Activation of PPARα by clofibrate sensitizes pancreatic cancer cells to radiation through the Wnt/β-catenin pathway

Xue, Jiao; Zhu, Wei; Song, Jia; Jiao, Yang; Luo, Jing; Yu, Chengbin; Zhou, Jundong; Wu, Junli; Chen, M.; Ding, Wei‐Qun; Cao, Jianping; Zhang, S.

doi:10.1038/onc.2017.401

Cited by 42 publications

(36 citation statements)

References 50 publications

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“…Recently, several studies have shown the participation of Wnt6, Barx1, ptprz1, and other genes in the regulation of Wnt/β-catenin signalling and their involvement in the development of malignant tumours [31][32][33][34][35][36][37][38][39][40][41]. These ndings support our hypothesis that dlx6-as1 may affect the mRNA expression of Wnt6, Barx1, ptprz1 and other genes through ceRNA network to regulate Wnt/β-catenin signalling and participate in the distant bone metastasis of breast cancer.…”

Section: Discussionsupporting

confidence: 88%

ceRNA Network Development and Tumour-infiltrating Immune Cell Analysis in Metastatic Breast Cancer of Bone

Liu

Song

Zhou

et al. 2020

Preprint

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Background: Advanced breast cancer commonly metastasises to the bone and the molecular mechanism explaining the bone affinity of breast cancer cells is unclear. Thus, we developed nomograms based on a competing endogenous RNA (ceRNA) network and analysed tumour-infiltrating immunecells to elucidate the molecular pathways that may predict the prognosis of breast cancer patients.Methods: We obtained the RNA expression profile of 1091 primary breast cancer samples from The Cancer Genome Atlas database, 58 of which had bone metastasis. We analysed differential RNA expression patterns between breast cancer with and without bone metastasis and developed a ceRNA network. Cibersort was employed to differentiate between immune cell types based on tumour transcripts. Nomograms were then established using the ceRNA network and immune cell analysis. The value of prognostic factors was evaluated by Kaplan-Meier survival analysis and Cox proportional risk model.Results: There were significant differences in lncRNAs, 18 miRNAs, and 20mRNAs between breast cancer with and without bone metastasis, which were used to construct a ceRNA network. We found that the protein-coding genes gjb3, cammv, ptprz1,and fbn3 were significant in our Kaplan-Meier analysis. We also observed significant differences in plasma cell and follicular helper T cell populations between the two groups. In addition, the proportions of mast cells, gamma delta T cells, and plasma cells differed depending on disease location and stage. Our analysis revealed that a high proportion of follicular helper T cells and a low proportion of eosinophils promoted survival and that dlx6-as1, wnt6,and gabbr2expression may be related to bone metastasis of breast cancer.Conclusions: We provided a bioinformatic basis for exploring the molecular mechanism of bone metastasis in breast cancer patients and identified factors that may predict this.

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Section: Discussionsupporting

confidence: 88%

ceRNA Network Development and Tumour-infiltrating Immune Cell Analysis in Metastatic Breast Cancer of Bone

Liu

Song

Zhou

et al. 2020

Preprint

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“…Moreover, the LXXLL motif and mass spectrographic analysis of CLPTM1L revealed a potential ability of CLPTM1L to interact with many other nuclear receptors, such as RXRα, RXRβ and PPARα. It has been reported that the nuclear receptors are involved in modulating the radiosensitivity of cancer cells during radiotherapy [94][95][96]. Above all, our results reveal a new character of CLPTM1L, which functions in the nucleus through interacting with nuclear receptors during NSCLC radiotherapy.…”

