Showing papers by "Japanese Foundation for Cancer Research published in 2008"
TL;DR: Time-lapse imaging is performed to explore the spatiotemporal patterns of cell-cycle dynamics during the epithelial-mesenchymal transition of cultured cells, the migration and differentiation of neural progenitors in brain slices, and the development of tumors across blood vessels in live mice.
1,946 citations
TL;DR: In the present first investigation of EML4-ALK fusion in a large study of lung cancers, an interesting histotype-genotype relationship is found and the fusion protein could be detected by immunohistochemistry, pointing to possible clinical applications.
443 citations
TL;DR: The LECS procedure for dissection of gastric submucosal tumors such as GIST may be performed safely with reasonable operation times, less bleeding, and adequate cut lines.
Abstract: Laparoscopic wedge resections are increasingly applied for gastric submucosal tumors such as gastrointestinal stromal tumor (GIST). Despite this, no defined strategy exists to guide the surgeon in choosing the appropriate laparoscopic technique for an individual case on the basis of tumor characteristics such as location or size. This study aimed to introduce a laparoscopic and endoscopic cooperative surgery (LECS) for gastric wedge resection that is applicable for submucosal tumor resection independent of tumor location and size. Seven patients underwent LECS for the resection of gastric submucosal tumors. Both mucosal and submucosal layers around the tumor were circumferentially dissected using endoscopic submucosal dissection via intraluminal endoscopy. Subsequently, the seromusclar layer was laparoscopically dissected on the exact three-fourths cut line around the tumor. The submucosal tumor then was exteriorized to the abdominal cavity and dissected with a standard endoscopic stapling device. In all cases, the LECS procedure was successful for dissecting out the gastric submucosal tumor. In four of seven cases, the tumor was located in the upper gastric portion near the esophagogastric junction. The remaining three tumors were in the posterior gastric wall. In two cases, the tumors were more than 5 cm in diameter, and one was a GIST of the remnant stomach. The mean operation time was 169 ± 17 min, and the estimated blood loss was 7 ± 2 ml. The postoperative course was uneventful in all cases. The LECS procedure for dissection of gastric submucosal tumors such as GIST may be performed safely with reasonable operation times, less bleeding, and adequate cut lines. In addition, the success of the procedure does not depend on the tumor location such as the vicinity of the esophagogastric junction or pyloric ring.
401 citations
TL;DR: Findings suggest that ACLY is involved in lung cancer pathogenesis associated with metabolic abnormality and might offer a novel therapeutic target.
Abstract: Enhanced glucose and lipid metabolism is one of the most common properties of malignant cells. ATP citrate lyase (ACLY) is a key enzyme of de novo fatty acid synthesis responsible for generating cytosolic acetyl-CoA and oxaloacetate. To evaluate its role in lung cancer progression, we here analyzed ACLY expression in a subset of human lung adenocarcinoma cell lines and showed a relationship with the phosphatidyl-inositol-3 kinase–Akt pathway. The introduction of constitutively active Akt into cells enhanced the phosphorylation of ACLY, whereas dominant-negative Akt caused attenuation. In human lung adenocarcinoma samples, ACLY activity was found to be significantly higher than in normal lung tissue. Immunohistochemical analysis further showed phosphorylated ACLY overexpression in 162 tumors, well-correlating with stage, differentiation grade, and a poorer prognosis. Finally, to show the therapeutic potential and mechanism of ACLY inhibition for lung cancer treatment, we assessed the effect of RNA interference targeting ACLY on lipogenesis and cell proliferation in A549 cells. ACLY inhibition resulted in growth arrest in vitro and in vivo. Interestingly, increased intracellular lipids were found in ACLY knockdown cells, whereas de novo lipogenesis was inhibited. Supplementation of insulin could rescue the proliferative arrest elicited by ACLY inhibition; however, in contrast, fatty acid palmitate induced cell death. Taken together, these findings suggest that ACLY is involved in lung cancer pathogenesis associated with metabolic abnormality and might offer a novel therapeutic target. [Cancer Res 2008;68(20):8547–54]
320 citations
TL;DR: ZO-1 may be functionally important for cell remodeling and tissue organization in both the embryonic and extraembryonic regions, thus playing an essential role in embryonic development.
