Crk and CrkL as Therapeutic Targets for Cancer Treatment

Crk and CrkL are cellular counterparts of the viral oncoprotein v-Crk. Crk and CrkL are overexpressed in many types of human cancer, correlating with poor prognosis. Furthermore, gene knockdown and knockout of Crk and CrkL in tumor cell lines suppress tumor cell functions, including cell proliferation, transformation, migration, invasion, epithelial-mesenchymal transition, resistance to chemotherapy drugs, and in vivo tumor growth and metastasis. Conversely, overexpression of tumor cells with Crk or CrkL enhances tumor cell functions. Therefore, Crk and CrkL have been proposed as therapeutic targets for cancer treatment. However, it is unclear whether Crk and CrkL make distinct or overlapping contributions to tumor cell functions in various cancer types because Crk or CrkL have been examined independently in most studies. Two recent studies using colorectal cancer and glioblastoma cells clearly demonstrated that Crk and CrkL need to be ablated individually and combined to understand distinct and overlapping roles of the two proteins in cancer. A comprehensive understanding of individual and overlapping roles of Crk and CrkL in tumor cell functions is necessary to develop effective therapeutic strategies. This review systematically discusses crucial functions of Crk and CrkL in tumor cell functions and provides new perspectives on targeting Crk and CrkL in cancer therapy.

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Modulating Tumor Cell Functions by Tunable Nanopatterned Ligand Presentation

Nanomaterials ◽

10.3390/nano10020212 ◽

2020 ◽

Vol 10 (2) ◽

pp. 212

Author(s):

Katharina Amschler ◽

Michael P. Schön

Keyword(s):

Extracellular Matrix ◽

Tumor Cell ◽

Cell Fate ◽

Epithelial Mesenchymal Transition ◽

Model Systems ◽

Cellular Functions ◽

Biophysical Parameters ◽

Ligand Density ◽

Mesenchymal Transition ◽

Cell Functions

Cancer comprises a large group of complex diseases which arise from the misrouted interplay of mutated cells with other cells and the extracellular matrix. The extracellular matrix is a highly dynamic structure providing biochemical and biophysical cues that regulate tumor cell behavior. While the relevance of biochemical signals has been appreciated, the complex input of biophysical properties like the variation of ligand density and distribution is a relatively new field in cancer research. Nanotechnology has become a very promising tool to mimic the physiological dimension of biophysical signals and their positive (i.e., growth-promoting) and negative (i.e., anti-tumoral or cytotoxic) effects on cellular functions. Here, we review tumor-associated cellular functions such as proliferation, epithelial-mesenchymal transition (EMT), invasion, and phenotype switch that are regulated by biophysical parameters such as ligand density or substrate elasticity. We also address the question of how such factors exert inhibitory or even toxic effects upon tumor cells. We describe three principles of nanostructured model systems based on block copolymer nanolithography, electron beam lithography, and DNA origami that have contributed to our understanding of how biophysical signals direct cancer cell fate.

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Human Cancer Cells Express Slug-based Epithelial-Mesenchymal Transition Gene Signature Obtained in Vivo

Nature Precedings ◽

10.1038/npre.2011.6243.1 ◽

2011 ◽

Author(s):

Jessica Kandel ◽

Dimitris Anastassiou ◽

Viktoria Rumjantseva ◽

Wei-yi Cheng ◽

Jianzhong Huang ◽

...

Keyword(s):

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Gene Signature ◽

Mesenchymal Transition ◽

Human Cancer Cells

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β-Sitosterol and Gemcitabine Exhibit Synergistic Anti-pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial–Mesenchymal Transition by Deactivating Akt/GSK-3β Signaling

Frontiers in Pharmacology ◽

10.3389/fphar.2018.01525 ◽

2019 ◽

Vol 9 ◽

Cited By ~ 8

Author(s):

Zhang-qi Cao ◽

Xue-xi Wang ◽

Li Lu ◽

Jing-wen Xu ◽

Xiao-bin Li ◽

...

