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Liu Y.L.,University of Newcastle | Lai F.,University of Newcastle | Wilmott J.S.,University of Sydney | Yan X.G.,University of Newcastle | And 9 more authors.
Oncotarget | Year: 2014

Reduction in the expression of the anti-survival BH3-only proteins PUMA and Bim is associated with the pathogenesis of melanoma. However, we have found that the expression of the other BH3-only protein Noxa is commonly upregulated in melanoma cells, and that this is driven by oncogenic activation of MEK/ERK. Immunohistochemistry studies showed that Noxa was expressed at higher levels in melanomas than nevi. Moreover, the expression of Noxa was increased in metastatic compared to primary melanomas, and in thick primaries compared to thin primaries. Inhibition of oncogenic BRAFV600E or MEK downregulated Noxa, whereas activation of MEK/ERK caused its upregulation. In addition, introduction of BRAFV600E increased Noxa expression in melanocytes. Upregulation of Noxa was due to a transcriptional increase mediated by cAMP responsive element binding protein, activation of which was also increased by MEK/ERK signaling in melanoma cells. Significantly, Noxa appeared necessary for constitutive activation of autophagy, albeit at low levels, by MEK/ERK in melanoma cells. Furthermore, it was required for autophagy activation that delayed apoptosis in melanoma cells undergoing nutrient deprivation. These results reveal that oncogenic activation of MEK/ERK drives Noxa expression to promote autophagy, and suggest that Noxa has an indirect anti-apoptosis role in melanoma cells under nutrient starvation conditions. Source


Croft A.,University of Newcastle | Croft A.,Oncology and Immunology Unit | Tay K.H.,University of Newcastle | Boyd S.C.,University of Sydney | And 8 more authors.
Journal of Investigative Dermatology | Year: 2014

Cancer cells commonly undergo chronic endoplasmic reticulum (ER) stress, to which the cells have to adapt for survival and proliferation. We report here that in melanoma cells intrinsic activation of the ER stress response/unfolded protein response (UPR) is, at least in part, caused by increased outputs of protein synthesis driven by oncogenic activation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) and promotes proliferation and protects against apoptosis induced by acute ER stress. Inhibition of oncogenic BRAF V600E or MEK-attenuated activation of inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) signaling of the UPR in melanoma cells. This was associated with decreased phosphorylation of eukaryotic initiation factor 4E (eIF4E) and nascent protein synthesis and was recapitulated by knockdown of eIF4E. In line with this, introduction of BRAF V600E into melanocytes led to increases in eIF4E phosphorylation and protein production and triggered activation of the UPR. Similar to knockdown of glucose-regulated protein 78 (GRP78), inhibition of XBP1 decelerated melanoma cell proliferation and enhanced apoptosis induced by the pharmacological ER stress inducers tunicamycin and thapasigargin. Collectively, these results reveal that potentiation of adaptation to chronic ER stress is another mechanism by which oncogenic activation of the MEK/ERK pathway promotes the pathogenesis of melanoma. © 2014 The Society for Investigative Dermatology. Source


Wang S.,Shanxi Medical University | Gao S.,Shanxi Cancer Hospital and Institute | Yang W.,Shanxi Cancer Hospital and Institute | Guo S.,Shanxi Cancer Hospital and Institute | Li Y.,Shanxi Cancer Hospital and Institute
Techniques in Coloproctology | Year: 2016

Endoscopic submucosal dissection (ESD) and local excision (LE) are minimally invasive procedures that can be used to treat early rectal cancer. There are no current guidelines or consensus on the optimal treatment strategy for these lesions. A systematic review was conducted to compare the efficacy and safety of ESD and LE. A meta-analysis was conducted following all aspects of the Cochrane Handbook for systematic reviews and preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement. To perform the statistical analysis, the odds ratio (OR) was used for categorical variables and the weighted mean difference (WMD) for continuous variables. Four studies, involving a total of 307 patients, were identified. The length of hospital stay was longer in the group of patients undergoing LE [weighted mean difference (WMD) −1.94; 95 % CI −2.85 to −1.02; p < 0.0001]. The combined results of the individual studies showed no significant differences as regards en-bloc resection rate (OR 0.82; 95 % CI 0.25–2.70; p = 0.74), R0 resection rate (OR 1.53; 95 % CI 0.62–3.73; p = 0.35), overall complication rate (OR 0.67; 95 % CI 0.26–1.69; p = 0.40), and tumor size (WMD 0.57; 95 % CI −3.64 to 4.78; p = 0.79) between ESD and LE. When adopting the fixed effect model which takes into account the study size, ESD was associated with a lower recurrence rate than LE (OR 0.15; 95 % CI 0.03–0.87; p = 0.03), while with the random-effect model the difference was not significant (OR 0.18; 95 % CI 0.02–2.04; p = 0.17). Over the last decade improvements in technology have improved the technical feasibility of rectal ESD. In specialized centers with highly experienced endoscopists, ESD can provide high-quality en-bloc excision of rectal neoplasms equivalent to traditional local excision. © 2015, Springer-Verlag Italia Srl. Source


