miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint

Xu, Shaohua; Tao, Zhen; Bai, Hai; Huagen, Liang; Shi, Ying; Wang, Tao; Song, Wen; Chen, Yong; Ouyang, Jingping; Chen, Jinhong; Kong, Fanfei; Dong, Yishan; Jiang, Shi Wen; Li, Weiyong; Wang, Ping; Yuan, Zhiyong; Wan, Xiaoping; Wang, Chenguang; Li, Wencheng; Zhang, Xiaoping; Chen, Ke

doi:10.1038/ncomms11406

Cited by 247 publications

(208 citation statements)

References 38 publications

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“…Our previous studies (Llobet-Navas et al 2014a,b) and the new data shown here have revealed that this miRNA cluster modulates the expression of at least three well-known oncogenes (CDC25A, BCL-2, and IGF1R) in human and mouse primary breast cancers. Others have also shown that, in other cell types, this cluster targets additional genes involved in cell cycle progression (Nakashima et al 2010;Xu et al 2013b), angiogenesis (Ghosh et al 2010;Nakashima et al 2010), immune response (Xu et al 2016), cell metabolism (Long et al 2013), and cell adhesion (Chong et al 2014). Thus, we propose that aberrant high levels of these targets due to loss of miR-424(322)/ 503 support multiple hallmarks of cancer leading to tumorigenesis (Fig.…”

Section: Discussionmentioning

confidence: 57%

miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapy

et al. 2017

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The female mammary gland is a very dynamic organ that undergoes continuous tissue remodeling during adulthood. Although it is well established that the number of menstrual cycles and pregnancy (in this case transiently) increase the risk of breast cancer, the reasons are unclear. Growing clinical and experimental evidence indicates that improper involution plays a role in the development of this malignancy. Recently, we described the miR-424(322)/503 cluster as an important regulator of mammary epithelial involution after pregnancy. Here, through the analysis of ∼3000 primary tumors, we show that miR-424(322)/503 is commonly lost in a subset of aggressive breast cancers and describe the genetic aberrations that inactivate its expression. Furthermore, through the use of a knockout mouse model, we demonstrate for the first time that loss of miR-424(322)/503 promotes breast tumorigenesis in vivo. Remarkably, we found that loss of miR-424(322)/503 promotes chemoresistance due to the up-regulation of two of its targets: BCL-2 and insulin-like growth factor-1 receptor (IGF1R). Importantly, targeted therapies blocking the aberrant activity of these targets restore sensitivity to chemotherapy. Overall, our studies reveal miR-424(322)/ 503 as a tumor suppressor in breast cancer and provide a link between mammary epithelial involution, tumorigenesis, and the phenomenon of chemoresistance.

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Section: Discussionmentioning

confidence: 57%

miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapy

et al. 2017

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“…DU145/T cells co-culture model was done as described previously [17]. Peripheral blood mononuclear cells (PBMCs) from healthy human donors were isolated using Lymphoprep density gradient centrifugation (Accurate Chemical).…”

Section: Du145/t Co-culture Modelmentioning

confidence: 99%

“…The PBMCs were subsequently harvested and stained with PEconjugated PD-1, Alexa Fluor 488-conjugated annexin V and APC-conjugated CD8 antibodies, respectively. PD-1-dependent CD8+ T cell apoptosis was calculated as the percentage of annexin V+ cells in the gated PD-1+/CD8+ population [17].…”

Section: T Cell Apoptosis Assaymentioning

confidence: 99%

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MiR-195/-16 Family Enhances Radiotherapy via T Cell Activation in the Tumor Microenvironment by Blocking the PD-L1 Immune Checkpoint

