scholarly journals MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer

2021 ◽  
Author(s):  
ManSai Acón ◽  
Carsten Geiß ◽  
Jorge Torres-Calvo ◽  
Guillermo Oviedo ◽  
Jorge L Arias-Arias ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Dosage Compensation ◽  
Patient Survival ◽  
Gene Dosage ◽  
Negative Effects ◽  
Over Expression ◽  
Factor Interactions ◽  
Computational Platform ◽  
Omic Data

AbstractCancer complexity is consequence of genomic instability leading to aneuploidy. We hypothesize that dosage compensation of critical genes arise from systems-level properties for cancer cells to withstand the negative effects of aneuploidy. We developed a computational platform to identify a network of miRNAs and transcription factors interacting with candidate dosage-compensated genes using NCI-60 multi-omic data. We next constructed a mathematical model where the property of dosage compensation emerged for MYC and STAT3 and was dependent on the kinetic parameters of their feedback and feed-forward interactions with four miRNAs. We developed a genetic tug-of-war approach by overexpressing an exogenous MYC sequence to experimentally validate MYC dosage compensation circuits as demonstrated by the over-expression of the three microRNAs involved and the respective down-regulation of endogenous MYC. In addition, MYC overexpression or inhibition of its compensating miRNAs led to dosage-dependent cytotoxicity in MYC-amplified colon cancer cells. The study of TCGA breast cancer patient data indicated that MYC dosage compensation could lead to lower patient survival, highlighting the potential of targeting gene dosage compensation to prevent aneuploid cancer progression.(BioNetUCR, available here: https://cloud.prislab.org/s/gt2W2jfZQx3E3Jm).

scholarly journals Alterations of the Hsp70/Hsp90 chaperone and the HOP/CHIP co-chaperone system in cancer

2012 ◽  
Vol 17 (3) ◽  
Author(s):  
Eva Ruckova ◽  
Petr Muller ◽  
Rudolf Nenutil ◽  
Borivoj Vojtesek
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Binding Sites ◽  
Patient Survival ◽  
Proliferating Cells ◽  
Response Elements ◽  
Over Expression ◽  
Hsp90 Activity ◽  
Hsp90 Chaperone ◽  
Client Proteins

AbstractActivation of the Hsp90 chaperone system is a characteristic of cancer cells. The regulation of chaperone activities involves their interaction with cochaperones; therefore we investigated the expression of Hsp70 and Hsp90 and their specific co-chaperones HOP and CHIP in cancer cell lines and primary cancers. Inhibition of Hsp90 by 17AAG increased the levels of Hsp70, Hsp90 and HOP but not CHIP mRNA in cancer cells. These changes are linked to activation of the HSF1 transcription factor and we show that the HOP promoter contains HSF1 binding sites, and that HSF1 binding to the HOP promoter is increased following 17AAG. The lack of alteration in the co-chaperone CHIP is explained by a lack of HSF response elements in the CHIP promoter. Non-proliferating cells expressed higher levels of CHIP and lower HOP, Hsp70 and Hsp90 levels compared to proliferating cells. Decreased expression of CHIP in proliferating cancer cells is in keeping with its proposed tumor suppressor properties, while over-expression of HOP in proliferating cells may contribute to excessive Hsp90 activity and stabilization of client proteins in tumors. In a panel of colorectal cancer samples, increased expression of Hsp70 and an increased ratio of HOP to CHIP were found, and were associated with decreased median survival. These data indicate that multiple changes occur in the chaperone/co-chaperone system in cancer that impact patient survival. It is likely that the ability to identify individual alterations to this system will be beneficial for treatment strategy decisions, particularly those that employ chaperone inhibitors.

EDD1 predicts prognosis and regulates gastric cancer growth in vitro and in vivo via miR-22

2016 ◽  
Vol 0 (0) ◽  
Author(s):  
Min Yang ◽  
Nan Jiang ◽  
Qi-wei Cao ◽  
Qing Sun
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Patient Survival ◽  
Underlying Mechanism ◽  
Gastric Cancer Cells ◽  
Cancer Tissues

