A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer
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ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Yongwei Sun
PROVIDER: PXD053962 | iProX | Fri Jul 26 00:00:00 BST 2024
REPOSITORIES: iProX
Publications
A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer.
Zheng Jia-Hao JH Zhu Yu-Heng YH Yang Jian J Ji Pei-Xuan PX Zhao Rui-Kang RK Duan Zong-Hao ZH Yao Hong-Fei HF Jia Qin-Yuan QY Yin Yi-Fan YF Hu Li-Peng LP Li Qing Q Jiang Shu-Heng SH Huo Yan-Miao YM Liu Wei W Sun Yong-Wei YW Liu De-Jun DJ
Cell reports 20240817 8
Pancreatic ductal adenocarcinoma (PDAC) features substantial matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, the complex interplay between these traits and their impact on tumor advancement remains inadequately explored. Here, we integrated clinical, cellular, and bioinformatics approaches to explore the connection between matrix stiffness and the Warburg effect in PDAC, identifying CLIC1 as a key mediator. Elevated CLIC1 expression, induced by ma ...[more]
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Project description:Pancreatic ductal adenocarcinoma (PDAC) features substantial matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, the complex interplay between these traits and their impact on tumor advancement remains inadequately explored. Here, we integrated clinical, cellular, and bioinformatics approaches to explore the connection between matrix stiffness and the Warburg effect in PDAC, identifying CLIC1 as a key mediator. Elevated CLIC1 expression, induced by matrix stiffness through Wnt/β-catenin/TCF4 signaling, signifies poorer prognostic outcomes in PDAC. Functionally, CLIC1 serves as a catalyst for glycolytic metabolism, propelling tumor proliferation. Mechanistically, CLIC1 fortifies HIF1α stability by curbing hydroxylation via ROS. Collectively, PDAC cells elevate CLIC1 levels in a matrix stiffness-responsive manner, bolstering the Warburg effect to drive tumor growth via ROS/HIF1α signaling. Our insights highlight opportunities for targeted therapies that concurrently address matrix properties and metabolic rewiring, with CLIC1 emerging as a promising intervention point.
2024-08-01 | GSE273398 | GEO
Project description:Purpose: Quantitative RT-PCR and ChIP analyses identified MAX as a transcriptional repressor of circadian BMAL1 target genes. The goal of this study is to compare the transcriptional effect of a knockdown of either MAX and BMAL1 in a human cell line (MDA-MB-231) Methods: Polyadenylated mRNA profiles of human breast cancer MDA-MB-231 cells with knocked down MAX or BMAL1 were generated by deep sequencing, in triplicate, using Illumina HiSeq 2000 sequencer. Cells transfected with a non-targeting siRNA sequence were used as a control. RNA sequencing counts were used to determine differentially expressed genes with DeSeq2 package included in the Galaxy web platform (usergalaxy.org). Differentially expressed genes (DEGs) were defined adopting an adjust P < 0.001 as a statistical cut-off value. Results: Transcript assembly and quantification of RNA-sequencing reads identified 4863 and 4247 differentially expressed genes (DEGs) upon knockdown of BMAL1 or MAX, respectively. The comparison of the two set of genes revealed that 2391 of siBMAL1 DEGs (almost 50%) were also differentially expressed in MAX-silenced cells. Heat map and clustering analysis of this sub-set of genes revealed that more than 90% (2241 out of 2391) were coherently altered in both conditions (i.e. their expression was altered in the same direction). Consistent with our quantitative RT-PCR experiments, genes belonging to the circadian rhythm signalling were altered by both MAX and BMAL1 silencing. Conclusion: This study indicate that MAX is a part of the molecular clock transcriptional network.
2020-04-29 | GSE127212 | GEO
Project description: Not available
| S-EPMC10854616 | biostudies-literature
Project description:Rice in tropical and sub-tropical areas is often subjected to cold stress at the seedling stage resulting in poor growth and yield loss. In general, japonica rice has stronger cold tolerance (CT) than indica rice. However, several favorite alleles for CT exist in indica rice and can be used to enhance CT under japonica background. Genome-wide gene expression profiling is the efficient way to decipher the molecular genetic mechanism of CT enhancement and provide valuable information for the CT improvement in rice molecular breeding. In this study, the transcriptome of a CT introgressed line (IL) K354 and its recurrent parent C418 under cold stress were comparatively analyzed to explore the possible CT enhancement mechanism of K354.Totally 3184 differentially expressed genes (DEGs) including 195 transcription factors were identified in both lines under cold stress, about half of them were commonly regulated, which were involved in the major cold responsive pathways including OsDREB1s regulon. The K354-specific cold-induced DEGs were mainly related to stimulus response, cellular cell wall organization, and microtubule-based movement process compared with commonly cold-induced DEGs by GO analysis. Moreover, 296 constitutive DEGs with significantly different transcription level between C418 and K354 were detected under both control and cold stress conditions. K354-specific cold-regulated and constitutive DEGs jointly account for the CT improvement of K354. Pathway analysis unraveled up-regulation of starch and sucrose metabolism in both genotypes and presumably weaker defense response to stress in K354 than C418 under cold stress. Candidate genes prediction based on previous putative CT genetic networks revealed genotype-dependent CT enhancement mechanism in CT IL K354 vs recurrent parent C418, including Sir2, OsFAD7, OsWAK112d, and PCD related genes, etc.We propose a hypothesis of the CT enhancement mechanism in rice based on the results in present study. Firstly, a number of cold-regulated genes are able to express constitutively at high level or absent under control condition for standing by the arrival of cold stress. Next, under cold stress slower perception of stress signal from the more cold-tolerant membrane can postpone the activation of defensive system which may have possible negative effects on rice growth. Then, PCD will be launched to sacrifice a few cells for maintaining the basal growth of most cells. Finally, the protective responses on multiple aspects of cold damage will be postponed because of delayed several cold-defensive pathways (i.e. OsDREB1C regulon). It might explain why the recovery capacity of K354 from cold stress to control condition is stronger than C418. The CT enhancement mechanism can be regarded as the possible way to improve CT of japonica rice using indica germplasm in rice breeding program. In this study, the specific gene expression patterns of two genotypes (C418 and K354) at 2h, 6h, 12h, 24h and 48h during cold stress treatment (4 C) and control were characterized by using the Affymetrix rice microarray platform.
