High BLM Expression Predicts Poor Clinical Outcome and Contributes to Malignant Progression in Human Cholangiocarcinoma

Du, Xiaoqiang; Zhang, Chen; Yin, Chuanzheng; Wang, Wenjie; Yan, Xueke; Xie, Dawei; Zheng, Xichuan; Zheng, Qi; Li, Min; Song, Zifang

doi:10.3389/fonc.2021.633899

Cited by 9 publications

(10 citation statements)

References 66 publications

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“…The high expression of BLM is a poor prognostic biomarker for multiple cancers (114,115). Biallelic pathogenic variants in BLM cause bloom syndrome with severe pre-and postnatal growth deficiency, immune abnormalities, sensitivity to sunlight, insulin resistance, and a high risk for many cancers that occur at an early age (116).…”

Section: Blmmentioning

confidence: 99%

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

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DNA replication is a process fundamental in all living organisms in which deregulation, known as replication stress, often leads to genomic instability, a hallmark of cancer. Most malignant tumors sustain persistent proliferation and tolerate replication stress via increasing reliance to the replication stress response. So whilst replication stress induces genomic instability and tumorigenesis, the replication stress response exhibits a unique cancer-specific vulnerability that can be targeted to induce catastrophic cell proliferation. Radiation therapy, most used in cancer treatment, induces a plethora of DNA lesions that affect DNA integrity and, in-turn, DNA replication. Owing to radiation dose limitations for specific organs and tumor tissue resistance, the therapeutic window is narrow. Thus, a means to eliminate or reduce tumor radioresistance is urgently needed. Current research trends have highlighted the potential of combining replication stress regulators with radiation therapy to capitalize on the high replication stress of tumors. Here, we review the current body of evidence regarding the role of replication stress in tumor progression and discuss potential means of enhancing tumor radiosensitivity by targeting the replication stress response. We offer new insights into the possibility of combining radiation therapy with replication stress drugs for clinical use.

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Section: Blmmentioning

confidence: 99%

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

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“…The BLM mutations resulting in alterations in the nuclear targeting signal (NLS) domain ( 36) or dysregulation of mechanisms responsible for nuclear targeting might be another reason for mis-localization of BLM in glioma cells. The high BLM expression inversely correlated with survival of breast cancer (34) or cholangiocarcinoma patients (37). BLM protein levels were elevated in all 7 tested glioma cell lines when compared to its levels in normal human astrocytes.…”

Section: Discussionmentioning

confidence: 94%

BLM helicase determines chemotherapy-induced responses of human glioma cells and shifts between apoptosis, senescence or polyploidy

Wojnicki

Kaczmarczyk

Wojtaś

et al. 2023

Preprint

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Most of anti-tumour therapies eliminate neoplastic cells by introducing DNA damage which ultimately triggers cell death. These effects are counteracted by activated DNA repair pathways and RECQL family helicases, including BLM, participate in replication stress, DNA damage and repair. Glioblastoma (GBM) is a common, malignant brain tumour that inevitably recurs despite surgical resection, radiotherapy, and chemotherapy with temozolomide (TMZ). Expression and functions of the BLM helicase in therapy resistant GBMs have not been elucidated. We analysed expression and localisation of BLM in human gliomas and several glioma cell lines using TCGA datasets, immunostaining and Western blotting. BLM depleted human glioma cells were generated with CRISPR/Cas9. Effects of chemotherapeutics on cell proliferation, DNA damage and apoptosis were determined with flow cytometry, immunofluorescence Western blotting and RNA sequencing. We found upregulated BLM mRNA levels in malignant gliomas, increased cytosolic localisation and poor survival of BLM highly expressing GBM patients. BLM deficiency in LN18 and LN229 glioma cells resulted in profound transcriptomic alterations, reduced cell proliferation, and altered cell responses to chemotherapeutics. BLM-deficient glioma cells were resistant to the TMZ and PARP inhibitor treatment and underwent polyploidy or senescence depending on the TP53 activity. These dependencies were not detected in RECQL4-deficient cells. Our findings of high BLM expression in GBMs and its roles in responses to chemotherapeutics provide a rationale for targeting BLM helicase in those tumours. BLM deficiency affects responses of glioma cells to chemotherapeutics targeting PARP-1 dependent pathways, while these effects are not detected in RECQL4 deficient cells implying distinct functions of these helicases.

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“…However, these predictions should be validated experimentally to ultimately decipher this phenomenon. The high BLM expression inversely correlated with survival of breast cancer (37) or cholangiocarcinoma patients (41). BLM protein levels were elevated in all 7 tested glioma cell lines when compared to normal human astrocytes.…”

Section: Discussionmentioning

confidence: 94%

BLM helicase overexpressed in human gliomas contributes to diverse responses of human glioma cells to chemotherapy

Wojnicki

Kaczmarczyk

Wojtaś

et al. 2023

Preprint

View full text Add to dashboard Cite

Most of anti-tumour therapies eliminate neoplastic cells by introducing DNA damage which ultimately triggers cell death. These effects are counteracted by activated DNA repair pathways to sustain tumour proliferation capacity. RECQL helicases family, including BLM, participate in DNA damage and repair, and prevent the replication stress. Glioblastoma (GBM) is a common, malignant brain tumour that inevitably recurs despite surgical resection, radiotherapy, and chemotherapy with temozolomide (TMZ). Expression and functions of the BLM helicase in GBM therapy resistance have not been elucidated. We analysed expression and localisation of BLM in human gliomas and several glioma cell lines using TCGA datasets, immunostaining and Western blotting. BLM depleted human glioma cells were generated with CRISPR/Cas9. Effects of chemotherapeutics on cell proliferation, DNA damage and apoptosis were determined with flow cytometry, immunofluorescence, Western blotting and RNA sequencing. We found upregulated BLM mRNA levels in malignant gliomas, increased cytosolic localisation and poor survival of BLM highly expressing GBM patients. BLM deficiency in LN18 and LN229 glioma cells resulted in profound transcriptomic alterations, reduced cell proliferation, and altered cell responses to chemotherapeutics. BLM-deficient glioma cells were resistant to the TMZ and PARP inhibitor treatment and underwent polyploidy or senescence depending on the TP53 activity. Our findings of high BLM expression in GBMs and its roles in responses to chemotherapeutics provide a rationale for targeting BLM helicase in those tumours. BLM deficiency affects responses of glioma cells to chemotherapeutics targeting PARP1 dependent pathways.

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High BLM Expression Predicts Poor Clinical Outcome and Contributes to Malignant Progression in Human Cholangiocarcinoma

Cited by 9 publications

References 66 publications

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

BLM helicase determines chemotherapy-induced responses of human glioma cells and shifts between apoptosis, senescence or polyploidy

BLM helicase overexpressed in human gliomas contributes to diverse responses of human glioma cells to chemotherapy

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