scholarly journals Anti-invasion and anti-proliferation effects of 3-acetyl-5,8-dichloro-2-((2,4-di-chlorophenyl)amino)quinolin-4(1H)-one (ADQ) via regulation of Akt and Twist1 in liver cancer cells

2020 ◽  
Author(s):  
Jain Ha ◽  
Sewoong Lee ◽  
Jiyoung Park ◽  
Jihye Seo ◽  
Eunjeong Kang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Drug ◽  
Multicellular Tumor Spheroid ◽  
Carcinogenic Activity ◽  
Mesenchymal Transition ◽  
Cellular Invasion ◽  
Aggressive Cancer ◽  
Limited Oxygen

Abstract When primary cancer faces limited oxygen and nutrient supply, it undergoes an epithelial-mesenchymal transition, which increases cancer cell motility and invasiveness. The migratory and invasive cancer cells often exert aggressive cancer development or even cancer metastasis. In this study, we investigated a novel compound, 3-acetyl-5,8-dichloro-2-((2,4-dichlorophenyl)amino)quinolin-4(1H)-one (ADQ), that showed significant suppression of wound healing and cellular invasion. This compound also inhibited anchorage-independent cell growth, multicellular tumor spheroid survival/invasion, and metalloprotease activities. The anti-proliferative effects of ADQ were mediated by inhibition of the Akt pathway. In addition, ADQ reduced the expression of mesenchymal markers of cancer cells, which was associated with the suppressed expression of Twist1. In conclusion, ADQ successfully suppressed carcinogenic activity by inhibiting the Akt signaling pathway and Twist1, which suggests that ADQ may be an efficient candidate for cancer drug development.

scholarly journals Identification of a novel inhibitor of liver cancer cell invasion and proliferation through regulation of Akt and Twist1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jain Ha ◽  
Sewoong Lee ◽  
Jiyoung Park ◽  
Jihye Seo ◽  
Eunjeong Kang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Drug ◽  
Multicellular Tumor Spheroid ◽  
Carcinogenic Activity ◽  
Mesenchymal Transition ◽  
Cellular Invasion ◽  
Aggressive Cancer

AbstractWhen primary cancer faces limited oxygen and nutrient supply, it undergoes an epithelial–mesenchymal transition, which increases cancer cell motility and invasiveness. The migratory and invasive cancer cells often exert aggressive cancer development or even cancer metastasis. In this study, we investigated a novel compound, 3-acetyl-5,8-dichloro-2-((2,4-dichlorophenyl)amino)quinolin-4(1H)-one (ADQ), that showed significant suppression of wound healing and cellular invasion. This compound also inhibited anchorage-independent cell growth, multicellular tumor spheroid survival/invasion, and metalloprotease activities. The anti-proliferative effects of ADQ were mediated by inhibition of the Akt pathway. In addition, ADQ reduced the expression of mesenchymal markers of cancer cells, which was associated with the suppressed expression of Twist1. In conclusion, ADQ successfully suppressed carcinogenic activity by inhibiting the Akt signaling pathway and Twist1, which suggests that ADQ may be an efficient candidate for cancer drug development.

scholarly journals Oxidized Phospholipids in Tumor Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 558
Author(s):  
Jin Kyung Seok ◽  
Eun-Hee Hong ◽  
Gabsik Yang ◽  
Hye Eun Lee ◽  
Sin-Eun Kim ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Autophagic Flux ◽  
Oxidized Phospholipids ◽  
Mcf7 Cells ◽  
Mesenchymal Transition ◽  
Tumor Tissues

Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.

scholarly journals Therapeutic Targeting of Epithelial Plasticity Programs: Focus on the Epithelial-Mesenchymal Transition

2017 ◽  
Vol 203 (2) ◽  
pp. 114-127 ◽  
Author(s):  
Reem Malek ◽  
Hailun Wang ◽  
Kekoa Taparra ◽  
Phuoc T. Tran
Keyword(s):  
Cancer Cells ◽  
Regulatory Networks ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
Therapeutic Targets ◽  
Treatment Resistance ◽  
Mesenchymal Transition ◽  
Epithelial Plasticity ◽  
Canonical Pathways

