Interleukin‐6 production mediated by the <scp>IRE</scp>1‐<scp>XBP</scp>1 pathway confers radioresistance in human papillomavirus‐negative oropharyngeal carcinoma

Lyu, Xintong; Zhang, Miao; Li, Guangqi; Cai, Yiru; Qiao, Qiao

doi:10.1111/cas.14094

Cited by 20 publications

(11 citation statements)

References 35 publications

(49 reference statements)

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“…Consistently, Esra A Akbay et al identified a correlation between EGFR pathway activation and a signature of immunosuppression manifested by decreasing CTLs and increasing markers of T-cell exhaustion [ 30 ]. The transcription factor JUN was reported to activate the transcription of the promoters of several key UPR effectors, such as XBP1 and ATF4, to inhibit tumour cell apoptosis [ 45 , 46 ]. The hallmark of the exhausted subgroup, SERPINE1, induced by TGF-β in the microenvironment, may act as a target to reverse the exhausted immune response [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of an immune classification for cervical cancer and integrative analysis of multiomics data

Lyu

Qiao

2021

J Transl Med

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Background To understand the molecular mechanisms of the antitumour response, we analysed the immune landscape of cervical cancer to identify novel immune molecular classes. Methods We established a stable immune molecular classification using a nonnegative matrix factorization algorithm and validated the correlation in two validation sets of 249 samples. Results Approximately 78% of cervical cancers (CCs) (228/293) were identified to show significant enrichment in immune cells (e.g., CD8 T cells and macrophages), a type I IFN response, enhanced cytolytic activity and high PDCD1, and these CCs were referred to as the “immune class”. We further identified two subtypes of the immune class: active immune and exhausted subtypes. Although the active immune subtype was characterized by enrichment of IFN signatures and better survival, the exhausted subtype expressed activated stroma, a wound healing signature, enhanced M2 macrophages and absence of CD8 T cells and the TGF-β response signature. Integrative analysis of multiomics data identified EGFR, JUN, MYC, FN1 and SERPINE1 as key modulators of the tumour immune microenvironment and potential targets for combination therapies which was validated in two validation sets. Conclusions Our study introduces a novel immune classification that might predict ideal candidates to receive immunotherapy or specific combination therapies.

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Section: Discussionmentioning

confidence: 99%

Identification of an immune classification for cervical cancer and integrative analysis of multiomics data

Lyu

Qiao

2021

J Transl Med

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“…The oncogenic roles of XBP1 in CRC and other types of cancer have been reported in numerous studies; the activation of the IRE1/XBP1 pathway induced cell proliferation and invasion in CRC 3, whereby XBP1 was demonstrated to promote with poor prognosis (24); in breast cancer, the expression levels of XBP1s in the nucleus were correlated with shorter survival (25); whereas in ovarian cancer, the IRE1/XBP1 signaling pathway controlled T-cell functions, thus, mediating ER stress or targeting the IRE1/XBP1 pathway may restore the antitumor ability of T-cells (26). In addition, XBP1 positively regulated the cytolytic activity of human natural killer cells against leukemia cells (27); in hepatocellular carcinoma, the IRE1/XBP1 pathway controlled the expression of interleukin-6 (IL-6) and promoted hepatocarcinoma progression (28); and in oropharyngeal carcinoma without papillomavirus, the IRE1/XBP1 pathway induced resistance to radiotherapy by mediating IL-6 production (29). Thus, the transcription factor XBP1 may be a potential target to mediate tumor immunology and block cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Thapsigargin promotes colorectal cancer cell migration through upregulation of lncRNA MALAT1

