MicroRNA-146a induces immune suppression and drug-resistant colorectal cancer cells

Khorrami, Samaneh; Hosseini, Ahmad Zavaran; Mowla, Seyed Javad; Soleimani, Masoud; Rakhshani, Naser; Malekzadeh, Reza

doi:10.1177/1010428317698365

Cited by 49 publications

(33 citation statements)

References 38 publications

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“…29 Some publications have suggested an implication of miRNA in immune response regulation as well as PD-L1 and PD-1 expression regulation. [30][31][32][33][34][35][36][37][38][39][40][41] We report for the first time the association of down-regulation of circulating miRNA-320b and -375 expression and response to ICIs. miRNA-320b is down-regulated in various cancers, and it is associated with tumorigenesis and poor prognosis in glioma.…”

Section: Discussionmentioning

confidence: 67%

Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab

et al. 2018

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Immune checkpoint inhibitors, as nivolumab, are used in advanced non-small cell lung cancer (NSCLC). However, no associated biomarker is validated in clinical practice with this drug. We investigated herein immune-related blood markers in patients with advanced NSCLC treated with nivolumab. Plasma of 43 consecutive patients were prospectively collected at time of the diagnosis of cancer, at the initiation of nivolumab and at the first tumour evaluation (2 months). Concentrations of PD-L1 (sPD-L1), soluble PD-L2 (sPD-L2), Interleukine-2 (sIl-2), Interferon-gamma (sIFN-γ), and Granzyme B (sGranB) were quantified by ELISA. Cell free RNA was quantified by Reverse Transcriptase -PCR), and plasmatic microRNAs (miRNAs) were evaluated by targeted sequencing. Expression of PD-L1 on tumour biopsies was performed by immunohistochemistry using E13LN. High sPD-L1 at 2 months and increase of sPD-L1 concentrations were associated with poor response and absence of clinical benefit (nivolumab treatment less than 6 months). The variation of sPD-L1 concentrations were confirmed by RNA quantification. sPD-L1 concentrations were not correlated with PD-L1 expression on corresponding tumour samples. Low sGranB at nivolumab initiation was also associated with poor response. High sPD-L1 and low sGranB were associated with poor progression-free survival (PFS) and overall survival (OS). Low sPD-L2, low sIl-2 and high sIFN-γ were associated with grade 3-4 toxicities. Finally, miRNA screening showed that patients with clinical benefit (n = 9) had down-expression of miRNA-320b and -375 compared to patients with early progression at 2 months (n = 9). In conclusion, our results highlight the interest of circulating biomarkers in patients treated with nivolumab.

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Section: Discussionmentioning

confidence: 67%

Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab

et al. 2018

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“…Knocking down miR‐146a decreases the proliferation of p53‐mutant basal‐like breast cancers . In the CRC cell line HT29, ectopic expression of miR‐146a promotes resistance to 5‐fluorouracil and irinotecan . Furthermore, coculturing miR‐146a‐expressing HT29 cells with peripheral blood mononuclear cells (PBMCs) increases the frequency of regulatory T‐cells (Tregs) .…”

Section: Discussionmentioning

confidence: 99%

“…In the CRC cell line HT29, ectopic expression of miR‐146a promotes resistance to 5‐fluorouracil and irinotecan . Furthermore, coculturing miR‐146a‐expressing HT29 cells with peripheral blood mononuclear cells (PBMCs) increases the frequency of regulatory T‐cells (Tregs) . miR‐146a mediates the expression of some M2 macrophage markers, and knocking down miR‐146a in macrophages inhibits the tumorigenesis of breast 4T1 cells .…”

Section: Discussionmentioning

confidence: 99%

RAB27B‐activated secretion of stem‐like tumor exosomes delivers the biomarker microRNA‐146a‐5p, which promotes tumorigenesis and associates with an immunosuppressive tumor microenvironment in colorectal cancer