Abstract Gastric cancer is the most common digestive malignant tumor worldwild. EDD1 was reported to be frequently amplified in several tumors and played an important role in the tumorigenesis process. However, the biological role and potential mechanism of EDD1 in gastric cancer remains poorly understood. In this study, we are aim to investigate the effect of EDD1 on gastric cancer progression and to explore the underlying mechanism. The results showed the significant up-regulation of EDD1 in -gastric cancer cell tissues and lines. The expression level of EDD1 was also positively associated with advanced clinical stages and predicted poor overall patient survival and poor disease-free patient survival. Besides, EDD1 knockdown markedly inhibited cell viability, colony formation, and suppressed tumor growth. Opposite results were obtained in gastric cancer cells with EDD1 overexpression. EDD1 knockdown was also found to induce gastric cancer cells apoptosis. Further investigation indicated that the oncogenic role of EDD1 in regulating gastric cancer cells growth and apoptosis was related to its PABC domain and directly through targeting miR-22, which was significantly down-regulated in gastric cancer tissues. Totally, our study suggests that EDD1 plays an oncogenic role in gastric cancer and may be a potential therapeutic target for gastric cancer.

scholarly journals Complex networks of miRNA-transcription factors mediate gene dosage compensation in aneuploid cancer

2020 ◽  
Author(s):  
ManSai Acón ◽  
Guillermo Oviedo ◽  
Edwin Baéz ◽  
Gloriana Vásquez-Vargas ◽  
José Guevara-Coto ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Complex Networks ◽  
Dosage Compensation ◽  
Computational Models ◽  
Therapeutic Potential ◽  
Gene Dosage ◽  
Cancer Cell Line ◽  
Transcriptional Level ◽  
Negative Effects ◽  
Copy Numbers

AbstractCancer complexity is consequence of enormous genomic instability leading to aneuploidy, a hallmark of most cancers. We hypothesize that dosage compensation of critical genes could arise from systems-level properties of complex networks of microRNAs (miRNA) and transcription factors (TF) as a way for cancer cells to withstand the negative effects of aneuploidy. We studied gene dosage compensation at the transcriptional level on data of the NCI-60 cancer cell line panel with the aid of computational models to identify candidate genes with low tolerance to variation in gene expression despite high variation in copy numbers. We identified a network of TF and miRNAs validated interactions with those genes to construct a mathematical model where the property of dosage compensation emerged for MYC and STAT3. Compensation was mediated by feedback and feed-forward motifs with 4 miRNAs and was dependent on the kinetic parameters of these TF-miRNA interactions, indicating that network analysis was not enough to identify this emergent property. The inhibition of miRNAs compensating MYC suggest a therapeutic potential of targeting gene dosage compensation against aneuploid cancer.

scholarly journals ERK1/2-dependent activation of FCHSD2 drives cancer cell-selective regulation of clathrin-mediated endocytosis

2018 ◽  
Author(s):  
Guan-Yu Xiao ◽  
Aparna Mohanakrishnan ◽  
Sandra L. Schmid
Keyword(s):  
Cell Surface ◽  
Cancer Patient ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Patient Survival ◽  
Expression Level ◽  
Downstream Signaling ◽  
And Migration ◽  
Proliferation And Migration

AbstractClathrin-mediated endocytosis (CME) regulates the uptake of cell surface receptors, as well as their downstream signaling activities. We recently reported that signaling reciprocally regulates CME in cancer cells and that the crosstalk can contribute to cancer progression. To further explore the nature and extent of the crosstalk between signaling and CME in cancer cell biology, we analyzed a panel of oncogenic signaling kinase inhibitors for their effects on CME. Inhibition of several kinases selectively affected CME function in cancer cells. Among these, ERK1/2 inhibition selectively inhibited CME in cancer cells by decreasing the rate of CCP initiation. We identified an ERK1/2 substrate, the FCH/F-BAR and SH3 domain-containing protein, FCHSD2, as being essential for the ERK1/2-dependent effects on CME and CCP initiation. ERK1/2 phosphorylation activates FCHSD2 and regulates EGFR endocytic trafficking as well as downstream signaling activities. Loss of FCHSD2 activity in non-small-cell lung cancer cells leads to increased cell surface expression and altered signaling downstream of EGFR, resulting in enhanced cell proliferation and migration. The expression level of FCHSD2 is positively correlated with higher cancer patient survival rate, suggesting that FCHSD2 negatively affects cancer progression. These findings provide new insight into the mechanisms and consequences of the reciprocal regulation of signaling and CME in cancer cells.SignificanceClathrin-mediated endocytosis (CME) determines the internalization of receptors and their downstream signaling. We discovered that CME is differentially regulated by specific signaling kinases in cancer cells. In particular, ERK1/2-mediated phosphorylation of the FCH/F-BAR and double SH3 domains-containing protein 2 (FCHSD2) regulates CME, and the trafficking and signaling activities of EGF receptors. This reciprocal interaction negatively regulates cancer proliferation and migration. The expression level of FCHSD2 is positively correlated with higher cancer patient survival rates. This study identifies signaling pathways that impinge on the endocytic machinery and reveals a molecular nexus for crosstalk between intracellular signaling and CME. Cancer cells specifically adapt this crosstalk as a determinant for tumor progression, which has implications for novel therapeutics against cancers.