Abstract: Zonula occludens (ZO)-1/2/3 are the members of the TJ-MAGUK family of membrane-associated guanylate kinases associated with tight junctions. To investigate the role of ZO-1 (encoded by Tjp1) in viv...
280 citations
TL;DR: It is shown that all the Pim family members (Pim1, Pim2, and Pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(Kip1), which plays a crucial role in tumor suppression by inhibiting abnormal cell cycle progression and tumorigenesis.
Abstract: The serine/threonine kinase Pim is known to promote cell cycle progression and to inhibit apoptosis leading to tumorigenesis. However, the precise mechanisms remain unclear. We show, herein, that all the Pim family members (Pim1, Pim2, and Pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27 Kip1 at threonine-157 and threonine-198 residues in cells and in vitro . The Pim-mediated phosphorylation induced p27 Kip1 binding to 14-3-3 protein, resulting in its nuclear export and proteasome-dependent degradation. Ectopic expression of Pim kinases overcome the G 1 arrest mediated by wild-type p27 Kip1 but not by phosphorylation-resistant T157A-p27 Kip1 or T198A-p27 Kip1 . In addition to the posttranslational regulations, p27 Kip1 promoter assay revealed that Pim kinases also had the ability to suppress p27 Kip1 transcription. Pim-mediated phosphorylation and inactivation of forkhead transcription factors, FoxO1a and FoxO3a, was involved in the transcriptional repression of the p27 Kip1 gene. In contrast, inhibition of Pim signaling by expressing the dominant-negative form of Pim1 increased nuclear p27 Kip1 level and attenuated cell proliferation. Because the CDK inhibitor p27 Kip1 plays a crucial role in tumor suppression by inhibiting abnormal cell cycle progression, Pim kinases promote cell cycle progression and tumorigenesis by down-regulating p27 Kip1 expression at both transcriptional and posttranslational levels. [Cancer Res 2008;68(13):5076–85]
263 citations
TL;DR: Members of the transforming growth factor‐β (TGF‐β) family are multifunctional proteins that regulate a wide variety of cellular responses, such as proliferation, differentiation, migration and apoptosis.
Abstract: Members of the transforming growth factor-beta (TGF-beta) family, including TGF-beta, activin and bone morphogenetic proteins (BMPs), are multifunctional proteins that regulate a wide variety of cellular responses, such as proliferation, differentiation, migration and apoptosis. Alterations in their downstream signaling pathways are associated with a range of human diseases like cancer. TGF-beta family members transduce signals through membrane serine/threonine kinase receptors and intracellular Smad proteins. The ubiquitin-proteasome pathway, an evolutionarily conserved cascade, tightly regulates TGF-beta family signaling. In this pathway, E3 ubiquitin ligases play a crucial role in the recognition and degradation of target proteins by the 26S proteasomes. Smad degradation regulates TGF-beta family signaling; HECT (homologous to the E6-accessory protein C-terminus)-type E3 ubiquitin ligases, Smad ubiquitin regulatory factor 1 (Smurf1), Smurf2, and a RING-type E3 ubiquitin ligase, ROC1-SCF(Fbw1a) have been implicated in Smad degradation. Smurf1 and Smurf2 bind to TGF-beta family receptors via the inhibitory Smads, Smad6 and Smad7, to induce their ubiquitin-dependent degradation. Arkadia, a RING-type E3 ubiquitin ligase, induces the ubiquitination and degradation of Smad7 and corepressors, c-Ski and SnoN, to enhance TGF-beta family signaling. Abnormalities in E3 ubiquitin ligases that control components of TGF-beta family signaling may lead to the development and progression of various cancers.
231 citations
TL;DR: It is suggested that BMPs as well as TGF-β promote invasion and bone metastasis of breast cancer.
Abstract: Transforming growth factor (TGF)-β is known to promote tumor invasion and metastasis. Although bone morphogenetic proteins (BMPs), members of the TGF-β family, are expressed in a variety of human carcinoma cell lines, their roles in tumor progression have not been fully clarified. In this study, we sought to determine the roles of BMPs in the progression of breast cancer bone metastasis using human breast cancer samples and a mouse xenograft model. Immunohistochemical analysis of samples from breast cancer patients as well as a mouse xenograft model of MDA-231-D, highly metastatic human breast cancer cells, revealed phospho-Smad2 and phospho-Smad1/5/8 staining in the nuclei of cancer cells in primary tumor and/or bone metastasis. Using a functional in vivo bioluminescence imaging system, we showed that TGF-β- and BMP-induced transcriptional pathways are active in bone metastatic lesions in vivo. In addition, both TGF-β3 and BMP-2 promoted the motility and invasiveness of the MDA-231-D cells in vitro. Moreover, expression of dominant-negative receptors for TGF-β and/or BMPs in the MDA-231-D cells inhibited invasiveness in vitro and bone metastasis in the xenograft model. These results suggest that BMPs as well as TGF-β promote invasion and bone metastasis of breast cancer.