Guo S.T.,Shanxi Cancer Hospital and Institute | Jiang C.C.,University of Newcastle | Jiang C.C.,Hunter Medical Research Institute | Wang G.P.,Shanxi Cancer Hospital and Institute | And 14 more authors.
Oncogene | Year: 2013

Past studies have shown that amplified insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1-R) signalling has an important role in colorectal cancer (CRC) development, progression and resistance to treatment. In this report, we demonstrate that downregulation of microRNA-497 (miR-497) as a result of DNA copy number reduction is involved in upregulation of IGF1-R in CRC cells. MiR-497 and miR-195 of the miR-15/16/195/424/497 family that share the same 3′ untranslated region (3′UTR) binding seed sequence and are predicted to target IGF1-R were concurrently downregulated in the majority of CRC tissues relative to paired adjacent normal mucosa. However, only overexpression of miR-497 led to suppression of the IGF1-R 3′UTR activity and downregulation of the endogenous IGF1-R protein in CRC cells. This was associated with inhibition of cell survival, proliferation and invasion, and increased sensitivity to apoptosis induced by various stimuli including the chemotherapeutic drugs cisplatin and 5-fluorouracil, and the death ligand tumour necrosis factor-related apoptosis-inducing ligand. The biological effect of miR-497 on CRC cells was largely mediated by inhibition of phosphatidylinositol 3-kinase/Akt signalling, as overexpression of an active form of Akt reversed its impact on cell survival and proliferation, recapitulating the effect of overexpression of IGF1-R. Downregulation of miR-497 and miR-195 appeared to associate with copy number loss of a segment of chromosome 17p13.1, where these miRs are located at proximity. Similarly to miR-195, the members of the same miR family, miR-424 that was upregulated, and miR-15a, miR-15b and miR-16 that were unaltered in expression in CRC tissues compared with paired adjacent normal mucosa, did not appear to have a role in regulating the expression of IGF1-R. Taken together, these results identify downregulation of miR-497 as an important mechanism of upregulation of IGF1-R in CRC cells that contributes to malignancy of CRC. © 2013 Macmillan Publishers Limited. All rights reserved. Source


Wu P.Y.,Shanxi Medical University | Zhang X.D.,University of Newcastle | Zhang X.D.,Shanxi Cancer Hospital and Institute | Zhu J.,Shanghai Institute of Hematology | And 2 more authors.
Human Pathology | Year: 2014

Although diffuse large B-cell lymphoma (DLBCL) encompasses a biologically and clinically diverse set of diseases, increasing evidence has pointed to an important role of microRNAs (miRs) in the pathogenesis of DLBCL. We report here that low expression of miR-146b-5p and miR-320d is associated with poor prognosis of DLBCL patients treated with the standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen and that this is related to the inhibitory effect of these miRs on DLBCL cell proliferation. Analysis of a retrospective cohort of 106 primary nodal DLBCL samples from patients who were treated with CHOP showed that, when the median survival period (40.8 months) was used as the cutoff point, miR-146b-5p and miR-320d were expressed at lower levels in DLBCLs with poor prognosis. Indeed, whereas low expression of miR-146b-5p was correlated with reduced progression-free survival, low expression of miR-320d was associated with decreases in both progression-free survival and overall survival. Moreover, miR-146b-5p and miR-320d were expressed at significantly lower levels in DLBCLs with the MYC t(8;14) translocation. Functional studies demonstrated that overexpression of miR-146b-5p or miR-320d inhibited DLBCL cell proliferation, wheareas knockdown of miR-146b-5p or miR-320d promoted proliferation of DLBCL cells. Taken together, these results suggest that low expression of miR-146b-5p and miR-320d may be predictive of compromised responses of a subset of DLBCL patients to treatment with the CHOP regimen and that restoration of these miRs may be useful to improve the therapeutic efficacy of CHOP. © 2014 Elsevier Inc. Source

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