scholarly journals Abnormal level of paxillin in cervical cancer cells is involved in tumor progression and invasion

2021 ◽  
Author(s):  
Hongqing Gu ◽  
Jing Wen
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Uterine Cervical Cancer ◽  
Cancer Growth ◽  
Over Expression ◽  
Apoptosis Inhibition ◽  
Cervical Cancer Cells ◽  
Elevated Expression ◽  
Abnormal Level

Human papillomavirus (HPV) is the primary causative agent for the uterine cervical cancer. The expression of oncoproteins E6/E7 promotes apoptosis inhibition and increases the risk of cervical cancer progression. Some research reported that elevated expression of paxillin (PXN) stimulated cancer growth and invasion. However, the clinical significance of PXN in cervical cancer has not been well characterized so far. We found that PXN mRNA expression and protein level are significantly upregulated in cervical cancer cells compared to adjacent normal cells. Furthermore, the paxillin over-expression was correlated with potential of tumorigenesis and invasion. Cervical cancer cells with increased paxillin expression had an ability to form more tumor clones and were characterized by higher invasiveness as well. Therefore, our findings suggest that paxillin may act as an important prognostic factor for cervical cancer patients as it promotes tumor regeneration and invasion.

scholarly journals Knockdown of PD-L1 in Human Gastric Cancer Cells Inhibits Tumor Progression and Improves the Cytotoxic Sensitivity to CIK Therapy

2017 ◽  
Vol 41 (3) ◽  
pp. 907-920 ◽  
Author(s):  
Jing Li ◽  
Lujun Chen ◽  
Yuqi Xiong ◽  
Xiao Zheng ◽  
Quanqin Xie ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
Over Expression ◽  
Gastric Cancer Cell Lines ◽  
Cancer Tissues

Background/Abstract: PD-L1 has been an important target of cancer immunotherapy. We have showed that in human gastric cancer tissues, over-expression of PD-L1 was significantly associated with cancer progression and patients’ postoperative prognoses. However, as of now, how PD-L1 regulates the biological function of gastric cancer cells still remains elusive. Methods: We constructed the stable PD-L1 knockdown expression gastric cancer cell lines by using RNAi method, and further investigated the changes of biological functions including cell viability, migration, invasion, cell cycle, apoptosis, tumorigenicity in vivo, and the cytotoxic sensitivity to CIK therapy, in contrast to the control cells. Results: In the current study, we demonstrated that the knockdown of PD-L1 expression in human gastric cancer cells could significantly suppress the cell proliferation, migration, invasion, apoptosis, cell cycle, tumorigenicity in vivo and the cytotoxic sensitivity to CIK therapy. Conclusion: Our results indicate that PD-L1 contributes towards transformation and progression of human gastric cancer cells, and its intervention could prove to be an important therapeutic strategy against gastric cancer.

SphK1 Promotes Cancer Progression through Activating JAK/STAT Pathway and Up-Regulating S1PR1 Expression in Colon Cancer Cells

2021 ◽  
Vol 21 ◽  
Author(s):  
Jianting Long ◽  
Zhijia YaoYi Sui ◽  
Yi Sui ◽  
Shi Fang
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Gene Transcription ◽  
Cancer Progression ◽  
Colon Cancer Cells ◽  
Rt Pcr ◽  
Western Blot Assay ◽  
Stat3 Pathway ◽  
Over Expression ◽  
Ht 29

