Interleukin-34-CSF1R Signaling Axis Promotes Epithelial Cell Transformation and Breast Tumorigenesis

Poudel, Muna; Kım, Garam; Bhattarai, Poshan Yugal; Kim, Jin‐Young; Choi, Hong Seok

doi:10.3390/ijms22052711

Cited by 10 publications

(20 citation statements)

References 56 publications

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“…6B ). Previous research also testified that M-CSF could promote the activation of ERK, STAT3, and non-canonical NF-κB pathways ( 17 22 23 ). Our results further indicated that IL-34 and M-CSF combination had an excellent synergistic effect, and the presence of IL-34 and M-CSF could further increase the activation of ERK1/2, STAT3, and NF-κB non-canonical pathways.…”

Section: Resultsmentioning

confidence: 99%

“…We further testify that consistent with the function of M-CSF and IL-34 also could promote the differentiation of osteoclasts. IL-34 may function in coordination with M-CSF to activate the downstream signal pathway ( 17 ), which indicates that CSF-1R may work in concert to promote the osteoclastogenesis of macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, IL-34 can function as an osteoclastogenic cytokine to enhance osteolysis. IL-34 activates the downstream MEK/ERK, JNK/c-Jun, and NF-κB pathway through the binding with colony-stimulating factor 1 receptor (CSF1R), which is a receptor tyrosine kinase that is activated upon binding to its ligands of IL-34 and M-CSF ( 17 ). All of these indicate that IL-34 may be targeted to maintain the integrity of the femoral head in osteonecrosis.…”

Section: Introductionmentioning

confidence: 99%

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IL-34 Aggravates Steroid-Induced Osteonecrosis of the Femoral Head via Promoting Osteoclast Differentiation

et al. 2022

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IL-34 can promote osteoclast differentiation and activation, which may contribute to steroid-induced osteonecrosis of the femoral head (ONFH). Animal model was constructed in both BALB/c and IL-34 deficient mice to detect the relative expression of inflammation cytokines. Micro-CT was utilized to reveal the internal structure. In vitro differentiated osteoclast was induced by culturing bone marrow-derived macrophages with IL-34 conditioned medium or M-CSF. The relative expression of pro-inflammation cytokines, osteoclast marker genes, and relevant pathways molecules was detected with quantitative real-time RT-PCR, ELISA, and Western blot. Up-regulated IL-34 expression could be detected in the serum of ONFH patients and femoral heads of ONFH mice. IL-34 deficient mice showed the resistance to ONFH induction with the up-regulated trabecular number, trabecular thickness, bone value fraction, and down-regulated trabecular separation. On the other hand, inflammatory cytokines, such as TNF-α, IFN-γ, IL-6, IL-12, IL-2, and IL-17A, showed diminished expression in IL-34 deficient ONFH induced mice. IL-34 alone or works in coordination with M-CSF to promote osteoclastogenesis and activate ERK, STAT3, and non-canonical NF-κB pathways. These data demonstrate that IL-34 can promote the differentiation of osteoclast through ERK, STAT3, and non-canonical NF-κB pathways to aggravate steroid-induced ONFH, and IL-34 can be considered as a treatment target.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IL-34 Aggravates Steroid-Induced Osteonecrosis of the Femoral Head via Promoting Osteoclast Differentiation

et al. 2022

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“…As potential upstream regulators of GOLT1B, JUN and SIN3A have been gained increasing attention in diagnosis and treatment of breast cancer. Many studies have declaimed that JUN is a biomarker and regulatory gene in breast cancer (21)(22)(23). In patients with short survival time (< 5 years), the expression of JUN in breast cancer tissue is down-regulated and the risk of recurrence of breast cancer is increased (24).…”

Section: Discussionmentioning

confidence: 99%

“…In patients with short survival time (< 5 years), the expression of JUN in breast cancer tissue is down-regulated and the risk of recurrence of breast cancer is increased (24). Furthermore, JUN mediates the functions of some important cytokines in breast cancer, such as IL-34, IL-33, and IL-1b (22,23,25). On the other hand, SIN3A is a transcriptional suppressor promoting osteolytic destruction in ERa-positive breast cancer (26).…”