222 citations
TL;DR: It is shown that hepatic Irs1 and Irs2 function in a distinct manner in the regulation of glucose homeostasis and the concept of the existence of a dynamic relay in hepatic insulin signaling during fasting and feeding is proposed.
220 citations
TL;DR: It is proposed that claudin-15-based formation of TJs to organize the microenvironment including ion conductance is important for normal-sized morphogenesis of the small intestine.
194 citations
TL;DR: Combined use of PI3K inhibitors with other chemotherapeutic agents or with radiotherapy produced synergistic therapeutic efficacies in treating cancer and showed reduced side effects.
Abstract: Phosphatidylinositol 3-kinases (PI3K) are a group of lipid kinases that phosphorylate phosphoinositides at the 3-hydroxyl group of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate, a second messenger with key roles in fundamental cellular responses such as cell proliferation and metabolism. Frequent mutations found in or amplification of the PIK3CA gene and loss of phosphatase and tensin homolog deleted on chromosome 10 function in human tumors suggest that PI3K is a potential target for cancer therapy. During the last 5 years, several specific PI3K inhibitors were developed that were directed against various diseases. Some of them revealed potent anticancer efficacy and are now undergoing clinical trials. Some PI3K inhibitors showed antiangiogenic effects. Combined use of PI3K inhibitors with other chemotherapeutic agents or with radiotherapy produced synergistic therapeutic efficacies in treating cancer and showed reduced side effects. The rapid progress made in developing novel PI3K inhibitors in recent years promises bright prospects for finding a PI3K-targeted anticancer drug in the near future.
TL;DR: It is shown that mice deficient in TSC2, specifically in pancreatic β cells (βTSC2−/− mice), manifest increased IGF-1-dependent phosphorylation of p70 S6 kinase and 4E-BP1 in islets as well as an initial increased islet mass attributable in large part to increases in the sizes of individual β cells.
Abstract: Recent studies have demonstrated the importance of insulin or insulin-like growth factor 1 (IGF-1) for regulation of pancreatic beta-cell mass. Given the role of tuberous sclerosis complex 2 (TSC2) as an upstream molecule of mTOR (mammalian target of rapamycin), we examined the effect of TSC2 deficiency on beta-cell function. Here, we show that mice deficient in TSC2, specifically in pancreatic beta cells (betaTSC2(-/-) mice), manifest increased IGF-1-dependent phosphorylation of p70 S6 kinase and 4E-BP1 in islets as well as an initial increased islet mass attributable in large part to increases in the sizes of individual beta cells. These mice also exhibit hypoglycemia and hyperinsulinemia at young ages (4 to 28 weeks). After 40 weeks of age, however, the betaTSC2(-/-) mice develop progressive hyperglycemia and hypoinsulinemia accompanied by a reduction in islet mass due predominantly to a decrease in the number of beta cells. These results thus indicate that TSC2 regulates pancreatic beta-cell mass in a biphasic manner.
TL;DR: Time-resolved static light-scattering analyses revealed that, in the presence of the protein, amorphous calcium phosphate particles increased their fractal dimension and molecular mass without increasing their gyration radii during a short period before precipitation, indicating heterogeneous growth transformation.
