KRT6A enhances radiotherapy resistance in lung squamous cell carcinoma via activation of the autophagy pathway through RAB39B [RNA-Seq 2]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE301226 | GEO | 2026/06/29
REPOSITORIES: GEO
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Project description:Abstract Background: Radiotherapy is the cornerstone for lung squamous cell carcinoma (LUSC) treatment, yet its efficacy is often limited by the development of radioresistance. Understanding the molecular mechanisms driving this resistance is critical for improving therapeutic outcomes. Results: In this study, we established a radioresistant LUSC cell line and identified KRT6A as a pivotal gene involved in radiotherapy resistance. Transcriptome sequencing and further validation revealed RAB39B as a downstream target of KRT6A. The KRT6A-RAB39B axis promotes radioresistance by activating the autophagy pathway, enhancing cancer cell survival in response to radiation stress. Mechanistic studies confirmed that KRT6A regulates autophagy through modulation of RAB39B expression. Conclusions：This work is the first to uncover a role of the KRT6A-RAB39B axis in LUSC radioresistance, offering new insights into the mechanisms and potential targets underlying radiotherapy failure.
2026-06-29 | GSE301225 | GEO
Project description:We have employed single cell RNA sequencing using the 10x Genomics platform to study the molecular mechanisms underlying resistance to treatment. In clinically relevant mouse models of G3 medulloblastoma, CT-guided fractionated radiotherapy was given to induce the clonal selection of radioresistant subpopulations. Comparison of recurrent and treatment naïve tumors revealed a prognostic gene expression signature reflective of radio-resistance.
2025-07-10 | E-MTAB-15292 | biostudies-arrayexpress
Project description:NanoString duplicate runs were created for CF- and HF-resistant cells, and for matched parental duplicate samples corresponding to each radioresistant cell type. Prostate cancer is the second most common cause of cancer death in men, and radiotherapy is a standard curative therapy for localized disease. Unfortunately, aggressive radioresistant relapses can arise, and the molecular underpinnings of radioresistance are unknown. Modern clinical radiotherapy is evolving to deliver higher doses of radiation in fewer fractions (hypofractionation). We therefore analyzed genomic, transcriptomic and proteomic data to characterize the determinants of prostate cancer radioresistance in cells treated with both conventionally fractionated and hypofractionated radiotherapy. Independent of fractionation schedule, resistance to radiotherapy involved massive genomic instability and abrogation of DNA mismatch repair. Specific prostate cancer driver genes were modulated at the RNA and protein levels, with distinct protein subcellular responses to radiotherapy. Conventional fractionation led to a far more aggressive biomolecular response than hypofractionation. Testing pre-clinical candidates identified in cell lines, we revealed POLQ as a radiosensitizer. POLQ-modulated radioresistance in model systems and was predictive of it in large patient cohorts. Pharmacologic and genetic inhibition of POLQ re-sensitized radioresistant cells, creating signatures seen in primary patient cohorts. The molecular response to radiation is highly multi-modal, and sheds light on prostate cancer lethality.
2024-08-24 | GSE241078 | GEO
Project description:The clinical management of locally advanced oesophageal adenocarcinoma (OAC) commonly involves neoadjuvant chemoradiotherapy (CRT), but complete pathological response to CRT only occurs in 20-30% of patients, as radioresistance remains a major clinical challenge. In this study we used an established isogenic cell line model of radioresistant OAC to detect proteomic signatures of radioresistance in order to identify novel potential molecular and cellular targets of radioresistance in OAC. Intracellular proteins obtained from radiosensitive (OE33P) and radioresistant (OE33R) cells were subjected to LC-MS/MS analysis. We identified 5785 proteins of which 251 were significantly modulated in OE33R cells, when compared to OE33P. Gene ontology and pathway analysis of the significantly modulated proteins demonstrated altered metabolism in radioresistant cells accompanied by an inhibition of apoptosis in OE33R cells. In addition, radioresistant cells were predicted to have an activation of inflammatory and angiogenic pathways when compared to the radiosensitive cells. For the first time, we performed a comprehensive proteomic profiling of our established isogenic cell line model of radioresistant OAC, providing insights into the molecular and cellular pathways which regulates radioresistance in OAC, and we provided pathway specific signatures of radioresistance that will aid further studies on the development of targeted therapies and personalised approaches to radiotherapy, with the ultimate goal of improving response to radiotherapy in cancer patients.