Section: Discussionmentioning

confidence: 99%

Multi-Omics Analyses Revealed GOLT1B as a Potential Prognostic Gene in Breast Cancer Probably Regulating the Immune Microenvironment

et al. 2022

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As recently reported by The International Agency for Research on Cancer (IARC), breast cancer has the highest incidence of all cancers in 2020. Many studies have revealed that golgi apparatus is closely associated with the development of breast cancer. However, the role of golgi apparatus in immune microenvironment is still not clear. In this study, using RNA-Seq datasets of breast cancer patients from the public database (n = 1080), we revealed that GOLT1B, encoding a golgi vesicle transporter protein, was significantly higher expressed in human breast cancer tissues versus normal tissues. Besides, we verified GOLT1B expression in five breast cancer cell line using our original data and found GOLT1B was significantly up-regulated in MDA-MB-231, MCF-7, SKBR3. Subsequently, we identified GOLT1B as a potential independent prognostic factor for breast cancer. After a multi-omics analysis, we uncovered that the higher expression of GOLT1B in breast cancer tissues versus normal tissues might be due to the amplification of GOLT1B and altered phosphorylation of its potential transcriptional factors, including JUN and SIN3A. Subsequently, we discovered that GOLT1B potentially regulated the immune microenvironment basing on the finding that its expression was closely related to the tumor microenvironment score and infiltration of immune cells. Moreover, we revealed that GOLT1B might affect the overall survival rates of breast cancer through regulating the immune cell infiltration. Finally, we disclosed the potential pathways involved in the functions of GOLT1B in breast cancer, including metabolism and ECM-receptor interaction pathways. To sum up, we identified GOLT1B as a potential prognostic gene for breast cancer and disclosed its role in regulating the immune microenvironment.

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2022

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We thank Dr. Hume for his interest in our Hepatology article.Dr. Hume argued that colony stimulating factor 1 receptor (CSF1R) and allograft inflammatory factor 1 (AIF1) are specifically expressed in mononuclear phagocytes, whereas we and others have shown that CSF1R and AIF1 are expressed elsewhere in addition to mononuclear phagocytes. Poudel et al. demonstrate that IL-34 induces epithelial cell transformation through CSF1R. [1] The CSF1/CSF1R axis was involved in the regulation of osteoblast proliferation and differentiation. [2] Furthermore, AIF-1 was associated with inflammation in cells other than macrophages, such as endothelial and peritoneal mesothelial cells. [3] A similar debate was focused on the discussion of Kupffer cells contaminated with liver sinusoidal endothelial cells. It was concluded that "researchers need to go beyond the concept of absolute lineage markers and address data with an open mind."Additionally, Dr. Hume believed that AIF1 + CSF1R + MSCs (mesenchymal stem cells) should be defined as PDGFRβ + macrophages, whereas no evidence supports this notion in the literature. Conversely, our study identified mesenchymal stem-cell-like cells (MSCLCs) by wellrecognized markers (such as Cd44, Nt5e [CD73], and others) often used to identify MSCs. We noticed a unique MSCLC subpopulation that, in addition to expressing common MSC markers, also highly expressed inflammation-related genes Csf1r, Aif1, and Cd74. We also ruled out the interference of cell doublets by DoubleTFinder in R. Furthermore, we validated our results by multicolor immunohistochemical staining and confirmed this MSC subgroup as AIF1 + CSF1R + MSCs. In fact, the gene expression profiles of AIF1 + CSF1R + MSCs exhibited similar patterns as MSCs and stromal cells, rather than that of macrophages.Finally, Dr. Hume states that our AIF1 + CSF1R + MSCs may be an artifact attributable to contamination by macrophage disaggregation. Though single-cell sequencing technology may have certain technical defects, we believe that if there is a contamination of fragmented macrophages, the majority of cells from the tissue should be affected as shown, [4] not just in this MSC subpopulation. It should be noted that MSCs and macrophages closely interact in tissue niches, thus their transcriptional profiles or surface markers could have partially converged, which may explain why some markers were shared, as found in our study and others. [5] In any case, subsequent studies using single-cell sequencing technology should pay attention to detection methods, such as single-nuclei sequencing and imaging flow cytometry, to further verify single-cell RNA-sequencing-based findings. CONFLICTS OF INTERESTNothing to report.

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Interleukin-34-CSF1R Signaling Axis Promotes Epithelial Cell Transformation and Breast Tumorigenesis

Cited by 10 publications

References 56 publications

IL-34 Aggravates Steroid-Induced Osteonecrosis of the Femoral Head via Promoting Osteoclast Differentiation

IL-34 Aggravates Steroid-Induced Osteonecrosis of the Femoral Head via Promoting Osteoclast Differentiation

Multi-Omics Analyses Revealed GOLT1B as a Potential Prognostic Gene in Breast Cancer Probably Regulating the Immune Microenvironment

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