Abstract: An animal's hard tissue is mainly composed of crystalline calcium phosphate. In vitro, small changes in the reaction conditions affect the species of calcium phosphate formed, whereas, in vivo, distinct types of crystalline calcium phosphate are formed in a well-controlled spatiotemporal-dependent manner. A variety of proteins are involved in hard-tissue formation; however, the mechanisms by which they regulate crystal growth are not yet fully understood. Clarification of these mechanisms will not only lead to the development of new therapeutic regimens but will also provide guidance for the application of biomineralization in bionanotechnology. Here, we focused on the peptide motifs present in dentin matrix protein 1 (DMP1), which was previously shown to enhance hydroxylapatite (HAP) formation when immobilized on a glass substrate. We synthesized a set of artificial proteins composed of combinatorial arrangements of these motifs and successfully obtained clones that accelerated formation of HAP without immobilization. Time-resolved static light-scattering analyses revealed that, in the presence of the protein, amorphous calcium phosphate (ACP) particles increased their fractal dimension and molecular mass without increasing their gyration radii during a short period before precipitation. The protein thus facilitated reorganization of the internal structure of amorphous particles into ordered crystalline states, i.e., the direct transformation of ACP to HAP, thereby acting as a nucleus for precipitation of crystalline calcium phosphate. Without the protein, the fractal dimension, molecular mass, and gyration radii of ACP particles increased concurrently, indicating heterogeneous growth transformation.
TL;DR: Although ENKL is sensitive to radiotherapy, it shows a poorer response to chemotherapeutic agents than other lymphomas due to expression of p‐glycoprotein, so new therapeutic approaches must be considered.
Abstract: Extranodal NK/T-cell lymphoma, nasal type (ENKL) is mostly endemic to East Asia. It predominantly occurs in the nasal or paranasal areas and less frequently in the skin. Most of the tumours show NK-cell, but rarely T-cell, phenotypes. The Epstein-Barr virus (EBV) genome can be usually detected in lymphoma cells. Geographic localization of ENKL matches the endemic distribution of EBV, suggesting that EBV plays an important role in lymphomagenesis. Originally, NK-cell and T-cell types were believed to present the same clinicopathologic characteristics, but recent data suggest more aggressive characteristics for the NK-cell phenotype. Although ENKL is sensitive to radiotherapy, it shows a poorer response to chemotherapeutic agents than other lymphomas due to expression of p-glycoprotein. Therefore, new therapeutic approaches must be considered. Several new clinical trials are now being conducted in East Asia.
TL;DR: Modulation of the intrinsic ubiquitinligase activity could be a novel strategy to develop small molecules for therapeutic purposes to treat cancers expressing cIAP1, which interferes with treatment.
TL;DR: After initial management and 3 month follow-up, larger size (more than 10 mm) and a history of lung cancer are risk factors for GGO growth, and therefore should be considered when making a follow- up plan.
TL;DR: It is reported that functional ATX is selectively expressed in high endothelial venules (HEVs) of both lymph nodes and Peyer's patches, and surmise that ATX expressed by HEVs acts on HEVs in situ to facilitate lymphocyte binding to ECs and that ATx in the general circulation does not play a major role in this process.
Abstract: Autotaxin (ATX) is a secreted protein with lysophospholipase D activity that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine. Here we report that functional ATX is selectively expressed in high endothelial venules (HEVs) of both lymph nodes and Peyer's patches. ATX expression was developmentally regulated and coincided with lymphocyte recruitment to the lymph nodes. In adults, ATX expression was independent of HEV-expressed chemokines such as CCL21 and CXCL13, innate immunity signals including those via TLR4 or MyD88, and of the extent of lymphocyte trafficking across the HEVs. ATX expression was induced in venules at sites of chronic inflammation. Receptors for the ATX enzyme product LPA were constitutively expressed in HEV endothelial cells (ECs). In vitro, LPA induced strong morphological changes in HEV ECs. Forced ATX expression caused cultured ECs to respond to lysophosphatidylcholine, up-regulating lymphocyte binding to the ECs in a LPA receptor-dependent manner under both static and flow conditions. Although in vivo depletion of circulating ATX did not affect lymphocyte trafficking into the lymph nodes, we surmise, based on the above data, that ATX expressed by HEVs acts on HEVs in situ to facilitate lymphocyte binding to ECs and that ATX in the general circulation does not play a major role in this process. Tissue-specific inactivation of ATX will verify this hypothesis in future studies of its mechanism of action.
TL;DR: FEC followed by docetaxel is an active and manageable preoperative regimen for women with early stage breast cancer and QpCR following preoperative chemotherapy predicts favorable DFS.