Tao

Ruan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Radiotherapy is the standard treatment option for advanced prostate cancer. Unfortunately, despite significant advances in radiation delivery, prostate cancer radioresistance occurs in a large proportion of patients undergoing radiotherapy. As a way to enhance radiotherapy effectiveness, research advances into the mechanisms regulating the immune response have revived interest in combination radiation and immune-based therapies. Methods: miR-195/-16 family and PD-L1 levels were analyzed in samples from a GSE21032 data set. Kaplan-Meier analysis was used to evaluate the difference in biochemical recurrence-free survival associated with miR-195 and miR-16 expression. qRT-PCR and western blot were used to evaluate the miR-195, miR-16 and PD-L1 expression. Then, we used bioinformatics analysis and luciferase reporter assay to predict and confirm the miR-195 and miR-16 target gene. Finally, we elucidate the miR-195 and miR-16 function on immune evasion in the DU145/T cell co-culture model and syngeneic mouse model treated with radiotion through qRT-PCR, western blot, Flow cytometry and ELISA. Results: High levels of miR-195 and miR-16 were positively correlated with the biochemical recurrence-free survival of prostate cancer patients. miR-195 and miR-16 were inversely correlated with PD-L1, PD-1, CD80 and CTLA-4 expression. Further mechanistic investigations revealed that miR-195 and miR-16 inhibited PD-L1 expression. Additionally, restoration of miR-195 and miR-16 expression enhanced radiotherapy via T cell activation in the tumor microenvironment by blocking PD-L1 expression. This synergistic effect of immunotherapy and radiotherapy was associated with the proliferation of functional cytotoxic CD8+ T cells and inhibition of myeloid-derived suppressor cells and regulatory T cells. Conclusions: Our data revealbiological and functional interactions between immunotherapy and radiotherapy through the miR-195/-16 family regulatory cascade.

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“…16,17 Briefly, total RNA from tissues was extracted with TRIzol reagent (Invitrogen, Carlsbad, CA, USA). Reverse transcription (RT) of RNA was conducted using the RevertAid™ First Strand cDNA Synthesis Kit (Fermentas, Vilnius, Lithuania).…”

Section: Isolation Of Rna and Quantitative Reverse Transcription Polymentioning

confidence: 99%

Diagnostic and prognostic value of scavenger receptor class B type 1 in clear cell renal cell carcinoma

Lou

et al. 2017

Tumour Biol.

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Aberrant expression of scavenger receptor class B type 1 has been reported in several human cancers. Nevertheless, the roles of scavenger receptor class B type 1 in clear cell renal cell carcinoma remain unclear. The aim of this study was to evaluate the diagnostic and prognostic value of scavenger receptor class B type 1 in clear cell renal cell carcinoma. The messenger RNA level of scavenger receptor class B type 1 in clear cell renal cell carcinoma tissues was detected by quantitative reverse transcription polymerase chain reaction, while protein level was determined by western blot and immunohistochemistry. The lipid content between clear cell renal cell carcinoma tissues and normal kidney tissues was differentiated by Oil Red O and hematoxylin-eosin staining. The diagnostic value of scavenger receptor class B type 1 was determined by receiver operating characteristic curve. The prognostic significance of scavenger receptor class B type 1 was assessed by Kaplan-Meier analysis and Cox regression analysis. Our results showed that the expression of scavenger receptor class B type 1 in clear cell renal cell carcinoma tissues at both messenger RNA and protein level was much higher than that in normal kidney tissues. Receiver operating characteristic curve analysis exhibited a significant value of area under the curve (0.8486, 95% confidence interval: 0.7926-0.9045) with strong sensitivity (0.75, 95% confidence interval: 0.6535-0.8312) and specificity (0.90, 95% confidence interval: 0.8238-0.9510). Kaplan-Meier analysis revealed that patients with higher scavenger receptor class B type 1 expression had shorter progression-free survival time. Cox analysis indicated that scavenger receptor class B type 1 was an independent prognostic biomarker. In conclusion, our findings implied that scavenger receptor class B type 1 might serve as a diagnostic and independent prognostic biomarker in clear cell renal cell carcinoma.

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miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint

Cited by 247 publications

References 38 publications

miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapy

miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapy

MiR-195/-16 Family Enhances Radiotherapy via T Cell Activation in the Tumor Microenvironment by Blocking the PD-L1 Immune Checkpoint

Diagnostic and prognostic value of scavenger receptor class B type 1 in clear cell renal cell carcinoma

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