using targeted deep next-generation sequencing (NGS) for 89 cancer-related genes. A total of 997 mutations within exons were analyzed for their mutational spectrum and prevalence of mutation, and 685 non-synonymous variants were investigated to identify mutations in individual genes and pathways. PD-L1 expression from 21 MM and 18 CM were assessed by immunohistochemistry.

Results: Mutational spectrum analysis revealed a lower frequency of UV-induced DNA damage in MM than in CM (p = 0.001), while tobacco exposure was indicated as a potential etiologic factor for MM. In accordance with low UV damage signatures, MM demonstrated an overall lower number of mutations compared to CM (6.5 mutations/Mb vs 14.8 mutations/Mb, p = 0.001), and less PD-L1 expression (p = 0.003). Compared to CM, which showed frequent mutations in known driver genes (BRAF 50.0%, NRAS 29.2%), MM displayed lower mutation frequencies (BRAF; 12.2%, p < 0.001, NRAS; 17.1%), and was significantly more enriched for triple wild-type (no mutations in BRAF, RAS, or NF1, 70.7% vs 25.0%, p < 0.001), IGF2R mutation (31.7% vs 6.3%, p = 0.002), and KIT mutation (9.8% vs 0%, p = 0.042). Of clinical relevance, presence of DCC mutations was significantly associated with poorer overall survival in MM (log-rank test, p = 0.02). Furthermore, mutational spectrum analysis distinguished primary anorectal MM from CM metastasized to the bowel (spectrum analysis p < 0.001, number of mutations p = 0.002).

Conclusions: These findings demonstrated a potential etiologic factor and driver mutation for MM and strongly suggested that MM initiation or progression involves distinct molecular-mechanisms from CM. This study also identified mutational signatures that are clinically relevant for MM treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-018-4977-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206730PMC
October 2018

MiR-200a Regulates CDK4/6 Inhibitor Effect by Targeting CDK6 in Metastatic Melanoma.

J Invest Dermatol 2017 09 16;137(9):1955-1964. Epub 2017 May 16.

Department of Translational Molecular Medicine, Division of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA; Sequencing Center, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA. Electronic address:

The CDK4/6 pathway is frequently dysregulated in cutaneous melanoma. Recently, CDK4/6 inhibitors have shown promising clinical activity against several cancer types, including melanoma. Here, we show that microRNA-200a decreases CDK6 expression and thus reduces the response of CDK4/6 inhibitor in highly proliferative metastatic melanoma. Down-regulation of microRNA-200a expression in melanoma cells is associated with disease progression and a higher number of lymph node metastases. Furthermore, microRNA-200a expression is epigenetically modulated by both DNA methylation at the promoter region and chromatin accessibility of an upstream genomic region with enhancer activity. Mechanistically, overexpression of miR-200a in metastatic melanoma cells induces cell cycle arrest by targeting CDK6 and decreases the levels of phosphorylated-Rb1 and E2F-downstream targets, diminishing cell proliferation; these effects are recovered by CDK6 overexpression. Conversely, low microRNA-200a expression in metastatic melanoma cells results in higher levels of CDK6 and a more significant response to CDK4/6 inhibitors. We propose that microRNA-200a functions as a "cell cycle brake" that is lost during melanoma progression to metastasis and provides the ability to identify melanomas that are highly proliferative and more prompted to respond to CDK4/6 inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2017.03.039DOI Listing
September 2017

Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-κB Pathway in Melanoma.

Clin Cancer Res 2017 Aug 7;23(16):4831-4842. Epub 2017 Apr 7.

Division of Molecular Oncology, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, California.

Abnormal activation of the NF-κB pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-κB activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of the NF-κB pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma. The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue microarrays; = 137, JWCI cohort; = 40) and The Cancer Genome Atlas database (TCGA cohort, = 370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-κB, and the epigenetic regulations of KPC1, including DNA methylation and miRNA expression. We verified that KPC1 suppresses melanoma proliferation by processing NF-κB1 p105 into p50, thereby modulating NF-κB target gene expression. Concordantly, KPC1 expression was downregulated in American Joint Committee on Cancer stage IV melanoma compared with early stages (stage I/II = 0.013, stage III = 0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma ( = 137; HR 1.810; = 0.006). Furthermore, our data showed that high miR-155-5p expression, which is controlled by DNA methylation at its promoter region (TCGA; Pearson's -0.455; < 0.001), is significantly associated with KPC1 downregulation (JWCI; = 0.028, TCGA; = 0.003). This study revealed novel epigenetic regulation of KPC1 associated with NF-κB pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-17-0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559338PMC
August 2017

Dual mechanisms of rapid expression of anxiety-related behavior in pilocarpine-treated epileptic mice.