Abstract: Purpose This multicenter phase II study examined the impact of pathological effect on survival after preoperative chemotherapy in Japanese women with early stage breast cancer. Patients and methods Prior to surgery, patients received four cycles of FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 q3w) followed by four cycles of docetaxel (75 mg/m2 q3w). Primary endpoint was 3 year disease free survival (DFS) stratified by the absence or presence of Quasi-pCR (QpCR; absence of invasive tumor or only focal residual tumor cells). Secondary endpoints were predictors for QpCR, clinical response, breast conservation rate, and safety. Results Between June 2002 and June 2004, 202 women were enrolled. Among 191 assessable patients, 25% achieved QpCR. With 40 months median follow-up, 3 year DFS was estimated at 91% for all patients. 3 year DFS for patients with QpCR was 98% vs. 89% without QpCR (hazard ratio 0.38 [95% Confidence Interval 0.09–0.84], P = 0.0134). HER2 status and response to FEC were independent predictors of QpCR. The overall clinical response was 75%; 85% of patients achieved breast conservation. Grade 3/4 neutropenia was the most common adverse event, observed in 44% and 35% of patients during FEC and docetaxel, respectively. Treatment related side effects were manageable; there were no treatment related fatalities. Conclusion FEC followed by docetaxel is an active and manageable preoperative regimen for women with early stage breast cancer. QpCR following preoperative chemotherapy predicts favorable DFS. HER2 overexpression and clinical response to FEC predict QpCR.
TL;DR: Evidence is provided that C/EBPbeta is a crucial cofactor in the promotion of osteoblast maturation by Runx2 and ATF4, and the expression of type X collagen as well as chondrocyte hypertrophy were suppressed in mutant bone, providing new insight into the possible roles of C/ EBPbeta.
Abstract: Although CCAAT/enhancer-binding protein beta (C/EBPbeta) is involved in osteocalcin gene expression in osteoblast in vitro, the physiological importance of and molecular mechanisms governing C/EBPbeta in bone formation remain to be elucidated In particular, it remains unclear whether C/EBPbeta acts as a homodimer or a heterodimer with other proteins during osteoblast differentiation Here, deletion of the C/EBPbeta gene from mice resulted in delayed bone formation with concurrent suppression of chondrocyte maturation and osteoblast differentiation The expression of type X collagen as well as chondrocyte hypertrophy were suppressed in mutant bone, providing new insight into the possible roles of C/EBPbeta in chondrocyte maturation In osteoblasts, luciferase reporter, gel shift, DNAP, and ChIP assays demonstrated that C/EBPbeta heterodimerized with activating transcription factor 4 (ATF4), another basic leucine zipper transcription factor crucial for osteoblast maturation This complex interacted and transactivated osteocalcin-specific element 1 (OSE1) of the osteocalcin promoter C/EBPbeta also enhanced the synergistic effect of ATF4 and Runx2 on osteocalcin promoter transactivation by enhancing their interaction Thus, our results provide evidence that C/EBPbeta is a crucial cofactor in the promotion of osteoblast maturation by Runx2 and ATF4
TL;DR: Histopathological criteria for assessment of response to neoadjuvant therapy for breast cancer have been established according to the degree of histological change of cancer tissue as described below.
Abstract: In preoperative drug therapy (chemo-, endocrine, molecular-targeting, and other therapies) and/or radiotherapy for breast cancer, various degrees of histological changes of cancer tissue occur depending on the sensitivity of cancer cells to the particular treatment, kinds of therapeutic agents, dosage of drugs, method of administration, kind of combination, type and dosage of isotope, method of irradiation, duration of treatment, interval from the last treatment, and resection of cancer tissue. Histopathological criteria for assessment of response to neoadjuvant therapy for breast cancer have been established according to the degree of histological change of cancer tissue as described below. Histological diagnosis should be confirmed before treatment using biopsy materials, and it is important to compare the histopathological findings of cancer tissues before and after treatment for the assessment of response to therapy. Pathological response should be evaluated only from histological changes in the invasive area, and the presence of residual ductal components should be described. If only ductal components remain, the pathological response is evaluated as Grade 3.
TL;DR: The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi‐institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross‐sectional approach based on genetic factors estimated from personal and family histories.