Keyword(s):

Pancreatic Cancer ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Combined Treatment ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Gsk 3Β ◽

Cancer Activity

β-sitosterol (BS), a major bioactive constituent present in plants, has shown potent anti-cancer activity against many human cancer cells, but its activity in pancreatic cancer (PC) cells has rarely been reported. Gemcitabine (GEM) is one of the first-line drugs for PC therapy, however, the treatment effect is not sustained due to prolonged drug resistance. In this study, we firstly studied the anti-PC activity and the mechanism of BS alone and in combination with GEM in vitro and in vivo. BS effectively inhibited the growth of PC cell lines by inhibiting proliferation, inducing G0/G1 phase arrest and apoptosis, suppressed the NF- kB activity, and increased expression of the protein Bax but decreased expression of the protein Bcl-2. Moreover, BS inhibited migration and invasion and downregulated epithelial–mesenchymal transition (EMT) markers and AKT/GSK-3β signaling pathways. Furthermore, the combination of BS and GEM exhibited a significant synergistic effect in MIAPaCa-2 and BXPC-3 cells. More importantly, the combined treatment with BS and GEM lead to significant growth inhibition of PC xenografts. Overall, our data revealed a promising treatment option for PC by the combination therapy of BS and GEM.

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P11.16 The stemness andinvasiveness of glioblastoma tumorspheres were suppressed by combined treatment with2’-hydroxycinnamaldehyde andtemozolomide

Neuro-Oncology ◽

10.1093/neuonc/noz126.162 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii45-iii46

Author(s):

W Kim

Keyword(s):

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Expression Profiles ◽

Combined Treatment ◽

Xenograft Model ◽

Therapeutic Effects ◽

Mesenchymal Transition ◽

Orthotopic Xenograft ◽

Orthotopic Xenograft Model

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive human primary brain malignancy. The key properties of GBM, stemness and invasiveness, are known to be associated with a highly unfavorable prognosis. Notably, the process of epithelial-mesenchymal transition (EMT) is closely related to the progression of GBM. On the basis of reports that 2′-hydroxycinnamaldehyde (HCA) and its derivative, 2′-benzoyloxycinnamaldehyde (BCA), suppresses EMT in several human cancer cells, we sought to evaluate the therapeutic efficacy of HCA and BCA, alone and in combination with temozolomide (TMZ), on GBM tumorspheres (TSs). MATERIAL AND METHODS Two human GBM TSs were treated with HCA, BCA, or TMZ. Therapeutic effects were evaluated by measuring ATP levels, neurosphere formation, 3D-invasion in collagen matrix, and viability. Protein expression profiles after drug treatment were evaluated by western blotting. In vivo anticancer efficacy of drugs was examined in a mouse orthotopic xenograft model. RESULTS Combined treatment of GBM TSs with HCA or BCA and TMZ significantly reduced cell viability, stemness, and invasiveness. Expression levels of stemness-, invasiveness-, and mesenchymal transition-associated markers, Zeb1, N-cadherin, and β-catenin, were also substantially decreased by the combined treatment. The combined treatment also reduced tumor growth in a mouse orthotopic xenograft model. CONCLUSION Our findings suggest that HCA and BCA, combined with TMZ, are potential therapeutic agents in the treatment of GBM.

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Irradiation Activates MZF1 to Inhibit miR-541-5p Expression and Promote Epithelial-Mesenchymal Transition (EMT) in Radiation-Induced Pulmonary Fibrosis (RIPF) by Upregulating Slug

International Journal of Molecular Sciences ◽

10.3390/ijms222111309 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11309

Author(s):

Xinxin Liang ◽

Ziyan Yan ◽

Ping Wang ◽

Yuhao Liu ◽

Xingkun Ao ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Therapeutic Targets ◽

Alveolar Epithelial Cells ◽

Mesenchymal Transition ◽

Alveolar Epithelial ◽

Radiation Induced ◽

Myeloid Zinc Finger

Understanding miRNAs regulatory roles in epithelial-mesenchymal transition (EMT) would help establish new avenues for further uncovering the mechanisms underlying radiation-induced pulmonary fibrosis (RIPF) and identifying preventative and therapeutic targets. Here, we demonstrated that miR-541-5p repression by Myeloid Zinc Finger 1 (MZF1) promotes radiation-induced EMT and RIPF. Irradiation could decrease miR-541-5p expression in vitro and in vivo and inversely correlated to RIPF development. Ectopic miR-541-5p expression suppressed radiation-induced-EMT in vitro and in vivo. Knockdown of Slug, the functional target of miR-541-5p, inhibited EMT induction by irradiation. The upregulation of transcription factor MZF1 upon irradiation inhibited the expression of endogenous miR-541-5p and its primary precursor (pri-miR-541-5p), which regulated the effect of the Slug on the EMT process. Our finding showed that ectopic miR-541-5p expression mitigated RIPF in mice by targeting Slug. Thus, irradiation activates MZF1 to downregulate miR-541-5p in alveolar epithelial cells, promoting EMT and contributing to RIPF by targeting Slug. Our observation provides further understanding of the development of RIPF and determines potential preventative and therapeutic targets.

