Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy

Hwang‐Verslues, Wendy W.; Chang, Po Hsiang; Jeng, Yung‐Ming; Kuo, Wen‐Hung; Chiang, Pei-Hsun; Chang, Yi‐Cheng; Hsieh, Tsung‐Han; Su, Fang‐Yi; Lin, Liu-Chen; Abbondante, Serena; Yang, Chengyuan; Hsu, Huan-Ming; Yu, Jyh‐Cherng; Chang, King‐Jen; Shew, Jin‐Yuh; Lee, Eva Y.-H.P.; Lee, Wen‐Hwa

doi:10.1073/pnas.1222684110

Cited by 128 publications

(119 citation statements)

References 53 publications

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“…Twist1 is an EMT transcriptional activator, and its downstream genes can accelerate tumor cell progression toward EMT and result in increased aggressiveness and metastasis. 36 Hypoxia in the tumor microenvironment is the most important trigger of VM. 15 HIF-1a-induced MMP-2 expression and EMT play significant roles in VM.…”

Section: Discussionmentioning

confidence: 99%

Anti-angiogenic treatment promotes triple-negative breast cancer invasion via vasculogenic mimicry

Sun

Zhang

Yao

et al. 2017

Cancer Biology & Therapy

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Agents that target angiogenesis have shown limited efficacy for human triple-negative breast cancer (TNBC) in clinical trials. Along with endothelium-dependent vessels, there is also vasculogenic mimicry (VM) in the microcirculation of malignant tumors. The role of VM is not completely understood regarding anti-angiogenic treatment. In this study, human TNBC MDA-MB-231 and Hs578T and non-TNBC MCF-7 and BT474 tumor-bearing mice were treated with sunitinib, an anti-angiogenic drug, using a clinically relevant schedule. The drug was administered for one week and then discontinued. Tumor growth and invasion were observed, and the microcirculation patterns were detected with PAS/endomucin staining. Moreover, hypoxia and VM-associated proteins were evaluated with Hypoxyprobe kits and immunohistochemistry, respectively. Sunitinib significantly inhibited tumor growth in the TNBC and non-TNBC tumors. However, MDA-MB-231 and Hs578T tumors regrew and were more aggressive when the treatment was stopped. The discontinuation had no significant effect on the behavior of the non-TNBC MCF-7 and BT474 tumors. The growth of endothelium-dependent vessels in the TNBC MDA-MB-231 and Hs578T tumors were blocked by sunitinib, during which the number of VM channels significantly increased and resulted in a rebound of endothelium-dependent vessels after sunitinib discontinuation. Moreover, the VM-associated proteins VE-cadherin and Twist1 upregulated in the sunitinib-treated MDA-MB-231 and Hs578T tumors. Furthermore, the clinical significance of this upregulation was validated in 174 human breast cancers. The results from human breast cancer specimens indicated that there were more VM-positive TNBC cases than those in non-TNBC cases. HIF-1a, MMP2, VE-cadherin, and Twist1 were also expressed in a higher level in human TNBC compared with non-TNBC. In aconclusion, sunitinib promoted TNBC invasion by VM. The VM status could be helpful to predict the efficacy of anti-angiogenic therapy in patients with TNBC.

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Section: Discussionmentioning

confidence: 99%

Anti-angiogenic treatment promotes triple-negative breast cancer invasion via vasculogenic mimicry

Sun

Zhang

Yao

et al. 2017

Cancer Biology & Therapy

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“…Consistent with this notion, we demonstrate that the inhibition of either ERK or eHsp90 ablates the EZH2 repressive mark in histone lysates, further reinforcing an eHsp90-ERK regulatory node for EZH2 function. As EZH2 cooperates with a panoply of cofactors to elicit the repressive function (37,(45)(46)(47), further work will be required to delineate the accessory factors mediating EZH2 recruitment to E-cadherin, as well as how eHsp90-ERK signaling may impact upon these associations.…”