Abstract: The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi-institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross-sectional approach based on genetic factors estimated from personal and family histories. One hundred and thirty-five subjects were referred to the genetic counseling clinics and enrolled in the study. Full sequencing analysis of the BRCA1/2 gene showed 28 types of deleterious mutations in 36 subjects (26.7%), including 13 types of BRCA1 mutations in 17 subjects (12.6%) and 15 types of BRCA2 mutations in 19 subjects (14.1%). Subjects were classified into five groups and 22 subgroups according to their personal and family history of breast and/or ovarian cancer, and the prevalence of deleterious mutations was compared with previously reported data in non-Ashkenazi individuals. Statistical analysis using the Mantel-Haenszel test for groups I through IV revealed that the prevalence of Japanese subjects was significantly higher than that of non-Ashkenazi individuals (P = 0.005, odds ratio 1.87, 95% confidence interval 1.22-2.88). Family history of the probands suffering from breast cancer indicated risk factors for the presence of deleterious mutations of BRCA1/2 as follows: (1) families with breast cancer before age 40 within second degree relatives (P = 0.0265, odds ratio 2.833, 95% confidence interval 1.165-7.136) and (2) families with bilateral breast cancer and/or ovarian cancer within second degree relatives (P = 0.0151, odds ratio 2.88, 95% confidence interval 1.25-6.64).
TL;DR: CD5 expression was the only significant prognostic factor among the biomarkers examined in this study and further studies with larger numbers are warranted to confirm the prognostic significance of CD5 expression for patients with DLBCL receiving rituximab-containing chemotherapy.
01 Jan 2008
TL;DR: Aggrus is identified as a platelet-aggregating factor expressed on a number of human cancers and its main contribution to hematogenous metastasis of Aggrus-expressing cells is by promoting platelet aggregation.
Abstract: Metastasis is the major cause of death from cancer, yet the optimal strategy against it remains uncertain. The pathogenesis of hematogenous metastasis is dynamic and consists of the following steps: 1) detachment of tumor cells from the primary site, 2) invasion into the host's blood vessels, 3) migration in the host's blood stream, 4) transport along the circulation, 5) arrest in or adhesion to the capillary in a distant organ, 6) extravasation, and 7) proliferation within the foreign tissues. A key to successful hematogenous metastasis is tumor survival in the bloodstream because most circulating tumor cells are rapidly destroyed by the shear forces or are attacked by the immune system. Less than 0.01% of these cells result in metastasis. Tumor cell-induced platelet aggregation has been reported to facilitate hematogenous metastasis by increasing the arrest of tumor cell emboli in the microcirculation. Platelet aggregation is also believed to protect tumor cells from immunological assault in the circulation. We have identified Aggrus as a platelet-aggregating factor expressed on a number of human cancers. Because hematogenous metastasis is reduced when neutralizing antibodies or eliminating carbohydrates attenuates Aggrus function, Aggrus's main contribution to hematogenous metastasis of Aggrus-expressing cells, then, is by promoting platelet aggregation. Aggrus could serve as an ideal target for drug development to block metastasis.
TL;DR: New nomograms predicting prostate cancer on initial biopsy in men with PSA <20ng/ml are developed and predictive accuracy of these extended biopsy-based nomograms is better than those of previously established models based on 6-10-core biopsies.
TL;DR: The transcription factor Bach1 (BTB and CNC homology 1, basic leucine zipper transcription factor 1), which inhibits oxidative stress-inducible genes, is a crucial negative regulator of oxidative stress–induced cellular senescence.
Abstract: Cellular senescence is one of the key strategies to suppress expansion of cells with mutations. Senescence is induced in response to genotoxic and oxidative stress. Here we show that the transcription factor Bach1 (BTB and CNC homology 1, basic leucine zipper transcription factor 1), which inhibits oxidative stress-inducible genes, is a crucial negative regulator of oxidative stress-induced cellular senescence. Bach1-deficient murine embryonic fibroblasts showed a propensity to undergo more rapid and profound p53-dependent premature senescence than control wild-type cells in response to oxidative stress. Bach1 formed a complex that contained p53, histone deacetylase 1 and nuclear co-repressor N-coR. Bach1 was recruited to a subset of p53 target genes and contributed to impeding p53 action by promoting histone deacetylation. Because Bach1 is regulated by oxidative stress and heme, our data show that Bach1 connects oxygen metabolism and cellular senescence as a negative regulator of p53.
TL;DR: The standardized technique is considered to be safe and feasible for rectal transection and anastomosis using the double stapling technique (DST).