Mounting data points to epithelial plasticity programs such as the epithelial-mesenchymal transition (EMT) as clinically relevant therapeutic targets for the treatment of malignant tumors. In addition to the widely realized role of EMT in increasing cancer cell invasiveness during cancer metastasis, the EMT has also been implicated in allowing cancer cells to avoid tumor suppressor pathways during early tumorigenesis. In addition, data linking EMT to innate and acquired treatment resistance further points towards the desire to develop pharmacological therapies to target epithelial plasticity in cancer. In this review we organized our discussion on pathways and agents that can be used to target the EMT in cancer into 3 groups: (1) extracellular inducers of EMT, (2) the transcription factors that orchestrate the EMT transcriptome, and (3) the downstream effectors of EMT. We highlight only briefly specific canonical pathways known to be involved in EMT, such as the signal transduction pathways TGFβ, EFGR, and Axl-Gas6. We emphasize in more detail pathways that we believe are emerging novel pathways and therapeutic targets such as epigenetic therapies, glycosylation pathways, and immunotherapy. The heterogeneity of tumors and the dynamic nature of epithelial plasticity in cancer cells make it likely that targeting only 1 EMT-related process will be unsuccessful or only transiently successful. We suggest that with greater understanding of epithelial plasticity regulation, such as with the EMT, a more systematic targeting of multiple EMT regulatory networks will be the best path forward to improve cancer outcomes.

scholarly journals CD36 promotes the epithelial–mesenchymal transition and metastasis in cervical cancer by interacting with TGF-β

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Min Deng ◽  
Xiaodong Cai ◽  
Ling Long ◽  
Linying Xie ◽  
Hongmei Ma ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Cd36 Expression ◽  
Cervical Cancer Cells

Abstract Background Accumulating evidence indicates that CD36 initiates metastasis and correlates with an unfavorable prognosis in cancers. However, there are few reports regarding the roles of CD36 in initiation and metastasis of cervical cancer. Methods Using immunohistochemistry, we analyzed 133 cervical cancer samples for CD36 protein expression levels, and then investigated the correlation between changes in its expression and clinicopathologic parameters. The effect of CD36 expression on the epithelial–mesenchymal transition (EMT) in cervical cancer cells was evaluated by Western immunoblotting analysis. In vitro invasion and in vivo metastasis assays were also used to evaluate the role of CD36 in cervical cancer metastasis. Results In the present study, we confirmed that CD36 was highly expressed in cervical cancer samples relative to normal cervical tissues. Moreover, overexpression of CD36 promoted invasiveness and metastasis of cervical cancer cells in vitro and in vivo, while CD36 knockdown suppressed proliferation, migration, and invasiveness. We demonstrated that TGF-β treatment attenuated E-cadherin expression and enhanced the expression levels of CD36, vimentin, slug, snail, and twist in si-SiHa, si-HeLa, and C33a–CD36 cells, suggesting that TGF-β synergized with CD36 on EMT via active CD36 expression. We also observed that the expression levels of TGF-β in si-SiHa cells and si-HeLa cells were down-regulated, whereas the expression levels of TGF-β were up-regulated in C33a–CD36 cells. These results imply that CD36 and TGF-β interact with each other to promote the EMT in cervical cancer. Conclusions Our findings suggest that CD36 is likely to be an effective target for guiding individualized clinical therapy of cervical cancer.

scholarly journals NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype

2019 ◽  
Vol 11 (6) ◽  
pp. 251-263 ◽  
Author(s):  
Federico Bocci ◽  
Satyendra C Tripathi ◽  
Samuel A Vilchez Mercedes ◽  
Jason T George ◽  
Julian P Casabar ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Collective Cell Migration ◽  
Mesenchymal Transition ◽  
Regulatory Circuit ◽  
Clinical Records ◽  
E Cadherin

Abstract The epithelial-mesenchymal transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype – a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of circulating tumour cells (CTCs) – the prevalent mode of metastasis. Thus, identifying the molecular players that can enable cells to maintain a hybrid E/M phenotype is crucial to curb the metastatic load. Using an integrated computational-experimental approach, we show that the transcription factor NRF2 can prevent a complete EMT and instead stabilize a hybrid E/M phenotype. Knockdown of NRF2 in hybrid E/M non-small cell lung cancer cells H1975 and bladder cancer cells RT4 destabilized a hybrid E/M phenotype and compromised the ability to collectively migrate to close a wound in vitro. Notably, while NRF2 knockout simultaneously downregulated E-cadherin and ZEB-1, overexpression of NRF2 enriched for a hybrid E/M phenotype by simultaneously upregulating both E-cadherin and ZEB-1 in individual RT4 cells. Further, we predict that NRF2 is maximally expressed in hybrid E/M phenotype(s) and demonstrate that this biphasic dynamic arises from the interconnections among NRF2 and the EMT regulatory circuit. Finally, clinical records from multiple datasets suggest a correlation between a hybrid E/M phenotype, high levels of NRF2 and its targets and poor survival, further strengthening the emerging notion that hybrid E/M phenotype(s) may occupy the ‘metastatic sweet spot’.

