Exosomal lncRNA NEAT1 from cancer-associated fibroblasts facilitates endometrial cancer progression via miR-26a/b-5p-mediated STAT3/YKL-40 signaling pathway

Fan, Jiangtao; Zhou, Zhao-Yu; Luo, Yan-Lu; Luo, Qian; Chen, Sibang; Zhao, Jin‑Che; Chen, Qiao-Ru

doi:10.1016/j.neo.2021.05.004

Cited by 62 publications

(46 citation statements)

References 31 publications

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“…Previous reports have suggested that CHI3L1 is expressed by and secreted from cancer cells ( 31 - 33 ). Furthermore, CHI3L1 has been reported to serve a role in cancer progression by CAFs; however, this mechanism has only been investigated in the context of immune cells or exosomes, not cytokines ( 11 , 35 ). Accordingly, the present study focused on cytokines secreted from CAFs and demonstrated that CAFs, not cancer cells, mainly secreted CHI3L1 and IL-8.…”

Section: Discussionmentioning

confidence: 99%

“…Chitinase 3-like 1 (CHI3L1), a 40 kDa secreted glycoprotein also known as YKL-40 ( 25 , 26 ), was originally considered to be associated with inflammatory diseases, such as asthma, liver fibrosis and arthritis ( 27 - 29 ). A number of reports have described the involvement of CHI3L1 in cancer ( 11 , 30 - 35 ). For example, serum CHI3L1 levels are associated with prognosis in patients with colorectal cancer ( 30 ), and upregulation of CHI3L1 expression in tumors promotes tumor angiogenesis, proliferation, migration, invasion and radiation resistance ( 31 - 33 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, the mechanisms of CHI3L1 production and the mechanisms through which CHI3L1 induces tumor progression have not been clarified. Although two reports have described the association of CHI3L1 and CAFs, the mechanisms were found to involve immune cells or exosomes rather than cytokine secretion ( 11 , 35 ).…”

Section: Introductionmentioning

confidence: 99%

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Chitinase 3-like 1 secreted from cancer-associated fibroblasts promotes tumor angiogenesis via interleukin-8 secretion in colorectal cancer

et al. 2021

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The cancer-stromal interaction has been demonstrated to promote tumor progression, and cancer-associated fibroblasts (CAFs), which are the main components of stromal cells, have attracted attention as novel treatment targets. Chitinase 3-like 1 (CHI3L1) is a chitinase-like protein, which affects cell proliferation and angiogenesis. However, the mechanisms through which cells secrete CHI3L1 and through which CHI3L1 mediates tumor progression in the cancer microenvironment are still unclear. Accordingly, the present study assessed the secretion of CHI3L1 in the microenvironment of colorectal cancer and evaluated how CHI3L1 affects tumor angiogenesis. CAFs and normal fibroblasts (NFs) established from colorectal cancer tissue, and human colon cancer cell lines were evaluated using immunostaining, cytokine antibody array, RNA interference, reverse transcription-quantitative PCR (RT-qPCR), ELISA, western blotting and angiogenesis assays. The expression and secretion of CHI3L1 in CAFs were stronger than those in NFs and colorectal cancer cell lines. In addition, interleukin-13 receptor α2 (IL-13Rα2), a receptor for CHI3L1, was not expressed in colorectal cancer cell lines, but was expressed in fibroblasts, particularly CAFs. Furthermore, the expression and secretion of IL-8 in CAFs was stronger than that in NFs and cancer cell lines, and recombinant CHI3L1 addition increased IL-8 expression in CAFs, whereas knockdown of CHI3L1 suppressed IL-8 expression. Furthermore, IL-13Rα2 knockdown suppressed the enhancement of IL-8 expression induced by CHI3L1 treatment in CAFs. For vascular endothelial growth factor-A (VEGFA), similar results to IL-8 were observed in an ELISA for comparison of secretion between CAFs and NFs and for changes in secretion after CHI3L1 treatment in CAFs; however, no significant differences were observed for changes in expression after CHI3L1 treatment or IL-13Rα2 knockdown in CAFs assessed using RT-qPCR assays. Angiogenesis assays revealed that tube formation in vascular endothelial cells was suppressed by conditioned medium from CAFs with the addition of human CHI3L1 neutralizing antibodies compared with control IgG, and also suppressed by conditioned medium from CAFs transfected with CHI3L1, IL-8 or VEGFA small interfering RNA compared with negative control small interfering RNA. Overall, the present findings indicated that CHI3L1 secreted from CAFs acted on CAFs to increase the secretion of IL-8, thereby affecting tumor angiogenesis in colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chitinase 3-like 1 secreted from cancer-associated fibroblasts promotes tumor angiogenesis via interleukin-8 secretion in colorectal cancer

et al. 2021

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“…The downregulation of miR-31 in CAFs has been associated with a corresponding increase in expression of the homeobox gene SATB2 in the context of tumor cell migration and invasiveness in endometrial cancers [62,63]. An exosomal NEAT1 from CAFs has been reported to contribute to endometrial cancer progression via miR-26a/b-5p-mediated STAT3/YKL-40 pathway [64]. A direct transfer of CAF-secreted exosomal miR-320a to endometrial cancer cells has been demonstrated to inhibit their proliferation via downregulation of HIF1alpha, which also led to lowered VEGFA expression in vitro [65].…”

Section: Migration Invasion and Metastatic Progressionmentioning

confidence: 99%

Cancer-Associated Fibroblasts in Conversation with Tumor Cells in Endometrial Cancers: A Partner in Crime