Abstract: Rectal transection and anastomosis at the lower rectum is the most challenging part of laparoscopic low anterior resection. Therefore, some have demonstrated that rectal transection should be performed using instruments for open surgery with small laparotomy. In our institute, however, rectal transection using a currently available endostapler followed by anastomosis with a double stapling technique is usually performed. The important points of our technique are as follows: trocar placement, optimal device choice, harmonious movement between the operator and assistant for rectal transection, optimal point of piercing with the center rod of the circular stapler, and ideal positioning of the proximal colon. Seventy-eight patients underwent low anterior resection using this technique. There were no conversions to open surgery. All rectal transections were completed laparoscopically with an available endostapler. A diverting ileostomy was created in six cases. Anastomotic leakage occurred in only two patients (2.6%) and rectovaginal fistula in only one patient (1.3%). Our standardized technique is considered to be safe and feasible for rectal transection and anastomosis using the double stapling technique (DST).
TL;DR: In this article, the roles of β1 integrin/Fak/Src signaling to the PI3-K/Akt-1, MEK/Erk, and p38 pathways were investigated.
Abstract: The molecular determinants which dictate survival and apoptosis/anoikis in human intestinal crypt cells remain to be fully understood. To this effect, the roles of β1 integrin/Fak/Src signaling to the PI3-K/Akt-1, MEK/Erk, and p38 pathways, were investigated. The regulation of six Bcl-2 homologs (Bcl-2, Mcl-1, Bcl-XL, Bax, Bak, Bad) was likewise analyzed. We report that: (1) Anoikis causes a down-activation of Fak, Src, Akt-1 and Erk1/2, a loss of Fak–Src association, and a sustained/enhanced activation of p38β, which is required as apoptosis/anoikis driver; (2) PI3-K/Akt-1 up-regulates the expression of Bcl-XL and Mcl-1, down-regulates Bax and Bak, drives Bad phosphorylation (both serine112/136 residues) and antagonizes p38β activation; (3) MEK/Erk up-regulates Bcl-2, drives Bad phosphorylation (serine112 residue), but does not antagonize p38β activation; (4) PI3-K/Akt-1 is required for survival, whereas MEK/Erk is not; (5) Src acts as a cornerstone in the engagement of both pathways by β1 integrins/Fak, and is crucial for survival; and (6) β1 integrins/Fak and/or Src regulate Bcl-2 homologs as both PI3-K/Atk-1 and MEK/Erk combined. Hence, β1 integrin/Fak/Src signaling translates into integrated mediating functions of p38β activation and regulation of Bcl-2 homologs by PI3-K/Akt-1 and MEK/Erk, consequently determining their requirement (or not) for survival.
TL;DR: Results indicate that two related E3 ubiquitin ligases, Smurf1 andSmurf2, act in the same direction in TGF-β family signaling but play opposite roles in cell migration.
TL;DR: CD9 may act as a metastasis suppressor, at least in part, by neutralizing Aggrus-mediated platelet aggregation and metastasis induced by forced expression of Aggrus in CHO cells.
TL;DR: It is shown that p15INK4b and p19INK4d transcription is associated with FOXO-mediated G1 cell-cycle arrest and is involved in G1 arrest caused by Akt inactivation via p15inkle4band p19inkle4d.
Abstract: FOXO (Forkhead box O) transcription factors are involved in cell-cycle arrest or apoptosis induction by transcripting cell-cycle inhibitor p27(KIP1) or apoptosis-related genes, respectively. Akt/protein kinase B promotes cell proliferation and suppresses apoptosis, in part, by phosphorylating FOXOs. Phosphorylated FOXOs could not exhibit transcriptional activity because of their nuclear export. Here we show that p15(INK4b) and p19(INK4d) transcription is associated with FOXO-mediated G1 cell-cycle arrest. Inhibition of Akt signaling by PI3K inhibitors, a PDK1 inhibitor, or dominant-negative Akt transfection increased expression of p15(INK4b) and p19(INK4d) but not p16(INK4a) and p18(INK4c). Ectopic expression of wild type or active FOXO but not inactive form also increased p15(INK4b) and p19(INK4d) levels. FOXOs bound to promoter regions and induced transcription of these genes. No increase in the G1-arrested cell population, mediated by PI3K inhibitor LY294002, was observed in INK4b-/- or INK4d-/- murine embryonic fibroblasts. In summary, FOXOs are involved in G1 arrest caused by Akt inactivation via p15(INK4b) and p19(INK4d) transcription.