Section: Discussionsupporting

confidence: 56%

CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

Chen

Jiang

et al. 2020

Cell Commun Signal

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Introduction Radioresistance is a major challenge in lung cancer radiotherapy, and new radiosensitizers are urgently needed. Estrogen receptor β (ERβ) is involved in the progression of non-small cell lung cancer (NSCLC), however, the role of ERβ in the response to radiotherapy in lung cancer remains elusive. In the present study, we investigated the mechanism underlying ERβ-mediated transcriptional activation and radioresistance of NSCLC cells. Methods Quantitative real-time PCR, western blot and immunohistochemistry were used to detect the expression of CLPTM1L, ERβ and other target genes. The mechanism of CLPTM1L in modulation of radiosensitivity was investigated by chromatin immunoprecipitation assay, luciferase reporter gene assay, immunofluorescence staining, confocal microscopy, coimmunoprecipitation and GST pull-down assays. The functional role of CLPTM1L was detected by function assays in vitro and in vivo. Results CLPTM1L expression was negatively correlated with the radiosensitivity of NSCLC cell lines, and irradiation upregulated CLPTM1L in radioresistant (A549) but not in radiosensitive (H460) NSCLC cells. Meanwhile, IR induced the translocation of CLPTM1L from the cytoplasm into the nucleus in NSCLC cells. Moreover, CLPTM1L induced radioresistance in NSCLC cells. iTRAQ-based analysis and cDNA microarray identified irradiation-related genes commonly targeted by CLPTM1L and ERβ, and CLPTM1L upregulated ERβ-induced genes CDC25A, c-Jun, and BCL2. Mechanistically, CLPTM1L coactivated ERβ by directly interacting with ERβ through the LXXLL NR (nuclear receptor)-binding motif. Functionally, ERβ silencing was sufficient to block CLPTM1L-enhanced radioresistance of NSCLC cells in vitro. CLPTM1L shRNA treatment in combination with irradiation significantly inhibited cancer cell growth in NSCLC xenograft tumors in vivo. Conclusions The present results indicate that CLPTM1L acts as a critical coactivator of ERβ to promote the transcription of its target genes and induce radioresistance of NSCLC cells, suggesting a new target for radiosensitization in NSCLC therapy.

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“…Ptprz1 is included in the yellowgreen module and is expressed >10-times higher in δ-cells than α-cells or β-cells (DIGRUCCIO et al 2016), consistent with it playing a key role δ-cells. Ptprz1 is a receptor for the heparin-binding glycoprotein pleiotrophin (PTN), and has been associated with several cancers, including glioblastoma (SHI et al 2017), and pancreatic cancer (XUE et al 2017). In addition to δ-cell-specific transcripts, six genes that encode Ca 2+ -channels were included in the yellowgreen module, including R-type Ca 2+ channels (e.g., Cacna1e), which have been previously linked to glucose-stimulated somatostatin secretion (ZHANG et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Genetic Drivers of Pancreatic Islet Function

et al. 2018

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The majority of gene loci that have been associated with type 2 diabetes play a role in pancreatic islet function. To evaluate the role of islet gene expression in the etiology of diabetes, we sensitized a genetically diverse mouse population with a Western diet high in fat (45%-kcal) and sucrose (34%) and carried out genome-wide association mapping of diabetes-related phenotypes. We quantified mRNA abundance in the islets and identified 18,820 expression quantitative trait loci. We applied mediation analysis to identify candidate causal driver genes at loci that affect the abundance of numerous transcripts. These include two genes previously associated with monogenic diabetes (PDX1 and HNF4A), as well as three genes with nominal association with diabetes-related traits in humans (FAM83E, IL6ST, and SAT2). We grouped transcripts into gene modules and mapped regulatory loci for modules enriched with transcripts specific for α-cells, and another specific for δ-cells. However, no single module enriched for β-cell-specific transcripts, suggesting heterogeneity of gene expression patterns within the β-cell population. A module enriched in transcripts associated with branched chain amino acid metabolism was the most strongly correlated with physiological traits that reflect insulin resistance. Although the mice in this study were not overtly diabetic, the analysis of pancreatic islet gene expression under dietary-induced stress enabled us to identify correlated variation in groups of genes that are functionally linked to diabetes-associated physiological traits. Our analysis suggests an expected degree of concordance between diabetes-associated loci in the mouse with those found in human populations and demonstrates how the mouse can provide evidence to support nominal associations found in human genome-wide association mapping.4

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Activation of PPARα by clofibrate sensitizes pancreatic cancer cells to radiation through the Wnt/β-catenin pathway

Cited by 42 publications

References 50 publications

ceRNA Network Development and Tumour-infiltrating Immune Cell Analysis in Metastatic Breast Cancer of Bone

ceRNA Network Development and Tumour-infiltrating Immune Cell Analysis in Metastatic Breast Cancer of Bone

CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

Genetic Drivers of Pancreatic Islet Function

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