Cancer‐associated fibroblast‐derived exosomal microRNA‐20a suppresses the PTEN/PI3K‐AKT pathway to promote the progression and chemoresistance of non‐small cell lung cancer

Shi, Lin; Zhu, Wei; Huang, Yuanyuan; Zhuo, Lin; Wang, Siyun; Chen, Shaobing; Zhang, Bei; Ke, Bin

doi:10.1002/ctm2.989

Cited by 69 publications

(52 citation statements)

References 76 publications

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“…qRT-PCR analysis showed the decreased expressions of ZEB, FGF2, SMAD4, KLF4 and PTEN in SKM1-miR92a1 and SKM1-miR92a2 cells ( Figure 3 B). Among these five genes, PTEN expression significantly decreased and it was reported to correlate with drug resistance [ 15 , 25 ]. Therefore, we aimed at PTEN as the potential target of miR92a ( Figure 3 B).…”

Section: Resultsmentioning

confidence: 99%

“…Next, the TCGA database indicated increased expression of β-catenin in AML samples ( n = 173) compared to HD ( n = 70) ( Figure 4 C). Interestingly, when SKM1 and ML1 were incubated with a selective inhibitor of β-catenin, MSAB [ 15 ], the apoptosis of Exos-miR92a1/2-treated recipient cells was increased significantly compared to Exos-SKM1, which revealed that MSAB treatment reversed the Ara-C resistance of SKM1 and ML1 caused by Exos-miR92a1/2 ( Figure 4 D and Figure S3D ). Together, these data indicate that exosomal miR92a mediates the Ara-C resistance of SKM1 via inhibiting PTEN and activating β-catenin.…”

Section: Resultsmentioning

confidence: 99%

“…miRNAs are a class of small noncoding RNAs, which regulate gene expression by binding to the 3′ untranslated regions (UTR) of target mRNAs [ 13 ]. Exosomes can enwrap miRNAs, protect them from degradation, deliver them to recipient cells and modulate tumor immunity and the surrounding microenvironment, further facilitating tumor growth, invasion, metastasis, angiogenesis and drug resistance [ 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Exosomal miR92a Promotes Cytarabine Resistance in Myelodysplastic Syndromes by Activating Wnt/β-catenin Signal Pathway

Xie

et al. 2022

Biomolecules

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Cytarabine (Ara-C) has been one of the frontline therapies for clonal hematopoietic stem cell disorders, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but Ara-C resistance often occurs and leads to treatment failure. Exosomal microRNAs (miRNAs, miRs) as small noncoding RNA that play important roles in post-transcriptional gene regulation, can be delivered into recipient cells by exosomes and regulate target genes’ expression. miR92a has been reported to be dysregulated in many cancers, including MDS and AML. However, the effects of exosomal miR92a in hematologic malignancies have not been fully investigated. In this study, qualitative analysis showed the significantly enhanced expression of exosomal miR92a in MDS/AML plasma. Subsequent functional assays indicated that exosomal miR92a can be transported and downregulate PTEN in recipient cells and, furthermore, activate the Wnt/β-catenin signaling pathway and interfere with the Ara-C resistance of receipt MDS/AML cells in vitro and in vivo. Altogether, our findings offer novel insights into plasma exosomal miR92a participating in Ara-C resistance in MDS/AML and we propose miR92a as a potential therapeutic target for MDS/AML.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exosomal miR92a Promotes Cytarabine Resistance in Myelodysplastic Syndromes by Activating Wnt/β-catenin Signal Pathway

Xie

et al. 2022

Biomolecules

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“…The PTEN/PI3K/AKT axis is reported to implicate in diverse physiological and pathological conditions and plays an important role in the regulation of cell growth and apoptosis in diverse human cancer including prostate cancer, hepatocellular carcinoma, and pancreatic cancer [41][42][43][44]. As the key target of PTEN, PTEN is identified to negatively regulate PI3K/AKT signaling [45,46]. Based on the regulation relationship between PTEN and PI3K/AKT signaling, we speculated that the effect of miR-2a-3p/PTEN regulation axis in laryngocarcinoma might be also mediated by PI3K/ AKT signaling.…”

Section: Discussionmentioning

confidence: 99%

Human Bone Marrow Mesenchymal Stem Cell (hBMSCs)-Derived miR-29a-3p-Containing Exosomes Impede Laryngocarcinoma Cell Malignant Phenotypes by Inhibiting PTEN