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TGFβ-induced expression of long noncoding lincRNA Platr18 controls breast cancer axonogenesis

Life Science Alliance ◽

10.26508/lsa.202101261 ◽

2021 ◽

Vol 5 (2) ◽

pp. e202101261

Author(s):

Simon Grelet ◽

Cécile Fréreux ◽

Clémence Obellianne ◽

Ken Noguchi ◽

Breege V Howley ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Cell ◽

Tumor Progression ◽

Primary Tumor ◽

Epithelial Mesenchymal Transition ◽

Metastatic Progression ◽

Mesenchymal Transition ◽

Elevated Expression

Metastasis is the leading driver of cancer-related death. Tumor cell plasticity associated with the epithelial–mesenchymal transition (EMT), an embryonic program also observed in carcinomas, has been proposed to explain the colonization of distant organs by the primary tumor cells. Many studies have established correlations between EMT marker expression in the primary tumor and metastasis in vivo. However, the longstanding model of EMT-transitioned cells disseminating to secondary sites is still actively debated and hybrid states are presently considered as more relevant during tumor progression and metastasis. Here, we describe an unexplored role of EMT on the tumor microenvironment by controlling tumor innervation. Using in vitro and in vivo breast tumor progression models, we demonstrate that TGFβ-mediated tumor cell EMT triggers the expression of the embryonic LincRNA Platr18 those elevated expression controls the expression of the axon guidance protein semaphorin-4F and other neuron-related molecules such as IGSF11/VSIG-3. Platr18/Sema4F axis silencing abrogates axonogenesis and attenuates metastasis. Our observations suggest that EMT-transitioned cells are also locally required in the primary tumor to support distant dissemination by promoting axonogenesis, a biological process known for its role in metastatic progression of breast cancer.

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Impaired AGO2/miR-185-3p/NRP1 axis promotes colorectal cancer metastasis

Cell Death and Disease ◽

10.1038/s41419-021-03672-1 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Xisheng Liu ◽

Xiaole Meng ◽

Xiao Peng ◽

Qianlan Yao ◽

Fangming Zhu ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Mesenchymal Transition ◽

Mirna Processing ◽

Neuropilin 1 ◽

Microrna Sequencing

AbstractIncreasing evidence suggests that global downregulation of miRNA expression is a hallmark of human cancer, potentially due to defects in the miRNA processing machinery. In this study, we found that the protein expression of Argonaute 2 (AGO2), a key regulator of miRNA processing, was downregulated in colorectal cancer (CRC) tissues, which was also consistent with the findings of the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Furthermore, the correlation between the levels of AGO2 and epithelial-mesenchymal transition (EMT) markers (E-cadherin and vimentin) indicated that reduced levels of AGO2 promoted EMT in CRC. Low expression of AGO2 was an indicator of a poor prognosis among CRC patients. Knockdown of AGO2 in CRC cells promoted migration, invasion and metastasis formation in vitro and in vivo but had no influence on proliferation. To provide detailed insight into the regulatory roles of AGO2, we performed integrated transcriptomic, quantitative proteomic and microRNA sequencing (miRNA-seq) analyses of AGO2 knockdown cells and the corresponding wild-type cells and identified neuropilin 1 (NRP1) as a new substrate of AGO2 via miR-185-3p. Our data provided evidence that knockdown of AGO2 resulted in a reduction of miR-185-3p expression, leading to the upregulation of the expression of NRP1, which is a direct target of miR-185-3p, and elevated CRC cell metastatic capacity. Inhibition of NRP1 or treatment with a miR-185-3p mimic successfully rescued the phenotypes of impaired AGO2, which suggested that therapeutically targeting the AGO2/miR-185-3p/NRP1 axis may be a potential treatment approach for CRC.

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New Molecular Mechanisms and Clinical Impact of circRNAs in Human Cancer

Cancers ◽

10.3390/cancers13133154 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3154

Author(s):

Giulia Fontemaggi ◽

Chiara Turco ◽

Gabriella Esposito ◽

Silvia Di Agostino

Keyword(s):

Protein Interactions ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Biological Activities ◽