2022-08-18 | PXD020303 | Pride
Project description:Rationale：Glioblastoma (GBM) is a highly aggressive brain tumor, often associated with the activation of EGFR and NF-κB signaling pathways in radioresistant GBM cells. Concurrently targeting these pathways presents a promising strategy to overcome radioresistance and enhance therapeutic efficacy. Methods：We established a radioresistant glioblastoma stem cell (GSCs) model by exposing U87-derived GSCs to 5 Gy irradiation for 13 cycles. After differentiation and colony formation selection, we obtained a radioresistant cell line (Diff cells). These model cell lines mimic the progression of recurrence in GBM. Transcriptomic analysis of Diff cells, GSCs, and U87 cells, combined with public datasets from The Cancer Genome Atlas (TCGA), was conducted to identify key signaling pathways involved in radioresistance. Based on these findings, we designed a novel dual-functionalized nanoliposome (iRGD-OB-LP) for the co-delivery of Osimertinib and Bortezomib to simultaneously inhibit the EGFR and NF-κB pathways. The physicochemical properties, cellular uptake, and drug release profiles of iRGD-OB-LP were characterized, and its targeting capability, antitumor activity, and radiosensitization potential were evaluated both in vitro and in vivo. Results: We successfully established GSCs from U87 cells and induced radioresistance in these GSCs. The Diff cells derived from GSCs retained radioresistant characteristics and exhibited significant resistance to radiotherapy-induced cell death. Transcriptomic analysis of Diff cells, GSCs, and U87 cells, along with TCGA data, identified EGFR and NF-κB (RelA/p65) as key pathways involved in radioresistance. iRGD-OB-LP demonstrated efficient tumor-specific targeting, cellular uptake, and sustained drug release. In vitro, iRGD-OB-LP effectively inhibited EGFR and NF-κB pathway activation, prolonged DNA damage induced by radiotherapy, reduced tumor cell stemness, and enhanced radiotherapy-induced apoptosis. In vivo, studies using an orthotopic GBM mouse model revealed that iRGD-OB-LP successfully crossed the blood-tumor barrier, accumulated at tumor sites, and synergistically enhanced the efficacy of radiotherapy, as evidenced by suppressed tumor growth and prolonged survival. Conclusion: In this study, we established Diff cells as a radioresistant model derived from GSCs and identified EGFR and NF-κB (RelA/p65) as critical pathways in sustaining the radioresistant phenotype through RNA sequencing and TCGA data analysis. The iRGD-OB-LP nanoplatform offers a promising strategy for targeted delivery of dual inhibitors to simultaneously inhibit EGFR and NF-κB, overcoming GBM radioresistance. This innovative approach highlights a potential strategy to improve radiotherapy outcomes in GBM treatment.
2025-12-02 | GSE285885 | GEO
Project description:Radiotherapy has become a main treatment for patients with nasopharyngeal carcinoma (NPC), who often develop residual or recurrent tumors due to radioresistance. The lncRNA HOTAIRM1 plays crucial roles in the formation and development of various cancers, but the interaction between HOTAIRM1 and radioresistant NPC remains unclear. In this study, we evaluated the potential of HOTAIRM1 as a biomarker of NPC radioresistance. Proliferation, apoptosis, DNA damage, and RNA-seq analyses were conducted to examine the mechanisms by which HOTAIRM1 contributes to NPC radioresistance, and in vivo experiments were performed using nude mice. Our findings indicated that HOTAIRM1 levels were upregulated in radioresistant NPC tissues and cell lines. High HOTAIRM1 expression was associated with increased NPC cell proliferation, decreased apoptosis, and decreased cellular DNA damage after radiotherapy. Mechanistically, HOTAIRM1 promoted NPC radioresistance by increasing SLC7A11 stability and expression through METTL3-mediated m6A demethylation. Additionally, high HOTAIRM1 expression decreased SLC7A11-associated ferroptosis. Our findings demonstrate that HOTAIRM1 promotes METTL3-mediated m6A methylation to increase SLC7A11 expression and stability, thereby inhibiting ferroptosis to trigger NPC radioresistance. This novel molecular mechanism underlying the role of HOTAIRM1 in the regulation of radioresistant NPC may aid in the identification of biomarkers and therapeutic targets for the treatment of radioresistant NPC.
2023-04-12 | GSE229333 | GEO
Project description:Purpose: Predominant causes of head and neck cancer recurrence after radiotherapy are rapid repopulation, hypoxia, fraction of cancer stem cells and intrinsic radioresistance. Currently, intrinsic radioresistance can only be assessed by ex-vivo colony assays. Besides being time-consuming, colony assays do not identify causes of intrinsic resistance. We aimed to identify a biomarker for intrinsic radioresistance to be used before start of treatment and to reveal biological processes that could be targeted to overcome intrinsic resistance. Experimental design: We analyzed both micro- and messenger RNA expression in a large panel of HNSCC cell lines. Expression was measured on both irradiated and unirradiated samples. Results were validated using modified cell lines and a series of laryngeal cancer patients. Results: MiRs, mRNAs and gene sets that correlated with resistance could be identified from expression data of unirradiated cells. The presence of epithelial to mesenchymal transition (EMT) and low expression of miRs involved in the inhibition of EMT were important radioresistance determinants. This finding was validated in two independent cell line pairs, in which the induction of EMT reduced radiosensitivity. Moreover, low expression of the most important miR (miR-203) was shown to correlate with local disease recurrence after radiotherapy in a series of laryngeal cancer patients. Conclusions: These findings indicate that EMT and low expression of EMT-inhibiting miRs, especially miR-203, measured in pre-treatment material, causes intrinsic radioresistance of HNSCC, which could enable identification and treatment modification of radioresistant tumors. Matched pairs of pre-treatment biopsies of 34 patients treated at The Netherlands Cancer Institute between 2002 and 2010. Patients with T2-3 laryngeal cancers, all treated with radiotherapy alone with a curative intent. The series was designed to be a matched cohort of 17 patients with local recurrences matched with 17 local cures. There were no significant differences between groups with and without local recurrence in age, gender, subsite, T-stage or treatment year.
