ATP Synthase Subunit Epsilon Overexpression Promotes Metastasis by Modulating AMPK Signaling to Induce Epithelial-to-Mesenchymal Transition and Is a Poor Prognostic Marker in Colorectal Cancer Patients

Metastasis remains the major cause of death from colon cancer. We intend to identify differentially expressed genes that are associated with the metastatic process and prognosis in colon cancer. ATP synthase epsilon subunit (ATP5E) gene was found to encode the mitochondrial F0F1 ATP synthase subunit epsilon that was overexpressed in tumor cells compared to their normal counterparts, while other genes encoding the ATP synthase subunit were repressed in public microarray datasets. CRC cells in which ATP5E was silenced showed markedly reduced invasive and migratory abilities. ATP5E inhibition significantly reduced the incidence of distant metastasis in a mouse xenograft model. Mechanistically, increased ATP5E expression resulted in a prominent reduction in E-cadherin and an increase in Snail expression. Our data also showed that an elevated ATP5E level in metastatic colon cancer samples was significantly associated with the AMPK-AKT-hypoxia-inducible factor-1α (HIF1α) signaling axis; silencing ATP5E led to the degradation of HIF1α under hypoxia through AMPK-AKT signaling. Our findings suggest that elevated ATP5E expression could serve as a marker of distant metastasis and a poor prognosis in colon cancer, and ATP5E functions via modulating AMPK-AKT-HIF1α signaling.

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Patient-Derived, Drug-Resistant Colon Cancer Cells Evade Chemotherapeutic Drug Effects via the Induction of Epithelial-Mesenchymal Transition-Mediated Angiogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms21207469 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7469 ◽

Cited By ~ 1

Author(s):

Jin Hong Lim ◽

Kyung Hwa Choi ◽

Soo Young Kim ◽

Cheong Soo Park ◽

Seok-Mo Kim ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Xenograft Model ◽

Drug Effects ◽

Control Group ◽

Metastatic Colon Cancer ◽

Drug Resistant ◽

Colon Cancer Cells ◽

Mesenchymal Transition ◽

Mouse Xenograft Model

Cancer cells can exhibit resistance to different anticancer drugs by acquiring enhanced anti-apoptotic potential, improved DNA injury resistance, diminished enzymatic inactivation, and enhanced permeability, allowing for cell survival. However, the genetic mechanisms for these effects are unknown. Therefore, in this study, we obtained drug-sensitive HT-29 cells (commercially) and drug-resistant cancer cells (derived from biochemically and histologically confirmed colon cancer patients) and performed microarray analysis to identify genetic differences. Cellular proliferation and other properties were determined after treatment with oxaliplatin, lenvatinib, or their combination. In vivo, tumor volume and other properties were examined using a mouse xenograft model. The oxaliplatin and lenvatinib cotreatment group showed more significant cell cycle arrest than the control group and groups treated with either agent alone. Oxaliplatin and lenvatinib cotreatment induced the most significant tumor shrinkage in the xenograft model. Drug-resistant and metastatic colon cancer cells evaded the anticancer drug effects via angiogenesis. These findings present a breakthrough strategy for treating drug-resistant cancer.

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Downregulation of NEAT1 sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine through modulation of the miR-506-3p/ZEB2/EMT axis

10.21203/rs.3.rs-86053/v1 ◽

2020 ◽

Author(s):

Xiaowei Fu ◽

Xueqiang Deng ◽

Weidong Xiao ◽

Bo Huang ◽

Xuan Yi ◽

...

Keyword(s):

Pancreatic Cancer ◽

Drug Resistance ◽

Epithelial To Mesenchymal Transition ◽

Xenograft Model ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Mouse Xenograft ◽