Aske

Dey

2021

IJMS

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A tumor cell carrying characteristic genomic alteration(s) exists within its host’s microenvironment. The tumor microenvironment (TME) renders holistic support to the tumor via cross-talk between tumor cells and three components of TME, immune components, vascular components, and fibroblast components. The tempero-spatial interaction of tumor cells with its microenvironment is the deterministic factor for tumor growth, progression, resistance to therapy, and its outcome in clinics. TME (1) facilitates proliferation, and the ensuing metastasis-associated phenotypes, (2) perturbs immune surveillance and supports tumor cells in their effort to evade immune recognition, and (3) actively participates in developing drug-induced resistance in cancer cells. Cancer-Associated Fibroblast (CAF) is a unique component of TME. CAF is the host mesenchyme immediately surrounding the tumor cells in solid tumors. It facilitates tumor growth and progression and participates in developing drug resistance in tumor cells by playing a critical role in all the ways mentioned above. The clinical outcome of a disease is thus critically contributed to by the CAF component of TME. Although CAFs have been identified historically, the functional relevance of CAF-tumor cell cross-talk and their influence on angiogenic and immune-components of TME are yet to be characterized in solid tumors, especially in endometrial cancers. Currently, the standard of care for the treatment of endometrial cancers is primarily guided by therapies directed towards the disease’s tumor compartment and immune compartments. Unfortunately, in the current state of therapies, a complete response (CR) to the therapy is still limited despite a more commonly achieved partial response (PR) and stable disease (SD) in patients. Acknowledging the limitations of the current sets of therapies based on only the tumor and immune compartments of the disease, we sought to put forward this review based on the importance of the cross-talk between CAF of the tumor microenvironment and tumor cells. The premise of the review is to recognize the critical role of CAF in disease progression. This manuscript presents a systemic review of the role of CAF in endometrial cancers. We critically interrogated the active involvement of CAF in the tumor compartment of endometrial cancers. Here we present the functional characteristics of CAF in the context of endometrial cancers. We review (1) the characteristics of CAF, (2) their evolution from being anti-tumor to pro-tumor, (3) their involvement in regulating growth and several metastasis-associated phenotypes of tumor cells, (4) their participation in perturbing immune defense and evading immune surveillance, and (5) their role in mediating drug resistance via tumor-CAF cross-talk with particular reference to endometrial cancers. We interrogate the functional characteristics of CAF in the light of its dialogue with tumor cells and other components of TME towards developing a CAF-based strategy for precision therapy to supplement tumor-based therapy. The purpose of the review is to present a new vision and initiate a thought process which recognizes the importance of CAF in a tumor, thereby resulting in a novel approach to the design and management of the disease in endometrial cancers.

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“…Song et al demonstrated that adipocyte-derived exosomes-mediated SNHG9 inhibited inflammation and apoptosis of endothelial cells via downregulating TRADD [ 12 ]. Previous studies indicated that exosomal NEAT1 acted as a vital regulator in the pathogenesis of various diseases, such as autoimmune disorders [ 13 ], malignancies [ 14 ], and cardiovascular diseases [ 15 ]. Nevertheless, the involvement of exosome-mediated transfer of NEAT1 in AR is unclear.…”

Section: Introductionmentioning

confidence: 99%

Exosomal lncRNA Nuclear Paraspeckle Assembly Transcript 1 (NEAT1)contributes to the progression of allergic rhinitis via modulating microRNA-511/Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) axis

Wang

Cai

et al. 2021

Bioengineered

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Allergic rhinitis (AR) is a common chronic disease characterized by inflammation of the nasal mucosa. Long non-coding RNA (LncRNA) has been reported to be involved in the pathogenesis of various diseases. However, the biological roles of lncRNA Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) in AR are still unclear. The mRNA levels of NEAT1, miR-511, and Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) were detected by RT-qPCR. The protein levels of exosomal markers were examined by western blot. ELISA was used to assess the levels of GM-CSF, eotaxin-1, and MUC5AC. The cell viability and apoptosis were evaluated by CCK-8 and TUNEL assays. In this study, we found that the NEAT1 level was highly expressed in AR and IL-13-treated HNECs. NEAT1 interference significantly suppressed levels of GM-CSF, eotaxin-1, and MUC5AC and apoptosis rate, but promoted the viability of IL-13-treated human nasal epithelial cells (HNECs). Moreover, exosomes containing NEAT1 induced inflammatory cytokine production and apoptosis, while NEAT1 depletion abrogated these effects. In addition, NEAT1 directly interacted with miR-511, and the inhibition of miR-511 partially restored the inhibitory effects of NEAT1 silencing on inflammatory cytokine, mucus production, and apoptosis in IL-13-stimulated HNECs. Furthermore, miR-511 could bind to the 3ʹUTR of NR4A2, and the inhibition of miR-511 increased levels of inflammatory factors and apoptosis rate, which was counteracted by depleting NR4A2. In conclusion, our data revealed that exosomal NEAT1 contributed to the pathogenesis of AR through the miR-511/NR4A2 axis. These findings might offer novel strategies for the prevention and treatment of AR.

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Exosomal lncRNA NEAT1 from cancer-associated fibroblasts facilitates endometrial cancer progression via miR-26a/b-5p-mediated STAT3/YKL-40 signaling pathway

Cited by 62 publications

References 31 publications

Chitinase 3-like 1 secreted from cancer-associated fibroblasts promotes tumor angiogenesis via interleukin-8 secretion in colorectal cancer

Chitinase 3-like 1 secreted from cancer-associated fibroblasts promotes tumor angiogenesis via interleukin-8 secretion in colorectal cancer

Cancer-Associated Fibroblasts in Conversation with Tumor Cells in Endometrial Cancers: A Partner in Crime

Exosomal lncRNA Nuclear Paraspeckle Assembly Transcript 1 (NEAT1)contributes to the progression of allergic rhinitis via modulating microRNA-511/Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) axis

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