Jiang

Wang

et al. 2020

Oncol Rep

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Colorectal cancer (CRC) is the third most common tumor in the world; however, the role and mechanism of endoplasmic reticulum (ER) stress in CRC metastasis remains largely unclear. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA), which has previously been associated with CRC metastasis. It has been suggested that ER stress pathways regulate lncRNA expression; however, the effect of ER stress on MALAT1 expression in cancer is unknown. The present study aimed to investigate the relationship between ER stress pathways, MALAT1 expression and cell migration in CRC cells. ER stress was induced by thapsigargin (TG); low dose TG induced the migration of HT29 and HCT116 cells, but not SW1116 and SW620 cells. This effect was associated with increased expression levels of MALAT1, as the knockdown of MALAT1 prevented TG-induced cell migration. TG-induced MALAT1 expression was associated with inositol-requiring enzyme 1 (IRE1) expression and activation of the protein kinase R (PKR)-like ER kinase (PERK) signaling pathway. X-box-binding protein 1 (XBP1) and activating transcription factor 4 (ATF4) binding sites were predicted to be located in the MALAT1 gene promoter regions and the expression of MALAT1 was positively associated with XBP1 and ATF4 expression levels in CRC tissue samples. Thus, these findings indicated that ER stress may promote the migration of CRC cells and contribute to the progression of CRC through the activation of the IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways. In conclusion, to the best of our knowledge, this study is the first report that lncRNA MALAT1 expression is regulated by the IRE1/XBP1 pathway in CRC.

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“…IRE1 is another principal sensor of ERS pathway, and its overexpression in HPV-negative OPCC patients treated with RT has been correlated with poor outcomes. IRE1 promotes IL-6 activation, enhancing X-ray-induced DNA DSB and cell apoptosis ( 112 ). Another mechanism that activates ERS signaling is the activation of EGFR conferring RR in OSCC.…”

Section: Endoplasmic Reticulum Adaptations To Radiationmentioning

confidence: 99%

Biological Adaptations of Tumor Cells to Radiation Therapy

Carlos‐Reyes¹,

Muñiz-Lino

Romero-García³

et al. 2021

Front. Oncol.

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Radiation therapy has been used worldwide for many decades as a therapeutic regimen for the treatment of different types of cancer. Just over 50% of cancer patients are treated with radiotherapy alone or with other types of antitumor therapy. Radiation can induce different types of cell damage: directly, it can induce DNA single- and double-strand breaks; indirectly, it can induce the formation of free radicals, which can interact with different components of cells, including the genome, promoting structural alterations. During treatment, radiosensitive tumor cells decrease their rate of cell proliferation through cell cycle arrest stimulated by DNA damage. Then, DNA repair mechanisms are turned on to alleviate the damage, but cell death mechanisms are activated if damage persists and cannot be repaired. Interestingly, some cells can evade apoptosis because genome damage triggers the cellular overactivation of some DNA repair pathways. Additionally, some surviving cells exposed to radiation may have alterations in the expression of tumor suppressor genes and oncogenes, enhancing different hallmarks of cancer, such as migration, invasion, and metastasis. The activation of these genetic pathways and other epigenetic and structural cellular changes in the irradiated cells and extracellular factors, such as the tumor microenvironment, is crucial in developing tumor radioresistance. The tumor microenvironment is largely responsible for the poor efficacy of antitumor therapy, tumor relapse, and poor prognosis observed in some patients. In this review, we describe strategies that tumor cells use to respond to radiation stress, adapt, and proliferate after radiotherapy, promoting the appearance of tumor radioresistance. Also, we discuss the clinical impact of radioresistance in patient outcomes. Knowledge of such cellular strategies could help the development of new clinical interventions, increasing the radiosensitization of tumor cells, improving the effectiveness of these therapies, and increasing the survival of patients.

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Interleukin‐6 production mediated by the IRE1‐XBP1 pathway confers radioresistance in human papillomavirus‐negative oropharyngeal carcinoma

Cited by 20 publications

References 35 publications

Identification of an immune classification for cervical cancer and integrative analysis of multiomics data

Identification of an immune classification for cervical cancer and integrative analysis of multiomics data

Thapsigargin promotes colorectal cancer cell migration through upregulation of lncRNA MALAT1

Biological Adaptations of Tumor Cells to Radiation Therapy

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