Pancreatic Cancer Cells ◽

Mouse Xenograft Model ◽

Underlying Mechanisms

Abstract BackgroundChemoresistance is a major cause of treatment failure in pancreatic cancer (PC). It has been demonstrated that epithelial-to-mesenchymal transition (EMT) is closely related to drug resistance in PC; however, the underlying mechanisms are not yet fully understood. Recently found evidence has suggested that nuclear-enriched abundant transcript 1 (NEAT1) is involved in the development of chemoresistance. However, the role and mechanism of NEAT1 in PC gemcitabine resistance remain unknown.MethodsTwo independent gemcitabine-resistant (GR) PC cell lines, PANC-1/GR and SW1990/GR, were established. Transwell assays were used to validate whether GR cells acquired EMT. qRT-PCR and western blot were performed to detect the expression levels of NEAT1, miR-506-3p, and ZEB2 in GR cells. MTT and cell apoptosis assays were conducted to evaluate the sensitivity of GR cells to gemcitabine. Rescue experiments were employed to investigate whether NEAT1 mediates drug resistance of GR cells through modulation of the miR-506-3p/ZEB2/EMT axis. Furthermore, a mouse xenograft model was established to confirm these findings.ResultsGR cells displayed markedly enhanced migration and invasion abilities, decreased expression of E-cadherin, and upregulation of N-cadherin, Vimentin, Snail, ZEB1, and ZEB2. Furthermore, elevated expression of NEAT1 was observed in GR cells. Downregulation of NEAT1 sensitized GR cells to gemcitabine. More importantly, we demonstrated that downregulation of NEAT1 enhanced the sensitivity of GR cells to gemcitabine by reversing the EMT process. NEAT1 regulated ZEB2 expression by sponging miR-506-3p, and the function of NEAT1 in GR cells was dependent on miR-506-3p. These findings were further confirmed in a nude mouse xenograft model.ConclusionsTaken together, downregulation of NEAT1 sensitized the GR PC cells to gemcitabine through modulation of the miR-506-3p/ZEB2/EMT axis. These results provide a new direction for improving the chemotherapeutic effects in PC.

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Suppression of Notch1 and AKT mediated epithelial to mesenchymal transition by Verrucarin J in metastatic colon cancer

Cell Death and Disease ◽

10.1038/s41419-018-0810-8 ◽

2018 ◽

Vol 9 (8) ◽

Cited By ~ 13

Author(s):

Deeksha Pal ◽

Ashish Tyagi ◽

Balaji Chandrasekaran ◽

Houda Alattasi ◽

Murali K. Ankem ◽

...

Keyword(s):

Colon Cancer ◽

Epithelial To Mesenchymal Transition ◽

Metastatic Colon Cancer ◽

Mesenchymal Transition

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Coagulation abnormalities in patients with metastatic colon cancer on bevacizumab therapy

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14578 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14578-14578

Author(s):

P. Fradkina ◽

G. Locker ◽

H. Du

Keyword(s):

Colon Cancer ◽

Liver Tumors ◽

Xenograft Model ◽

Major Complication ◽

Liver Function Tests ◽

Bleeding Complications ◽

Tumor Type ◽

Metastatic Colon Cancer ◽

Human Colon Cancer ◽

Mouse Xenograft Model

14578 Background: Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF) that functions as an anti-angiogenic agent. VEGF is a glycoprotein, important for regulation of angiogenesis in normal and pathologic cells and is required for the maintenance of immature blood vessels, found in tumors. In addition to direct antiangiogenic effects, bevacizumab improves chemotherapy delivery by altering tumor vasculature as well as decreasing the size and number of liver tumors in mouse xenograft model of human colon cancer metastases. This study aimed to look for predictors of the development of major toxicities such as bleeding and clotting that would increase the incidence of such events in patients with metastatic colorectal carcinoma on Bevacizumab therapy. Methods: The study was a retrospective analysis over the past 2 years, reviewing the charts of 59 successive patients receiving bevacizumab in our institution. Particular emphasis was placed on age, gender, tumor type and location, location of metastases, chemotherapy regiment/number of cycles, past medical history, hemoglobin/hematocrit values, PT/INR values, liver function tests and albumin values at the time of the diagnosis and event. Utilizing univariant and multivariant analysis the goal was to determine contributing risk factors for increased incidence of bleeding and clotting. Results: 20.3% of the patients were found to have a major complication, such as clotting or bleeding. Once analyzed, there were four statistically significant indicators (p < 0.05) that predicted for the incidence of either one of the events. They included older patient age, low albumin values at the time of the event (as defined by the institution value of less than 3.6), location of the tumor (cecum, ascending colon and sigmoid colon were predominant), and the site of the metastasis (liver and lung). Conclusions: Clotting and bleeding complications in patients on Bevacizumab are not uncommon. It is clear that age, low albumin values, metastatic site and tumor location contribute to an increased incidence of such events in patients with metastatic colon cancer on Bevacizumab therapy. [Table: see text]