Epilepsy Res 2016 07 25;123:55-67. Epub 2016 Apr 25.

Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Minami-ku, Sagamihara-shi, Kanagawa 252-0374, Japan; Department of Biochemistry, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara-shi, Kanagawa 252-0374, Japan. Electronic address:

A mouse model of epilepsy was generated by inducing status epilepticus (SE) for either 1.5 or 4.5h with pilocarpine to study anxiety-related behaviors, changes in the electroencephalogram of the cerebral cortex and hippocampus, and expression of hippocampal proteins. The viability and rate of success of SE induction were high in C57BL/6N mice but not in C57BL/6J mice. C57BL/6N mice were immotile during the first 2days after SE; however, by the third day, most mice were recovered and exhibited strong anxiety-related behaviors in response to the light/dark preference test and open field test. There was a striking difference in the temporal appearance of anxiety-related behavior between the two SE durations: 1.5h SE mice exhibited strong anxiety-related behavior 3days after SE that gradually attenuated over the next few weeks, whereas 4.5h SE mice exhibited strong anxiety-related behavior 3days after SE that persisted even at nearly 1year after SE. Mice receiving both SE durations exhibited generalized seizures (GS) after SE; however, there was a marked difference in the timing and duration of GS appearance. Mice in the 4.5h SE group exhibited spontaneous GS from 4days to at least 96days after SE. In contrast, mice in the 1.5h SE group exhibited GS only within the first several days after SE; however, epileptic spike clusters continuously appeared in the cerebral cortex and hippocampus for up to twelve days after SE. Among the hippocampal proteins tested, only brain derived-neurotrophic factor (BDNF) exhibited altered expression in parallel with anxiety-related behavior. These results showed the possibility that BDNF expression in the hippocampus might cause anxiety-related behavior in adulthood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eplepsyres.2016.04.007DOI Listing
July 2016

Intraoperative colonoscopy in patients with colorectal cancer: Review of recent developments.

Dig Endosc 2016 Sep 28;28(6):633-40. Epub 2016 Apr 28.

Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

The use of intraoperative colonoscopy has increased alongside progress in the development of colonoscopy-associated devices and techniques, including the colonoscope itself. In the present review, we focus on four circumstances in which intraoperative colonoscopy is beneficial to colorectal surgery: (i) intraoperative determination of a tumor's location; (ii) observation of the proximal colon in cases of obstructive colorectal cancer; (iii) confirmation of the integrity of anastomosis; and (iv) novel surgical techniques that combine laparoscopic and endoscopic surgery. In light of the findings of our review, a combination of colonoscopy and surgery-especially laparoscopic surgery-is expected to facilitate the optimal handling of a variety of colorectal tumors, ranging from benign cases to advanced and obstructive cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/den.12663DOI Listing
September 2016

Phosphatidylserine-specific phospholipase A1 (PS-PLA1) expression in colorectal cancer correlates with tumor invasion and hematogenous metastasis.

Anticancer Res 2015 Mar;35(3):1459-64

Department of Surgical Oncology, Faculty of Medical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

Background: The function of phosphatidylserine-specific phospholipase A1 (PS-PLA1), a phospholipase that acts specifically on phosphatidylserine and produces lysophosphatidylserine, a lysophospholipid mediator, has not been fully elucidated. We evaluated the role of PS-PLA1 in oncogenesis and metastasis of colorectal cancer (CRC).

Materials And Methods: Specimens from 85 patients with CRC were immunostained with a monoclonal antibody against PS-PLA1. The correlation between PS-PLA1 expression and the clinicopathological variables was analyzed.

