PD-L1 promotes colorectal cancer stem cell expansion by activating HMGA1-dependent signaling pathways

Fang, Wei; Zhang, Tong; Deng, Shu-Chou; Wei, Jianchang; Yang, Ping; Wang, Qiang; Chen, Zhuanpeng; Li, Wanglin; Chen, Huacui; He, Hong; Cao, Jie

doi:10.1016/j.canlet.2019.02.022

Cited by 149 publications

(115 citation statements)

References 30 publications

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“…Together, these data indicate that PD-L1 expression in cancer cells not only inhibits antitumor immunity but also may contribute to the maintenance of stemness potential. Consistent with this model, Wei F et al demonstrated the existence of crosstalk between PD-L1 and the Hedgehog signaling pathway that is mediated through a direct interaction between PD-L1 and HMGA1 [64]. In this study, PD-L1 increased the frequency of intratumor CSCs and contributed to the maintenance of tumor cell self-renewal [64].…”

Section: Immunomodulatory Molecules Stimulating Tumor Stemness: the Dsupporting

confidence: 81%

“…Consistent with this model, Wei F et al demonstrated the existence of crosstalk between PD-L1 and the Hedgehog signaling pathway that is mediated through a direct interaction between PD-L1 and HMGA1 [64]. In this study, PD-L1 increased the frequency of intratumor CSCs and contributed to the maintenance of tumor cell self-renewal [64]. Additionally, CTLA4, another immune checkpoint protein that inhibits T cell proliferation, activation, and anticancer immune response [65], was shown to increase the stemness potential in melanoma cells [66] (Figure 2).…”

Section: Immunomodulatory Molecules Stimulating Tumor Stemness: the Dmentioning

confidence: 75%

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Cancer Stem Cells: Devil or Savior—Looking behind the Scenes of Immunotherapy Failure

Castagnoli

Santis

Volpari

et al. 2020

Cells

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Although the introduction of immunotherapy has tremendously improved the prognosis of patients with metastatic cancers of different histological origins, some tumors fail to respond or develop resistance. Broadening the clinical efficacy of currently available immunotherapy strategies requires an improved understanding of the biological mechanisms underlying cancer immune escape. Globally, tumor cells evade immune attack using two main strategies: avoiding recognition by immune cells and instigating an immunosuppressive tumor microenvironment. Emerging data suggest that the clinical efficacy of chemotherapy or molecularly targeted therapy is related to the ability of these therapies to target cancer stem cells (CSCs). However, little is known about the role of CSCs in mediating tumor resistance to immunotherapy. Due to their immunomodulating features and plasticity, CSCs can be especially proficient at evading immune surveillance, thus potentially representing the most prominent malignant cell component implicated in primary or acquired resistance to immunotherapy. The identification of immunomodulatory properties of CSCs that include mechanisms that regulate their interactions with immune cells, such as bidirectional release of particular cytokines/chemokines, fusion of CSCs with fusogenic stromal cells, and cell-to-cell communication exerted by extracellular vesicles, may significantly improve the efficacy of current immunotherapy strategies. The purpose of this review is to discuss the current scientific evidence linking CSC biological, immunological, and epigenetic features to tumor resistance to immunotherapy.

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Section: Immunomodulatory Molecules Stimulating Tumor Stemness: the Dsupporting

confidence: 81%

Section: Immunomodulatory Molecules Stimulating Tumor Stemness: the Dmentioning

confidence: 75%

Cancer Stem Cells: Devil or Savior—Looking behind the Scenes of Immunotherapy Failure

Castagnoli

Santis

Volpari

et al. 2020

Cells

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“…Another interesting finding regsrding CSC maintenance is that programmed death ligand 1 (PD-L1, also known as CD274) could stimulate CSC expansion via the high mobility group A (HMGA)-dependent Akt and ERK pathways [140]. PD-L1 in CSCs also confers immune evasion, thereby sustaining the tumorigenesis of CSCs [141].…”