miR-214 inhibits epithelial–mesenchymal transition of breast cancer cells via downregulation of RNF8

2019 ◽  
Vol 51 (8) ◽  
pp. 791-798 ◽  
Author(s):  
Lu Min ◽  
Chuanyang Liu ◽  
Jingyu Kuang ◽  
Xiaomin Wu ◽  
Lingyun Zhu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Proliferation And Invasion

Abstract MicroRNAs (miRNAs) are a class of endogenous noncoding genes that regulate gene expression at the posttranscriptional level. In recent decades, miRNAs have been reported to play important roles in tumor growth and metastasis, while some reported functions of a specific miRNA in tumorigenesis are contradictory. In this study, we reevaluated the role of miR-214, which has been reported to serve as an oncogene or anti-oncogene in breast cancer metastasis. We found that miR-214 inhibited breast cancer via targeting RNF8, a newly identified regulator that could promote epithelial–mesenchymal transition (EMT). Specifically, the survival rate of breast cancer patients was positively correlated with miR-214 levels and negatively correlated with RNF8 expression. The overexpression of miR-214 inhibited cell proliferation and invasion of breast cancer, while suppression of miR-214 by chemically modified antagomir enhanced the proliferation and invasion of breast cancer cells. Furthermore, miR-214 could modulate the EMT process via downregulating RNF8. To our knowledge, this is the first report that reveals the role of the miR-214–RNF8 axis in EMT, and our results demonstrate a novel mechanism for miR-214 acting as a tumor suppressor through the regulation of EMT.

Breast Cancer Metastasis: Role of Tumor Microenvironment and Resident Macropahges

2016 ◽  
Vol 1 (1) ◽  
pp. 48
Author(s):  
Khemraj Singh Baghel ◽  
Smrati Bhadauria
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Breast ◽  
Breast Cancer Metastasis ◽  
The Body ◽  
Tissue Remodelling ◽  
Mesenchymal Transition

Metastatic breast cancer is a stage of breast cancer wherever the disease has spread to distant parts of the body. Onset of metastasis is one of the biggest obstacles to the successful treatment of cancer. The potential of a tumor cell to metastasize profoundly depends on its microenvironment, or “niche” interactions with local components. Macrophages provide tropic support to tumors. Resident macrophages contribute a set of common functions, including their capability to defend against microbial infections, to maintain normal cell turnover and tissue remodelling, and to help repair sites of injury. Macrophages are recruited into the tumor microenvironment where they differentiate to become Tumor-associated-macrophages (TAMs). TAMs are the most abundant subpopulation of tumor-stroma and actively drive cancer cell invasion and metastasis. Cancer metastasis is not solely regulated by the deregulation of metastasis promoting or suppressing genes in cancer cells. Recently the interaction between the stromal cells and cancer cells has been demonstrated to promote cancer metastasis. TAMs can advocate epithelial-mesenchymal transition of cancer cells. Loss of e-cadherin, a major phenomenon of epithelial to mesenchymal transition (EMT), reduces adhesiveness and releases cancer cells to distant (secondary) sites. A positive correlation between tumor progression and the expression of matrix metallo proteinases (MMPs) in tumor tissues has been demonstrated in numerous human and animal studies. The dynamic interactions of cancer-cells with TAMs actively promote invasion-metastasis cascade through intercellular-signalling-networks that need better elucidation.

scholarly journals The long non-coding RNA ET-20 mediates EMT by impairing desmosomes in breast cancer cells

2021 ◽  
Author(s):  
Meera Saxena ◽  
Mizue Hisano ◽  
Melanie Neutzner ◽  
Maren Diepenbruck ◽  
Robert Ivanek ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Matrix Protein ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Cell Lines ◽  
Mesenchymal Transition ◽  
Invasive Human Breast Cancer