2016-03-23 | E-GEOD-79493 | biostudies-arrayexpress
Project description:Background: Radiotherapy plays an important role in the multimodal treatment of breast cancer. The response of a breast tumour to radiation depends not only on its innate radiosensitivity but also on tumour repopulation by cells that have developed radioresistance. Development of effective cancer treatments will require further molecular dissection of the processes that contribute to resistance. Methods: Radioresistant cell lines were established by exposing MDA-MB-231, MCF-7 and ZR-751 parental cells to increasing weekly doses of radiation. The development of radioresistance was evaluated through proliferation and colony formation assays. Phenotypic characterisation included migration and invasion assays and immunohistochemistry. Intrinsic differences and changes in response to radiation between parental and radioresistant cells were investigated by whole-transcriptome gene expression analysis. Gene enrichment and pathway-focused analyses identified signalling networks differentially activated in radioresistant cells, which were confirmed by western blotting. Results: Proliferation and colony formation assays confirmed radioresistance. Radioresistant cells exhibited enhanced migration and invasion, with evidence of epithelial-to-mesenchymal-transition, and limited activation of DNA damage and apoptotic pathways in response to 2 Gy ionising radiation. Significantly, acquisition of radioresistance in MCF-7 and ZR-751 cell lines resulted in a loss of expression of both ERα and PgR and an increase in EGFR expression; based on gene analysis they changed subtype classification from their parental luminal A to HER2-overexpressing (MCF-7 RR) and normal-like (ZR-751 RR) subtypes, indicating the extent of phenotypic changes and cellular plasticity involved in this process. Whole-transcriptome gene expression analysis identified down-regulation of ER signalling genes and up-regulation of genes associated with PI3K, MAPK and WNT pathway activity in radioresistant cell lines derived from ER+ cells; this was confirmed by western blot, which showed increased p-AKT and p-ERK expression following radiation. Conclusions: This is the first study to date that extensively describes the development and characterisation of three novel radioresistant breast cancer cell lines through both genetic and phenotypic analysis. More changes were identified between parental cells and their radioresistant derivatives in the ER+ (MCF-7 and ZR-751) compared with the ER- cell line (MDA-MB-231) model; however, multiple and likely interrelated mechanisms were identified that may contribute to the development of acquired resistance to radiotherapy.
2018-10-04 | GSE120798 | GEO
Project description:Most of the NPC patients suffer from local recurrences and distant metastases within 1.5 years after radiotherapy due to radioresistance. Distinct patterns of gene expression and signatures were found in NPC, and have been used to associate them with cell proliferation, apoptosis, invasion and metastasis, but few gene expression profiling studies have been focused on the tumor radioresistance.We used gene expression microarray analyses to identify the difference of mRNA in radioresistant NPC CNE2-IR cells and radiosensitive CNE2 cells. Radioresistant subclone of nasopharyngeal carcinoma CNE2-IR cell line was cultured and produced according to the experienment schedule to undergo five rounds of sublethal dose of irradiation (11 Gy), and the parent cell line CNE2 cell line sensitive to radiotherapy as the control
2013-12-10 | E-GEOD-48501 | biostudies-arrayexpress
Project description:Most of the NPC patients suffer from local recurrences and distant metastases within 1.5 years after radiotherapy due to radioresistance. Distinct patterns of miRNa expression and signatures were found in NPC, and have been used to associate them with cell proliferation, apoptosis, invasion and metastasis, but few miRNA expression profiling studies have been focused on the tumor radioresistance.We used miRNA expression microarray analyses to identify the difference of miRNA in radioresistant NPC CNE2-IR cells and radiosensitive CNE2 cells. Radioresistant subclone of nasopharyngeal carcinoma CNE2-IR cell line was cultured and produced according to the experienment schedule to undergo five rounds of sublethal dose of irradiation (11 Gy),and the parent cell line CNE2 sensitive to radiotherapy as the control
2013-12-10 | E-GEOD-48502 | biostudies-arrayexpress