Results: Tumor depth and hematogenous metastasis independently positively correlated with PS-PLA1 expression. High PS-PLA1 expression was associated with shorter disease-free survival, although it was not an independent predictive factor.

Conclusion: PS-PLA1 expression in CRC is associated with tumor invasion and metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
March 2015

MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A.

Oncotarget 2015 Feb;6(5):3211-24

Department of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.

To assess the role of microRNAs (miR) in hepatocellular carcinoma (HCC), we performed comprehensive microRNA expression profiling using HCC cell lines and identified miR-93 as a novel target associated with HCC. We further verified miR-93 expression levels in advanced HCC tumors (n=47) by a direct PCR assay and found that elevated miR-93 expression level is significantly correlated with poor prognosis. Elevated miR-93 expression significantly stimulated in vitro cell proliferation, migration and invasion, and additionally inhibited apoptosis. We confirmed that miR-93 directly bound with the 3' untranslated regions of the tumor-suppressor genes PTEN and CDKN1A, respectively,and inhibited their expression. As a result of this inhibition, the c-Met/PI3K/Akt pathway activity was enhanced. IHC analysis of HCC tumors showed significant correlation between c-Met protein expression levels and miR-93 expression levels. Knockdown of c-Met inhibited the activation of the c-Met/PI3K/Akt pathway regardless of hepatocyte growth factor (HGF) treatment, and furthermore reduced the expression of miR-93 in these HCC cells. miR-93 also rendered cells to be more sensitive to sorafenib and tivantinib treatment. We concluded that miR-93 stimulated cell proliferation, migration, and invasion through the oncogenic c-Met/PI3K/Akt pathway and also inhibited apoptosis by directly inhibiting PTEN and CDKN1A expression in human HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413648PMC
http://dx.doi.org/10.18632/oncotarget.3085DOI Listing
February 2015

A giant lymphatic cyst of the adrenal gland: report of a rare case and review of the literature.

Int Surg 2015 Jan;100(1):2-8

1 Department of Surgery, the Mutual Aid Association for Teachers and Officials Sanraku Hospital, 2-5 Kandasurugadai, Chiyoda-ku, Tokyo 101-8326, Japan.

Lymphatic type of adrenal cysts is most common; however, this type of endothelial cyst is quite rare in excessively large adrenal cysts. A 37-year-old Japanese woman was admitted to our institution with distension of her left flank and the upper quadrant of her abdomen. Abdominal ultrasonography revealed a cystic lesion with a homogenous anechoic texture, and measuring 21 cm in diameter. Computed tomography and magnetic resonance imaging displayed a giant cystic lesion adjacent to the liver, pancreas, kidney, and spleen. The origin of the cyst was not identified. We were not able to make a preoperative diagnosis; therefore, the patient underwent resection of the mass by open laparotomy for therapeutic diagnosis. Intraoperatively, the mass was identified to be cystic and adhered to the left adrenal gland. It was filled with more than 2000 mL of serous brown-red fluid. The content of the cyst contained no atypical cells on cytological examination. The wall of the cyst was composed of a lining of a single layer of lymphatic vessel-derived cells, and the cyst was pathologically classified as a true cyst. No abdominal symptoms were observed and a postoperative radiological work-up showed no evidence of recurrence during a 6-year follow-up period. We describe a case of a patient with a giant lymphatic cyst of the adrenal gland. The preset data suggest that surgeons should decide treatment strategy for large adrenal cysts in consideration of hormonal function, degree of size, and possibility of malignancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.9738/INTSURG-D-14-00125.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301289PMC
January 2015

Lysophosphatidylserine stimulates chemotactic migration of colorectal cancer cells through GPR34 and PI3K/Akt pathway.

Anticancer Res 2014 Oct;34(10):5465-72

Department of Surgical Oncology, Faculty of Medical Sciences, The University of Tokyo, Tokyo, Japan.

Background: Lysophosphatidylserine (lysoPS) is a type of lysophospholipid mediator, which is involved in allergic conditions and tumor progression. We investigated the physiological function of lysoPS on colorectal cancer (CRC) cell lines, as well as the involved receptor and signaling pathways.

Materials And Methods: Expression of lysoPS receptors on six cell lines was examined by reverse transcription-polymerase chain reaction (RT-PCR). The physiological functions of lysoPS were investigated, and experiments using small interfering RNA (siRNA) or inhibitors of the signaling pathways were conducted.