Cheng

Liao

Lin

et al. 2019

Intl Journal of Cancer

103

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The dynamic cell–cell communication is essential for tissue homeostasis in normal physiological circumstances and contributes to a diversified tumor microenvironment. Although exosomes are extracellular vesicles that actively participate in cell–cell interaction by shutting cellular components, impacts of tumor exosomes in the context of cancer stemness remain elusive. Here, we expand colorectal cancer stem cells (CRCSCs) as cancer spheroids and demonstrate that the β‐catenin/Tcf‐4‐activated RAB27B expression is required for the secretion of CRCSC exosomes. In an exosomal RNA sequencing analysis, a switch of exosomal RNA species from retrotransposons to microRNAs (miRNAs) is identified upon expanding CRCSCs. miRNA‐146a‐5p (miR‐146a) is the major miRNA in CRCSC exosomes and exosomal miR‐146a promotes stem‐like properties and tumorigenicity by targeting Numb in recipient CRC cells. Among 53 CRC patients, those with abundant exosomal miR‐146a expression in serum exhibits higher miR‐146aHigh/NumbLow CRCSC traits, an increased number of tumor‐filtrating CD66(+) neutrophils and a decreased number of tumor‐infiltrating CD8(+) T cells. Our study elucidates a unique mechanism of tumor exosome‐mediated stemness expansion.

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“…Evading immune destruction . Khorrami and colleagues showed how over-expression of miR-146 in a CRC cell line co-cultured with peripheral blood mononuclear cells extracted from healthy donors, increased T reg frequencies and anti-inflammatory cytokines like TGF-β and IL-10, leading to an overall immune suppression in the tumor microenvironment (Rusca and Monticelli, 2011 ; Khorrami et al, 2017 ). On the other hand, miR-152 was shown to be decreased in gastric cancer cell lines as well as in human gastric cancer tissues.…”

Section: Microrna and Cancermentioning

confidence: 99%

microRNAs Make the Call in Cancer Personalized Medicine

Detassis

Grasso

Vescovo

et al. 2017

Front. Cell Dev. Biol.

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Since their discovery and the advent of RNA interference, microRNAs have drawn enormous attention because of their ubiquitous involvement in cellular pathways from life to death, from metabolism to communication. It is also widely accepted that they possess an undeniable role in cancer both as tumor suppressors and tumor promoters modulating cell proliferation and migration, epithelial-mesenchymal transition and tumor cell invasion and metastasis. Moreover, microRNAs can even affect the tumor surrounding environment influencing angiogenesis and immune system activation and recruitment. The tight association of microRNAs with several cancer-related processes makes them undoubtedly connected to the effect of specific cancer drugs inducing either resistance or sensitization. In this context, personalized medicine through microRNAs arose recently with the discovery of single nucleotide polymorphisms in the target binding sites, in the sequence of the microRNA itself or in microRNA biogenesis related genes, increasing risk, susceptibility and progression of multiple types of cancer in different sets of the population. The depicted scenario implies that the overall variation displayed by these small non-coding RNAs have an impact on patient-specific pharmacokinetics and pharmacodynamics of cancer drugs, pushing on a rising need of personalized treatment. Indeed, microRNAs from either tissues or liquid biopsies are also extensively studied as valuable biomarkers for disease early recognition, progression and prognosis. Despite microRNAs being intensively studied in recent years, a comprehensive review describing these topics all in one is missing. Here we report an up-to-date and critical summary of microRNAs as tools for better understanding personalized cancer biogenesis, evolution, diagnosis and treatment.

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MicroRNA-146a induces immune suppression and drug-resistant colorectal cancer cells

Cited by 49 publications

References 38 publications

Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab

Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab

RAB27B‐activated secretion of stem‐like tumor exosomes delivers the biomarker microRNA‐146a‐5p, which promotes tumorigenesis and associates with an immunosuppressive tumor microenvironment in colorectal cancer

microRNAs Make the Call in Cancer Personalized Medicine

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