Section: Discussionmentioning

confidence: 99%

Tumor-secreted Hsp90 Subverts Polycomb Function to Drive Prostate Tumor Growth and Invasion

Nolan

Franco

Hance

et al. 2015

Journal of Biological Chemistry

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Background: Extracellular Hsp90 (eHsp90) is implicated in cancer cell motility and invasion. Results: Tumor eHsp90 regulates ERK signaling, EZH2 expression, and histone methylation to facilitate prostate tumor growth and invasion. Conclusion: Newly characterized epigenetic functions of eHsp90 contribute to prostate tumorigenesis. Significance: Epigenetic modulation by eHsp90 may be a key facilitator in the transition of indolent to aggressive disease, highlighting a novel molecular effector of disease progression.

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“…From a molecular point of view, the hallmark of EMT is the decreased E-caderin expression and the activation of transcription factors such as SNAIL, SLUG, TWIST1, and also STAT3 [26,27]. The interaction between the aforementioned transcription factors can also be found within malignancies, as they are involved in the generation and the progression of the tumor [28][29][30][31]. These molecular events are reflected in the cell phenotype, the transition from an epithelial phenotype to a mesenchymal one leading to a decrease in the expression of adhesion molecules, to a loss of cellular adhesion, of polarity, followed by the detachment of cells that acquire invasive properties, just as in the case of diffuse gastric carcinoma [32].…”

Section: Discussionmentioning

confidence: 99%

The Lauren Classification Highlights the Role of Epithelialto- Mesenchymal Transition in Gastric Carcinogenesis: an Immunohistochemistry Study of the STAT3 and Adhesion Molecules Expression

Şuşman¹,

Barnoud²,

Bibeau³

et al. 2015

JGLD

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Background & Aims: Despite some recent advances, gastric cancer remains an important cause of death at world level. This indicates an absence of therapeutic options, stemming from the limited understanding of the molecular mechanisms involved in carcinogenesis. Nearly fifty years ago Lauren classified gastric cancers, according to the morphological aspect, as intestinal or diffuse. The phenotype of the cells indicates the presence of different molecular mechanisms, which can be approached in the light of recent data and identified with the help of current techniques. The best described are the germline/somatic mutations or the hypermethylations of the E-cadherin 1 CDH1 gene promotor.Methods. We analyzed 195 gastric tumors,120 intestinal and 75 diffuse type, using immunohistochemistry (tissue microarray TMA method) for pStat3Tyr705, E-cadherin, α-catenin and β-catenin; 985 spots of gastric tumors, distributed on 4 TMA blocks were analyzed. For pStat3Tyr705 we took the nuclear staining into account and for the adhesion molecules, membrane staining.Results. In our study, in the diffuse type gastric cancer, pStat3Tyr705 nuclear expression was statistically significantly increased (p=0.003). Also we observed a decreased expression of the adhesion molecules in the same type of gastric cancer (E-cadherin p<0.0001, α-catenin p<0.0001, β-catenin p<0.0001), suggesting that epithelial-to-mesenchymal transition (EMT) may be involved not only in gastric carcinogenesis, but also in resistance to treatment.Conclusion. The Stat3 role has been recently highlighted in carcinogenesis of the diffuse type of gastric cancer. We found that the morphological features of the diffuse type also suggest the involvement of EMT in this type of gastric cancer. Therefore, targeting the key molecules involved in this process may interfere with EMT process in the diffuse type of gastric cancer.

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Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy

Cited by 128 publications

References 53 publications

Anti-angiogenic treatment promotes triple-negative breast cancer invasion via vasculogenic mimicry

Anti-angiogenic treatment promotes triple-negative breast cancer invasion via vasculogenic mimicry

Tumor-secreted Hsp90 Subverts Polycomb Function to Drive Prostate Tumor Growth and Invasion

The Lauren Classification Highlights the Role of Epithelialto- Mesenchymal Transition in Gastric Carcinogenesis: an Immunohistochemistry Study of the STAT3 and Adhesion Molecules Expression

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