2012-12-31 | E-GEOD-37940 | biostudies-arrayexpress
Project description:Rice in tropical and sub-tropical areas is often subjected to cold stress at the seedling stage resulting in poor growth and yield loss. In general, japonica rice has stronger cold tolerance (CT) than indica rice. However, several favorite alleles for CT exist in indica rice and can be used to enhance CT under japonica background. Genome-wide gene expression profiling is the efficient way to decipher the molecular genetic mechanism of CT enhancement and provide valuable information for the CT improvement in rice molecular breeding. In this study, the transcriptome of a CT introgressed line (IL) K354 and its recurrent parent C418 under cold stress were comparatively analyzed to explore the possible CT enhancement mechanism of K354.Totally 3184 differentially expressed genes (DEGs) including 195 transcription factors were identified in both lines under cold stress, about half of them were commonly regulated, which were involved in the major cold responsive pathways including OsDREB1s regulon. The K354-specific cold-induced DEGs were mainly related to stimulus response, cellular cell wall organization, and microtubule-based movement process compared with commonly cold-induced DEGs by GO analysis. Moreover, 296 constitutive DEGs with significantly different transcription level between C418 and K354 were detected under both control and cold stress conditions. K354-specific cold-regulated and constitutive DEGs jointly account for the CT improvement of K354. Pathway analysis unraveled up-regulation of starch and sucrose metabolism in both genotypes and presumably weaker defense response to stress in K354 than C418 under cold stress. Candidate genes prediction based on previous putative CT genetic networks revealed genotype-dependent CT enhancement mechanism in CT IL K354 vs recurrent parent C418, including Sir2, OsFAD7, OsWAK112d, and PCD related genes, etc.We propose a hypothesis of the CT enhancement mechanism in rice based on the results in present study. Firstly, a number of cold-regulated genes are able to express constitutively at high level or absent under control condition for standing by the arrival of cold stress. Next, under cold stress slower perception of stress signal from the more cold-tolerant membrane can postpone the activation of defensive system which may have possible negative effects on rice growth. Then, PCD will be launched to sacrifice a few cells for maintaining the basal growth of most cells. Finally, the protective responses on multiple aspects of cold damage will be postponed because of delayed several cold-defensive pathways (i.e. OsDREB1C regulon). It might explain why the recovery capacity of K354 from cold stress to control condition is stronger than C418. The CT enhancement mechanism can be regarded as the possible way to improve CT of japonica rice using indica germplasm in rice breeding program.
2012-12-31 | GSE37940 | GEO
Project description:The MYC transcription factor requires MAX for DNA binding and widespread activation of gene expression in both normal and neoplastic cells. Surprisingly, inactivating mutations in MAX are associated with a subset of neuroendocrine cancers including pheochromocytoma, pituitary adenoma and small cell lung cancer. Neither the extent nor the mechanisms of MAX tumor suppression are well understood. Deleting Max across multiple mouse neuroendocrine tissues, we find Max inactivation alone produces pituitary adenomas while Max inactivation loss cooperates with Rb1/Trp53 loss to accelerate medullary thyroid C-cell and pituitary adenoma development. In the thyroid tumor cell lines, MAX loss triggers a striking shift in genomic occupancy by other members of the MYC network (MNT, MLX, MondoA) supporting metabolism, survival and proliferation of neoplastic neuroendocrine cells. Our work reveals MAX as a broad suppressor of neuroendocrine tumorigenesis through its ability to maintain a balance of genomic occupancies among the diverse transcription factors in the MYC network.
2025-03-15 | GSE286458 | GEO
Project description:The MYC transcription factor requires MAX for DNA binding and widespread activation of gene expression in both normal and neoplastic cells. Surprisingly, inactivating mutations in MAX are associated with a subset of neuroendocrine cancers including pheochromocytoma, pituitary adenoma and small cell lung cancer. Neither the extent nor the mechanisms of MAX tumor suppression are well understood. Deleting Max across multiple mouse neuroendocrine tissues, we find Max inactivation alone produces pituitary adenomas while Max inactivation loss cooperates with Rb1/Trp53 loss to accelerate medullary thyroid C-cell and pituitary adenoma development. In the thyroid tumor cell lines, MAX loss triggers a striking shift in genomic occupancy by other members of the MYC network (MNT, MLX, MondoA) supporting metabolism, survival and proliferation of neoplastic neuroendocrine cells. Our work reveals MAX as a broad suppressor of neuroendocrine tumorigenesis through its ability to maintain a balance of genomic occupancies among the diverse transcription factors in the MYC network.
2025-03-15 | GSE286461 | GEO
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2025-07-31 | GSE300439 | GEO