The vast majority of breast cancer-associated deaths are due to metastatic spread of cancer cells, a process aided by epithelial-mesenchymal transition (EMT). Mounting evidence has indicated that long non-coding RNAs (lncRNAs) also contribute to tumor progression. We report the identification of 114 novel lncRNAs that change their expression during TGFβ-induced EMT in murine breast cancer cells (referred to as EMT-associated transcripts; ETs). Of these, the ET-20 gene localizes in antisense orientation within the Tenascin C (Tnc) gene locus. Tnc is an extra-cellular matrix protein which is critical for EMT and metastasis formation. Both ET-20 and Tnc are regulated by the EMT master transcription factor Sox4. Notably, ablation of ET-20 lncRNA effectively blocks Tnc expression and with it EMT. Mechanistically, ET-20 interacts with desmosomal proteins, thereby impairing epithelial desmosomes and promoting EMT. A short transcript variant of ET-20 is found upregulated in invasive human breast cancer cell lines where it also promotes EMT. Targeting ET-20 appears a therapeutically attractive lead to restrain EMT and breast cancer metastasis in addition to its potential utility as a biomarker for invasive breast cancer.

scholarly journals Comparative study of transcriptomics-based scoring metrics for the epithelial-hybrid-mesenchymal spectrum

2020 ◽  
Author(s):  
Priyanka Chakraborty ◽  
Jason T George ◽  
Shubham Tripathi ◽  
Herbert Levine ◽  
Mohit Kumar Jolly
Keyword(s):  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Multinomial Logistic Regression ◽  
M Cells ◽  
M Cell ◽  
Mesenchymal Transition ◽  
Tumor Types

AbstractThe Epithelial-mesenchymal transition (EMT) is a cellular process implicated in embryonic development, wound healing, and pathological conditions such as cancer metastasis and fibrosis. Cancer cells undergoing EMT exhibit enhanced aggressive behavior characterized by drug resistance, tumor-initiation potential, and the ability to evade immune system. Recent in silico, in vitro, and in vivo evidence indicates that EMT is not an all-or-none process; instead, cells stably acquire one or more hybrid epithelial/mesenchymal (E/M) phenotypes which often can be more aggressive than purely epithelial or mesenchymal cell populations. Thus, the EMT status of cancer cells can prove to be a critical estimate of patient prognosis. Recent attempts have employed different transcriptomics signatures to quantify EMT status in cell lines and patient tumors. However, a comprehensive comparison of these methods, including their accuracy in identifying cells in the hybrid E/M phenotype(s), is lacking. Here, we compare three distinct metrics that score EMT on a continuum, based on the transcriptomics signature of individual samples. Our results demonstrate that these methods exhibit good concordance among themselves in quantifying the extent of EMT in a given sample. Moreover, scoring EMT using any of the three methods discerned that cells undergo varying extents of EMT across tumor types. Separately, our analysis also identified tumor types with maximum variability in terms of EMT and associated an enrichment of hybrid E/M signatures in these samples. Moreover, we also found that the multinomial logistic regression (MLR) based metric was capable of distinguishing between ‘pure’ individual hybrid E/M vs. mixtures of epithelial (E) and mesenchymal (M) cells. Our results, thus, suggest that while any of the three methods can indicate a generic trend in the EMT status of a given cell, the MLR method has two additional advantages: a) it uses a small number of predictors to calculate the EMT score, and b) it can predict from the transcriptomic signature of a population whether it is comprised of ‘pure’ hybrid E/M cells at the single-cell level or is instead an ensemble of E and M cell subpopulations.

scholarly journals Hybrid Epithelial/Mesenchymal State in Cancer Metastasis: Clinical Significance and Regulatory Mechanisms

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 623 ◽  
Author(s):  
Tsai-Tsen Liao ◽  
Muh-Hwa Yang
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Normal Tissue ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Regulatory Mechanisms ◽  
Dynamic Changes ◽  
Mesenchymal Transition ◽  
Stressful Environment ◽  
Metastatic Process

Epithelial-mesenchymal transition (EMT) has been well recognized for its essential role in cancer progression as well as normal tissue development. In cancer cells, activation of EMT permits the cells to acquire migratory and invasive abilities and stem-like properties. However, simple categorization of cancer cells into epithelial and mesenchymal phenotypes misleads the understanding of the complicated metastatic process, and contradictory results from different studies also indicate the limitation of application of EMT theory in cancer metastasis. Nowadays, growing evidence suggests the existence of an intermediate status between epithelial and mesenchymal phenotypes, i.e., the “hybrid epithelial-mesenchymal (hybrid E/M)” state, provides a possible explanation for those conflicting results. Appearance of hybrid E/M phenotype offers a more plastic status for cancer cells to adapt the stressful environment for proceeding metastasis. In this article, we review the biological importance of the dynamic changes between the epithelial and the mesenchymal states. The regulatory mechanisms encompassing the translational, post-translational, and epigenetic control for this complex and plastic status are also discussed.

Sign in / Sign up

Export Citation Format

Share Document