Circular Rnas ◽

Mesenchymal Transition ◽

Rna Molecules ◽

Cell Functions ◽

Ability To Act

Next generation RNA sequencing techniques, implemented in the recent years, have allowed us to identify circular RNAs (circRNAs), covalently closed loop structures resulting in RNA molecules that are more stable than linear RNAs. This class of non-coding RNA is emerging to be involved in a variety of cell functions during development, differentiation, and in many diseases, including cancer. Among the described biological activities, circRNAs have been implicated in microRNA (miRNA) sequestration, modulation of protein–protein interactions and regulation of mRNA transcription. In human cancer, circRNAs were implicated in the control of oncogenic activities such as tumor cell proliferation, epithelial-mesenchymal transition, invasion, metastasis and chemoresistance. The most widely described mechanism of action of circRNAs is their ability to act as competing endogenous RNAs (ceRNAs) for miRNAs, lncRNAs and mRNAs, thus impacting along their axis, despite the fact that a variety of additional mechanisms of action are emerging, representing an open and expanding field of study. Furthermore, research is currently focusing on understanding the possible implications of circRNAs in diagnostics, prognosis prediction, effectiveness of therapies and, eventually, therapeutic intervention in human cancer. The purpose of this review is to discuss new knowledge on the mechanisms of circRNA action, beyond ceRNA, their impact on human cancer and to dissect their potential value as biomarkers and therapeutic targets.

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Long noncoding RNA AOC4P regulates tumor cell proliferation and invasion by epithelial–mesenchymal transition in gastric cancer

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284819827697 ◽

2019 ◽

Vol 12 ◽

pp. 175628481982769 ◽

Cited By ~ 9

Author(s):

Kecheng Zhang ◽

Canrong Lu ◽

Xiaohui Huang ◽

Jianxin Cui ◽

Jiyang Li ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Tumor Cell ◽

Epithelial Mesenchymal Transition ◽

Negative Control ◽

Tumor Cell Proliferation ◽

Mesenchymal Transition ◽

E Cadherin

Background: The clinical relevance and biological role of tissular AOC4P in gastric cancer (GC) remains to be clarified. Methods: The association between AOC4P expression and clinicopathological characteristics was investigated. In vitro, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were performed to explore the biological effects of AOC4P on GC cell proliferation, migration, invasion, and apoptosis in MGC-803 and BGC-823 cell lines. In vivo, animal experiments were conducted to confirm the in vitro findings. Quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence were used to investigate the potential mechanisms. Results: Expression levels of AOC4P were significantly higher in tumor tissues than in noncancerous tissues, and patients with high levels of AOC4P had poor overall and disease-free survival. AOC4P expression was correlated with lymphovascular invasion. In vitro, knockdown of AOC4P inhibited tumor cell proliferation, migration, and invasion, and promoted apoptosis of MGC-803 and BGC-823 cells. In vivo, BGC-823 cells transfected with AOC4P siRNA formed smaller and lighter tumors than BGC-823 cells transfected with negative control siRNA in severe combined immunodeficiency mice. Additionally, the si- AOC4P group had less proliferating cells and more apoptotic cells in tumor xenografts compared with the negative control. Mechanistically, knockdown of AOC4P decreased the expression of vimentin and MMP9, while increasing the expression of E-cadherin. Immunofluorescence confirmed the relationship between AOC4P expression and E-cadherin, vimentin, and MMP9 levels in clinical GC specimens. Conclusions: AOC4P promotes tumorigenesis and progression partly through epithelial–mesenchymal transition in GC. Additionally, AOC4P may serve as a prognostic biomarker for clinical decision making.

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Determining epithelial contribution to in vivo mesenchymal tumour expression signature using species-specific microarray profiling analysis of xenografts

Genetics Research ◽

10.1017/s0016672313000013 ◽

2013 ◽

Vol 95 (1) ◽

pp. 14-29 ◽

Cited By ~ 2

Author(s):

E. PURDOM ◽

C. RESTALL ◽

R. A. BUSUTTIL ◽

H. SCHLUTER ◽

A. BOUSSIOUTAS ◽

...

Keyword(s):

Gene Expression ◽

Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Drug Efficacy ◽

Cross Hybridization ◽

Mesenchymal Transition ◽

Human Cancer Cell Lines ◽

Species Specific

SummaryGene expression profiling using microarrays and xenograft transplants of human cancer cell lines are both popular tools to investigate human cancer. However, the undefined degree of cross hybridization between the mouse and human genomes hinders the use of microarrays to characterize gene expression of both the host and the cancer cell within the xenograft. Since an increasingly recognized aspect of cancer is the host response (or cancer–stroma interaction), we describe here a bioinformatic manipulation of the Affymetrix profiling that allows interrogation of the gene expression of both the mouse host and the human tumour. Evidence of microenvironmental regulation of epithelial mesenchymal transition of the tumour component in vivo is resolved against a background of mesenchymal gene expression. This tool could allow deeper insight to the mechanism of action of anti-cancer drugs, as typically novel drug efficacy is being tested in xenograft systems.

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