Results: Among the three lysoPS receptors, GPR34 was highly expressed on all cell lines. LysoPS stimulated the chemotactic migratory ability. Wortmannin inhibited the migratory ability, as well as the GPR34 knock-down, strongly suggestive of the involvement of this receptor in the PI3K/Akt pathway.

Conclusion: The involved receptor and pathways in the migratory ability in response to lysoPS was demonstrated, which opens premises for targeting as a new strategy for prevention and treatment of colorectal cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
October 2014

Proximal shift of colorectal cancer along with aging.

Clin Colorectal Cancer 2014 Dec 15;13(4):213-8. Epub 2014 Aug 15.

Department of Surgical Oncology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

Introduction: Although several reports have documented the increased incidence of right-sided colorectal cancer (CRC) in the elderly, especially in women, the gender-specific, age-related changes in the characteristics of CRCs, especially related to the cancer localization, have not been fully investigated. This study evaluated the age-related changes in the clinicopathologic features of CRCs, according to the gender.

Materials And Methods: A total of 1059 consecutive patients with CRCs who were admitted to the authors' surgical department between February 2005 and June 2012 were retrospectively reviewed. The patients were divided into male (n = 632) and female (n = 427) groups and then according to the age group, and the correlation between the age group and the other clinicopathologic features was analyzed by univariate and multivariate analysis.

Results: The number of concomitant adenomas found was significantly increased along with increasing age in men, and the presence of concomitant adenoma was the only independent age-related factor of male CRC in the multivariate analysis (P = .0044). In contrast, in women, the location of the CRC progressively shifted to the right side (proximal colon) with increasing age, and the presence of right-sided CRC was the only independent factor of female CRC in the multivariate analysis (P < .0001).

Conclusion: There was a significant gender-specific difference in the age-related changes in the characteristics of CRC. Increasing the number of concomitant adenomas and the shift of CRC localization to the proximal colon were the gender-specific characteristics of male and female CRC, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clcc.2014.06.005DOI Listing
December 2014

Temsirolimus and chloroquine cooperatively exhibit a potent antitumor effect against colorectal cancer cells.

J Cancer Res Clin Oncol 2014 May 12;140(5):769-81. Epub 2014 Mar 12.

Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan,

Purpose: Temsirolimus (TEM) is a novel, water-soluble mammalian target of rapamycin (mTOR) inhibitor that has shown activity against a wide range of cancers in preclinical models, but its efficacy against colorectal cancer (CRC) has not been fully explored.

Methods: We evaluated the antitumor effect of TEM in CRC cell lines (CaR-1, HT-29, Colon26) in vitro and in vivo. In vitro, cell growth inhibition was assessed using a MTS assay. Apoptosis induction and cell cycle effects were measured using flow cytometry. Modulation of mTOR signaling was measured using immunoblotting. Antitumor activity as a single agent was evaluated in a mouse subcutaneous tumor model of CRC. The effects of adding chloroquine, an autophagy inhibitor, to TEM were evaluated in vitro and in vivo.

Results: In vitro, TEM was effective in inhibiting the growth of two CRC cell lines with highly activated AKT, possibly through the induction of G1 cell cycle arrest via a reduction in cyclin D1 expression, whereas TEM reduced HIF-1α and VEGF in all three cell lines. In a mouse subcutaneous tumor model, TEM inhibited the growth of tumors in all cell lines, not only through direct growth inhibition but also via an anti-angiogenic effect. We also explored the effects of adding chloroquine, an autophagy inhibitor, to TEM. Chloroquine significantly potentiated the antitumor activity of TEM in vitro and in vivo. Moreover, the combination therapy triggered enhanced apoptosis, which corresponded to an increased Bax/Bcl-2 ratio.

Conclusions: Based on these data, we propose TEM with or without chloroquine as a new treatment option for CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-014-1628-0DOI Listing
May 2014

Eda/Edar signaling guides fin ray formation with preceding osteoblast differentiation, as revealed by analyses of the medaka all-fin less mutant afl.

Dev Dyn 2014 Jun 19;243(6):765-77. Epub 2014 Mar 19.