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N-Acetyltransferase 10 Enhances Doxorubicin Resistance in Human Hepatocellular Carcinoma Cell Lines by Promoting the Epithelial-to-Mesenchymal Transition

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/7561879 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Xiuming Zhang ◽

Jiang Chen ◽

Shi Jiang ◽

Shilin He ◽

Yanfeng Bai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Cell Lines ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Xenograft Model ◽

Mesenchymal Transition ◽

Mouse Xenograft Model ◽

Incorporation Assay ◽

Hcc Cells

Background. N-Acetyltransferase 10 (NAT10) has been reported to be expressed at high levels in hepatocellular carcinoma (HCC); however, its role in chemoresistance is unclear. This study is aimed at investigating whether NAT10 regulates the epithelial-mesenchymal transition (EMT) and chemoresistance in HCC. Methods. HCC cell lines (Huh-7, Bel-7402, SNU387, and SNU449) were treated with remodelin, an inhibitor of NAT10, or transfected with small inhibitory RNAs (siRNAs) targeting NAT10 or Twist. The EMT was induced by hypoxia. The CCK-8 assay was used to quantify cell viability, the EdU incorporation assay to assess cell proliferation. siRNA knockdown efficiency and epithelial/mesenchymal marker expression were assessed by western blotting. Results. Knockdown of NAT10 using siRNA or inhibition of NAT10 using remodelin increased the sensitivity of HCC cell lines to doxorubicin; similar effects were observed in cells transfected with the Twist siRNA. Inhibition of NAT10 using remodelin also reversed the ability of doxorubicin to induce the EMT in HCC cells. Furthermore, inhibiting NAT10 reversed the hypoxia-induced EMT. Finally, we confirmed that combining doxorubicin with remodelin delayed tumor growth and reduced tumor cell proliferation in a mouse xenograft model of HCC. Conclusions. NAT10 may contribute to chemoresistance in HCC by regulating the EMT. The mechanism by which NAT10 regulates the EMT and doxorubicin sensitivity in HCC cells merits further investigation.

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Modulation of the Cholesterol Pathway During Epithelial-to-Mesenchymal Transition Influences Tumor Molecular Differentiation and Disease-Free Survival in Colon Cancer Patients

SSRN Electronic Journal ◽

10.2139/ssrn.3989781 ◽

2021 ◽

Author(s):

Anaïs Aulas ◽

Maria Lucia Liberatoscioli ◽

Pascal Finetti ◽

Olivier Cabaud ◽

David J. Birnbaum ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Epithelial To Mesenchymal Transition ◽

Disease Free Survival ◽

Free Survival ◽

Mesenchymal Transition ◽

Molecular Differentiation ◽

Disease Free

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Hypoxia-inducible factor-1α induces CX3CR1 expression and promotes the epithelial to mesenchymal transition (EMT) in ovarian cancer cells

Journal of Ovarian Research ◽

10.1186/s13048-019-0517-1 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 9

Author(s):

Santosh Kumar Singh ◽

Manoj Kumar Mishra ◽

Rajesh Singh

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Hypoxia Inducible Factor ◽

Ovarian Cancer Cells ◽

Mesenchymal Transition ◽

Hypoxia Inducible Factor 1Α ◽

Cx3cr1 Expression

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Growing Evidence of Exosomal MicroRNA-Related Metastasis of Hepatocellular Carcinoma

BioMed Research International ◽

10.1155/2020/4501454 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Wenbing Sun ◽

Shuqi Fu ◽

Size Wu ◽

Rong Tu

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Cause Of Death ◽

Distant Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Regulate Gene Expression ◽

Mesenchymal Transition ◽

Exosomal Microrna ◽

Regulate Gene

Metastasis is the prominent cause of death in patients with hepatocellular carcinoma (HCC); however, the mechanisms behind HCC metastasis are not well understood. MicroRNAs (miRs) can regulate gene expression and affect HCC metastasis. Exosomes can transport miRs and other cargoes to and from different cells, thus being associated with tumour-distant metastasis. Exosomal miRs involve different processes of HCC metastasis through their functional effects, such as their induction of epithelial-to-mesenchymal transition, angiogenesis, and distant niche. In this review, data from the literature were analysed and summarised, with a focus on the evidence extraction of exosomal miRs in HCC metastasis with the purpose of increasing the understanding of the mechanisms behind HCC metastasis and acquiring implications for application.

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