Section: Mirnas Regulating Nf-κb Signaling and Pd-l1mentioning

confidence: 99%

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

Seo

Moeng

Sim³

et al. 2019

Cells

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The susceptibility of cancer cells to different types of treatments can be restricted by intrinsic and acquired therapeutic resistance, leading to the failure of cancer regression and remission. To overcome this problem, a combination therapy has been proposed as a fundamental strategy to improve therapeutic responses; however, resistance is still unavoidable. MicroRNA (miRNAs) are associated with cancer therapeutic resistance. The modulation of dysregulated miRNA levels through miRNA-based therapy comprising a replacement or inhibition approach has been proposed to sensitize cancer cells to other anti-cancer therapies. The combination of miRNA-based therapy with other anti-cancer therapies (miRNA-based combinatorial cancer therapy) is attractive, due to the ability of miRNAs to target multiple genes associated with the signaling pathways controlling therapeutic resistance. In this article, we present an overview of recent findings on the role of therapeutic resistance-related miRNAs in different types of cancer. We review the feasibility of utilizing dysregulated miRNAs in cancer cells and extracellular vesicles as potential candidates for miRNA-based combinatorial cancer therapy. We also discuss innate properties of miRNAs that need to be considered for more effective combinatorial cancer therapy.Cells 2020, 9, 29 2 of 32 to confer the ability to acquire CSC properties onto cancer cells, thereby contributing to therapeutic resistance [7]. Moreover, cell-to-cell communication via extracellular vesicles among different types of cells within the cancer microenvironment could affect the efficacy of cancer therapies by delivering miRNAs that regulate various signaling pathways connected to therapeutic resistance [8,9].Combination therapies have been proposed to overcome therapeutic resistance via the combined inhibition of different mechanisms. For example, the combination of cobimetinib and pictilisib was reported to be beneficial for the treatment of colorectal cancer cells. However, resistance is unavoidable even after the combination treatment [10]. Similarly, the simultaneous inhibition of phosphoinositide 3-kinase (PI3K) and a mechanistic target of rapamycin kinase (mTOR) was reported to activate extracellular signal-regulated kinase (ERK), a pro-survival factor, in acute myeloid leukemia [11]. Therefore, it is still necessary to explore new combination strategies to defeat therapeutic resistance. An improved understanding of the cellular basis of cancer therapeutic resistance can further provide promising opportunities to design and develop novel cancer treatment strategies to manage cancers.MicroRNAs (miRNAs) are widely recognized, small, regulatory RNAs modulating numerous intracellular signaling pathways in several diseases, including cancers. Based on the expression levels and intracellular functions of miRNAs, they could act as tumor-suppressive or oncogenic factors in cancer cells [12][13][14]. The abnormal expression of miRNAs is associated with therapeutic resistance in cancer, and the modulation of m...

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“…Therefore, we expanded our findings, focusing on HMGA1 protein, which is a crucial activator of the PI3K/Akt pathway (28). Both qPCR analysis (Fig.…”

Section: Mir-637 Directly Targets Hmga1 In Gliomamentioning

confidence: 99%

Oncogenic ZEB2/miR-637/HMGA1 signaling axis targeting vimentin promotes the malignant phenotype of glioma

Zeng

Que

Lin

et al. 2020

Preprint

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Background Glioma is the most common primary tumor of the central nervous system. We previously confirmed that zinc finger E-box binding homeobox (ZEB) 2 promotes the malignant progression of glioma, while microRNA-637 (miR-637) is associated with favorable prognosis in glioma. This study investigated the potential interaction between ZEB2 and miR-637 and its downstream signaling pathway in glioma. Methods Chromatin immunoprecipitation, luciferase reporter, and electrophoretic mobility shift assays were used to confirm ZEB2 binding to miR-637. Microarray and bioinformatic analyses were used to investigate targets of miR-637. MTT and EdU assays, transwell assays, and Boyden assays were utilized to assess cell viability, migration, and invasion, respectively. A subcutaneous xenograft model was utilized for analyzing the role of miR-637/high mobility group A1 (HMGA1) interaction in vivo. Immunohistochemistry staining of clinical samples and bioinformatic analysis of the Chinese Glioma Genome Atlas and The Cancer Genome Atlas databases were performed to further confirm the ZEB2/miR-637/HMGA1/vimentin axis. Results ZEB2 was bound directly bind to the E-box elements in the miR-637 promoter and promoted cell proliferation, migration, and invasion via miR-637 downregulation. Subsequent screening confirmed that HMGA1 was a direct target of miR-637, while miR-637 could propagate the malignant phenotype of glioma by suppressing HMGA1 both in vitro and in vivo. Furthermore, the interaction between cytoplasmic HMGA1 and vimentin was observed, and vimentin inhibition could abolish increased migration and invasion induced by HMGA1 overexpression. Notably, the ZEB2/miR-637/HMGA1/vimentin axis was also evident in glioma tissue samples and public glioma datasets, while both HMGA1 and vimentin were associated with an unfavorable prognosis in glioma. Additionally, upregulated HMGA1 and vimentin were found in isocitrate dehydrogenase (IDH) wild-type and 1p/19q non-codeletion diffusely infiltrating glioma. Conclusions We identified an oncogenic ZEB2/miR-637/HMGA1 signaling axis targeting vimentin that promotes both migration and invasion in glioma. This not only extends the current understanding of miR-637 regulation in glioma, but also unravels a novel signaling pathway that integrates a transcriptional factor, microRNA, and a chromatin remodeling factor to modulate the malignant phenotype of glioma.

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PD-L1 promotes colorectal cancer stem cell expansion by activating HMGA1-dependent signaling pathways

Cited by 149 publications

References 30 publications

Cancer Stem Cells: Devil or Savior—Looking behind the Scenes of Immunotherapy Failure

Cancer Stem Cells: Devil or Savior—Looking behind the Scenes of Immunotherapy Failure

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

Oncogenic ZEB2/miR-637/HMGA1 signaling axis targeting vimentin promotes the malignant phenotype of glioma

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