Background: SphK1 is a conserved lipid kinase, which can catalyze formation of tumor promoting factor sphingosine phosphate-1 (S1P). Objective: To investigate effect of SphK1 on proliferation/migration of colon cancer cells and associated mechanisms. Methods: Transcription of SphK1 gene in colon cancer cells was detected. Gene transcription of SphK1 was inhibited by transfecting with si-SphK1 gene in colon cancer cells. Effects of SphK1 inhibition (si-SphK1) on cell migration/proliferation were detected using transwell system and MTS. Gene transcription of SIP, S1PR1, S1PR2, S1PR3, and activation of JAK/STAT3 pathway were examined using RT-PCR and western blot assay. S1PR1 over-expressing plasmid was constructed and transfected into cells. Effects of S1PR1 over-expression on migration/proliferation of si-SphK1 transfected colon cancer cells and activation of JAK/STAT3 pathway were determined using RT-PCR and western blotting. Results: Gene transcription of SphK1 in SW480 and HT-29 colon cancer cells was significantly inhibited by transfection of si-SphK1 gene. Transwell migration and MTS findings showed that si-SphK1 transfection (si-SphK1 group) could reduce migration quantity and cell viability of colon cancer cells compared to negative control (NC) (p<0.0001). SphK1 inhibition (si-SphK1 group) significantly down-regulated S1PR1 and S1PR3 gene transcription in SW480 and HT-29 cells (p<0.0001), and decreased activation level of JAKSTAT3 signaling pathway compared to NC group (p<0.05). Over-expression of S1PR1 reversed inhibitory effects of si-SphK1 on migration/proliferation of SW480 and activation of JAK/Stat3. Conclusion: SphK1 promoted proliferation and migration of colon cancer cells through promoting JAK/STAT activation and up-regulating S1PR1 expression.

Oncogenic LncRNA CASC9 in Cancer Progression

2020 ◽  
Vol 26 ◽  
Author(s):  
Yuying Qi ◽  
Chaoying Song ◽  
Jiali Zhang ◽  
Chong Guo ◽  
Chengfu Yuan
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Cell Growth ◽  
Cancer Cells ◽  
Therapeutic Potential ◽  
Squamous Metaplasia ◽  
Neoplastic Transformation ◽  
Over Expression ◽  
Human Cancers ◽  
Current Review

Background: Long non-coding RNA (LncRNAs), with the length over 200 nucleotides, originate from intergenic, antisense, or promoter-proximal regions, is a large family of RNAs that lack coding capacity. Emerging evidences illustrated that LncRNAs played significant roles in a variety of cellular functions and biological processes in profuse human diseases, especially in cancers. Cancer susceptibility candidate 9 (CASC9), as a member of the LncRNAs group, was firstly found its oncogenic function in esophageal cancer. In following recent studies, a growing amount of human malignancies are verified to be correlated with CASC9, most of which are derived from the squamous epithelium tissue. This present review attempts to highlight the latest insights into the expression, functional roles, and molecular mechanisms of CASC9 in different human malignancies. Methods: In this review, the latest findings related to the pathophysiological processes of CASC9 in human cancers were summarized and analyzed, the associated studies were collected in systematically retrieval of PubMed used lncRNA and CASA9 as keywords. Results: CASC9 expression is identified to be aberrantly elevated in a variety of malignancies. The over-expression of CASC9 has been suggested to accelerate cell proliferation, migration, cell growth and drug resistance of cancer cells, while depress cell apoptosis, revealing its role as an oncogene. Moreover, the current review demonstrated CASC9 closely relates to neoplastic transformation of squamous epithelial cells and squamous metaplasia in non-squamous epithelial tissues. Finally, we discuss the limitations and tremendous diagnostic/therapeutic potential of CASC9 in various human cancers. Results: CASC9 expression is identified to be aberrantly elevated in a variety of malignancies. The over-expression of CASC9 has been suggested to accelerate cell proliferation, migration, cell growth and drug resistance of cancer cells, while depress cell apoptosis, revealing its role as an oncogene. Moreover, the current review demonstrated CASC9 closely relates to neoplastic transformation of squamous epithelial cells and squamous metaplasia in non-squamous epithelial tissues. Finally, we discuss the limitations and tremendous diagnostic/therapeutic potential of CASC9 in various human cancers. Conclusion: Long non-coding RNACASC9 likely served as useful disease biomarkers or therapy targets that could effectively apply in treatment of different kinds of cancers.

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