Department of Biological Information, Tokyo Institute of Technology, Yokohama, Japan.

Background: Ectodysplasin (Eda) signaling is essential for the morphogenesis of several ectodermal appendages.

Results: Here, we report a medaka mutant, all-fin less (afl), which has a nonsense mutation in its eda gene. The adult afl fish displayed various abnormalities of its dermal skeleton, such as short and twisted fin rays, missing and abnormally shaped scales and teeth, and skull deformation. Focusing on the developing fin rays in the caudal region of afl larvae, we found that the fin rays did not elongate; although the initial formation of fin rays proceeded normally. Additionally, eda expression was lost, and the expression pattern of edar, the gene for the receptor of Eda, was different from wild-type one. In vivo imaging of the double-transgenic medaka expressing enhanced green fluorescent protein under control of the edar promoter and DsRed under control of the osterix promoter revealed that edar expression preceded that of osterix and that the edar-expressing cells migrated in the direction of fin ray elongation, indicating that the Eda/Edar signaling event precedes osteoblast differentiation.

Conclusions: Our findings provide evidence that Eda signaling accompanied with the binding of Eda to Edar are essential for fin ray formation guided by cell migration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dvdy.24120DOI Listing
June 2014

Stress-induced phosphorylation of SNAP-25.

Neurosci Lett 2014 Feb 27;561:182-7. Epub 2013 Dec 27.

Department of Biochemistry, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.

Synaptosomal-associated protein of 25 kDa (SNAP-25), a t-SNARE protein, plays a crucial role in neurotransmitter release by exocytosis. Protein kinase C phosphorylates SNAP-25 at Ser(187), however the physiological significance of this phosphorylation event in brain function remains unclear. In the present study, we found that SNAP-25 phosphorylation increased rapidly in the mouse brain following cold-water restraint stress. Both basal and stress-induced phosphorylation of SNAP-25 were high in stress-related brain regions, including the cerebral cortex, hippocampus, and amygdala, and the extent of phosphorylation increased with increasing amounts of stress. Intravenous administration of adrenaline increased SNAP-25 phosphorylation, although stress-induced phosphorylation was still observed in adrenalectomized mice. These results indicate that SNAP-25 phosphorylation is regulated in a stress-dependent manner through both central and peripheral mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2013.12.044DOI Listing
February 2014

Protein phosphatase 2A dephosphorylates SNAP-25 through two distinct mechanisms in mouse brain synaptosomes.

Neurosci Res 2013 Mar 1;75(3):184-9. Epub 2013 Feb 1.

Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan.

Synaptosomal-associated protein 25 (SNAP-25) plays an essential role in exocytotic neurotransmitter release as a t-SNARE protein. SNAP-25 is phosphorylated at Ser(187) in a protein kinase C (PKC)-dependent manner, but the mechanism for dephosphorylation has yet to be clarified. We investigated SNAP-25 dephosphorylation by comparing it to growth associated protein 43 (GAP-43), another PKC-dependent presynaptic phosphoprotein, in crude mouse brain synaptosome preparations. Phosphorylation levels for both SNAP-25 and GAP-43 increased significantly after treatment with PKC activator phorbol 12, 13-dibutyrate (PDB), and ionomycin treatment induced a striking reduction in a time-dependent manner. This dephosphorylation occurred only in the presence of extracellular Ca(2+), indicating involvement of a Ca(2+)-dependent phosphatase. Ca(2+)-dependent dephosphorylation was not suppressed by calcineurin/PP2B inhibitors such as FK506 and cyclosporine A. SNAP-25 dephosphorylation, however, was suppressed by calyculin A, a non-selective inhibitor of PP1 and PP2A, and okadaic acid selective for PP2A, but not by tautomycin selective for PP1. In contrast, none of these inhibitors suppressed GAP-43 dephosphorylation. PDB-induced SNAP-25 phosphorylation was enhanced by okadaic acid in a concentration-dependent manner. These results suggest that PP2A participates in SNAP-25 dephosphorylation through Ca(2+)-dependent and Ca(2+)-independent mechanisms but is not involved in GAP-43 dephosphorylation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neures.2013.01.002DOI Listing
March 2013
-->