Up-regulated transcriptional regulators in mutant RAS gene signatures: a time-resolved multi-omics study in generic epithelial cell models

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 6, 2024

ABSTRACT The expression of mutated RAS genes drives extensive transcriptome alterations. Perturbation experiments have shown that the transcriptional responses to downstream effector pathways are partially unique and non-overlapping, suggesting a modular organization RAS-driven program. However, relationship between individual deregulated transcription factors entire cancer cell-specific genetic program is poorly understood. To identify potential regulators RAS/MAPK-dependent fraction program, we monitored proteome changes following conditional, time-resolved mutant HRAS G12V in human epithelial cells during neoplastic conversion. High mobility group AT hook2 (HMGA2), an architectural chromatin modulating protein oncofetal tumour marker, was recovered as earliest upregulated factor. Knock-down HMGA2 reverted anchorage-independent growth epithelial-mesenchymal transition not only HRAS-transformed but also independent, KRAS -driven rat model. Moreover, silencing 60% RAS-responsive target genes. These features qualify master regulator patterns. delayed deregulation FOSL1, ZEB1 other with known oncogenic activity suggests acts concert network regulatory trigger full Although considered difficult drug, central role factor well its relevance for prognosis has motivated attempts block function using small molecular weight compounds. further development direct antagonists may prove useful developed resistance signalling chain inhibition.

Language: Английский

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Therapeutic Strategies in Advanced Cervical Cancer Detection, Prevention and Treatment

OncoTargets and Therapy, Journal Year: 2024, Volume and Issue: Volume 17, P. 785 - 801

Published: Sept. 1, 2024

Cervical cancer is ranked the fourth most common cause of related deaths amongst women. The situation particularly dire in low to lower middle-income countries. It continues affect these countries due poor vaccine coverage and screening. mostly detected advanced stages leading outcomes. This review focuses on progress made date improve early detection targeted therapy using both circulating RNA. Vaccine has played a major role cervical control vaccinated young woman mainly developed yet low-income with challenges 3 dose vaccination affordability, be second deadly In this review, we show reducing that combination other treatments might survival cancer. We further miRNA siRNA specific markers ideal for These are either upregulated or down regulated providing clue stage

Language: Английский

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Significant Upregulationof the HMGA1 and HMGA2 genes in Iranian patients suffering from gastric cancer

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 15, 2024

Background Gastric cancer, a prevalent malignancy worldwide, is associated with high mortality rates. The HMGA family, comprising regulatory chromatin proteins, plays pivotal role in tumorigenesis. This study investigates alterations protein expression within the affected population of Khuzestan, Iran.Materials and Methods Sixty tissue samples—thirty gastric cancer tumors thirty non-tumor margins—were collected from institute Tehran. RNA extraction, nanodrop quantification, agarose gel electrophoresis were performed. Real-time PCR assessed HMGA1 HMGA2 genes. Statistical analysis employed GraphPad Prism 9.2.0.332, including t-tests ANOVAResults observed substantial increase relative gene (17-fold) (15-fold) tumor samples compared to (P-values: = 0.0001, 0.0038).Conclusion elevated genes cells Iran highlights their potential significance. Investigating underlying mechanisms could aid early diagnosis risk prediction. Further research recommended explore roles these in-depth.

Language: Английский

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HMGA2 alleviates ferroptosis by promoting GPX4 expression in pancreatic cancer cells

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 19, 2023

Abstract Pancreatic cancer is one of the most malignant tumor types characterized by high metastasis ability and low survival rate. As a chromatin-binding protein, HMGA2 widely overexpressed considered an oncogene with various undefined regulatory mechanisms. Herein, we demonstrated that highly expressed in pancreatic tissues promotes malignancy through cell proliferation, metastasis, xenograft growth vivo. Moreover, enhanced cellular redox status inhibiting reactive oxygen species promoting glutathione. Importantly, significantly ameliorated ferroptotic death was observed cells overexpressing HMGA2. Conversely, deletion exacerbated ferroptosis. Mechanistically, activated GPX4 expression regulation at transcription translation levels. promoted cis-element modification promoter region gene enhancing enhancer activity increased H3K4 methylation H3K27 acetylation. Furthermore, stimulated protein synthesis via mTORC1-4EBP1 -S6K signaling axis. The overexpression alleviated decreased level resulting from pharmacologic inhibition mTORC1. more pronouncedly reduced phosphorylation 4EBP1 S6K compared to control. A strong positive correlation between confirmed using immunohistochemistry staining. We also mitigated sensitivity combination treatment ferroptosis inducer mTORC1 or gemcitabine. In summary, our results revealed mechanism which coordinates underscores potential value targeting treatment.

Language: Английский

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