Dong

et al. 2022

Stem Cells International

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Although microRNA-29a-3p was reported to inhibit laryngocarcinoma progression, the potential mechanisms have not been explored clearly. Laryngocarcinoma tissues were collected for analyzing the levels of miR-29a-3p and phosphatase and tensin homolog (PTEN). The miR mimics or inhibitor was transfected into laryngocarcinoma cell lines M4E and Hep2 for the investigation of the biological functions (proliferative, invasion, migratory rates, and apoptotic rates) of this miRNA. The exosomes (Exo) from human bone marrow mesenchymal stem cells (hBMSCs) after the transfection of miR mimics/inhibitor/si-PTEN were isolated and used to stimulate M4E and Hep2 cells. The in vivo mouse model was constructed to verify our findings. The miR-29a-3p level was decreased, and PTEN level was elevated in laryngocarcinoma tissues and the cancer cell lines. MiR mimics could inhibit proliferative, invasive migratory rates while promoting apoptotic rates of M4E and Hep2 cells. MiR-29a-3p was enriched in hBMSC-derived Exo, and the Exo from miR-29a-3p mimics transfected hBMSCs could inhibit laryngocarcinoma cell malignant phenotypes in vitro and prevent tumor progression in vivo. In addition, the direct binding relationship between miR-29a-3p and PTEN in this disease was determined. In conclusion, hBMSC-derived Exo with upregulated miR-29a-3p inhibited laryngocarcinoma progression via regulating PTEN, providing a potential diagnostic and therapeutic target in this disease.

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“…Protein lysates were obtained according to the previously described procedures ( 21 ). BCA1-1KT kit was used for the protein quantification assay.…”

Section: Methodsmentioning

confidence: 99%

Irradiation enhances the malignancy-promoting behaviors of cancer-associated fibroblasts

Zhang¹,

Dong²,

Wu³

et al. 2022

Front. Oncol.

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BackgroundCancer-associated fibroblasts (CAFs) are the important component of the tumor microenvironment (TME). Previous studies have found that some pro-malignant CAFs participate in the resistance to radiotherapy as well as the initiation and progression of tumor recurrence. However, the exact mechanism of how radiation affects CAFs remains unclear. This study aimed to explore the effect and possible mechanism of radiation-activated CAFs, and its influence on lung cancer.MethodsCAFs were isolated from surgical specimens in situ and irradiated with 8Gy x-rays. The changes in cell morphology and subcellular structure were observed. CAFs marker proteins such as FAP and α-SMA were detected by Western Blotting. Cell counting kit-8 (CCK8) assay, flow cytometry, wound healing assay, and transwell chamber assay was used to detect the activation of cell viability and migration ability. A nude mouse xenograft model was established to observe the tumorigenicity of irradiated CAFs in vivo. The genomic changes of CAFs after radiation activation were analyzed by transcriptome sequencing technology, and the possible mechanisms were analyzed.ResultsThe CAFs showed a disorderly growth pattern after X-ray irradiation. Subcellular observations suggested that metabolism-related organelles exhibited more activity. The expression level of CAFs-related signature molecules was also increased. The CAFs irradiated by 8Gy had good proliferative activity. In the (indirect) co-culture system, CAFs showed radiation protection and migration induction to lung cancer cell lines, and this influence was more obvious in radiation-activated CAFs. The radiation protection was decreased after exosome inhibitors were applied. Vivo study also showed that radiation-activated CAFs have stronger tumorigenesis. Transcriptome analysis showed that genes were enriched in several pro-cancer signaling pathways in radiation-activated CAFs.ConclusionsOur study confirmed that CAFs could be activated by ionizing radiation. Irradiation-activated CAFs could promote cancer cell proliferation, migration, radiotherapy tolerance, and tumorigenesis. These results suggested that irradiation-activated CAFs might participate in the recurrence of lung cancer after radiotherapy, and the inhibition of CAFs activation may be an important way to improve clinical radiotherapy efficacy.

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Cancer‐associated fibroblast‐derived exosomal microRNA‐20a suppresses the PTEN/PI3K‐AKT pathway to promote the progression and chemoresistance of non‐small cell lung cancer

Abstract: 1. CAFs-derived exosomal miR-20a promotes the progression of NSCLC.2. CAFs-derived exosomal miR-20a promotes chemoresistance of NSCLC. 3. PTEN is a target gene of miR-20a. 4. miRNA-20a suppresses the PTEN/PI3K-AKT pathway.

Cited by 69 publications

References 76 publications

Exosomal miR92a Promotes Cytarabine Resistance in Myelodysplastic Syndromes by Activating Wnt/β-catenin Signal Pathway

Exosomal miR92a Promotes Cytarabine Resistance in Myelodysplastic Syndromes by Activating Wnt/β-catenin Signal Pathway

Human Bone Marrow Mesenchymal Stem Cell (hBMSCs)-Derived miR-29a-3p-Containing Exosomes Impede Laryngocarcinoma Cell Malignant Phenotypes by Inhibiting PTEN

Irradiation enhances the malignancy-promoting behaviors of cancer-associated fibroblasts

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