A novel E-cadherin/SOX9 axis regulates cancer stem cells in multiple myeloma by activating Akt and MAPK pathways

Samart, Parinya; Rojanasakul, Yon; Issaragrisil, Surapol; Luanpitpong, Sudjit

doi:10.1186/s40164-022-00294-x

Cited by 7 publications

(4 citation statements)

References 12 publications

(13 reference statements)

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“…Our findings suggest the presence of aberrantly activated Hedgehog and MAPK signaling pathways in CSCs. Studies have confirmed the involvement of the Hedgehog signaling pathway [51,52] and MAPK signaling pathway [53,54] in regulating CSC differentiation and drug resistance. Importantly, by combining Monocle3 pseudotime analysis and prognostic modeling, we have discovered that HSPB1 acts as a regulatory factor in CSCs development, and its high expression indicates a poor prognosis in HCC.…”

Section: Construction and Validation Of Clinical Prediction Modelmentioning

confidence: 86%

Single-cell RNA-Seq Elucidates the Crosstalk Between Cancer Stem Cells and the Tumor Microenvironment in Hepatocellular Carcinoma

Lin,

Li,

Yang

et al. 2024

J. Cancer

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Background: The challenge of systemic treatment for hepatocellular carcinoma (HCC) stems from the development of drug resistance, primarily driven by the interplay between cancer stem cells (CSCs) and the tumor microenvironment (TME). However, there is a notable dearth of comprehensive research investigating the crosstalk between CSCs and stromal cells or immune cells within the TME of HCC. Methods: We procured single-cell RNA sequencing (scRNA-Seq) data from 16 patients diagnosed with HCC. Employing meticulous data quality control and cell annotation procedures, we delineated distinct CSCs subtypes and performed multi-omics analyses encompassing metabolic activity, cell communication, and cell trajectory. These analyses shed light on the potential molecular mechanisms governing the interaction between CSCs and the TME, while also identifying CSCs' developmental genes. By combining these developmental genes, we employed machine learning algorithms and RT-qPCR to construct and validate a prognostic risk model for HCC. Results: We successfully identified CSCs subtypes residing within malignant cells. Through meticulous enrichment analysis and assessment of metabolic activity, we discovered anomalous metabolic patterns within the CSCs microenvironment, including hypoxia and glucose deprivation. Moreover, CSCs exhibited aberrant activity in signaling pathways associated with lipid metabolism. Furthermore, our investigations into cell communication unveiled that CSCs possess the capacity to modulate stromal cells and immune cells through the secretion of MIF or MDK, consequently exerting regulatory control over the TME. Finally, through cell trajectory analysis, we found developmental genes of CSCs. Leveraging these genes, we successfully developed and validated a prognostic risk model (APCS, ADH4, FTH1, and HSPB1) with machine learning and RT-qPCR. Conclusions: By means of single-cell multi-omics analysis, this study offers valuable insights into the potential molecular mechanisms governing the interaction between CSCs and the TME, elucidating the pivotal role CSCs play within the TME. Additionally, we have successfully established a comprehensive clinical prognostic model through bulk RNA-Seq data.

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Section: Construction and Validation Of Clinical Prediction Modelmentioning

confidence: 86%

Single-cell RNA-Seq Elucidates the Crosstalk Between Cancer Stem Cells and the Tumor Microenvironment in Hepatocellular Carcinoma

Lin,

Li,

Yang

et al. 2024

J. Cancer

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“…Clonotypic CD138 −/low cells exhibited robust stemness characteristics, drug resistance, and anti-apoptotic potential and a higher ability to sustain in G0 and G1 cell cycle phases [105][106][107].…”

Section: Cancer Surface Marker and Cancer-related Actionmentioning

confidence: 99%

“…In MM CSCs, loss of E-cadherin led to either G0/G1 or G2/M blockade, depending on the cellular milieu, by regulating its crucial cell cycle mediators in each phase, and also limited the side population phenotype. A new regulatory system of MM CSCs through the E-cadherin/SOX9 axis could contribute to the long-term cell survival and outgrowth associated with recurrent/refractory MM [106].…”

Section: Multiple Myeloma (Mm)mentioning

confidence: 99%

Cancer Stem Cells from Definition to Detection and Targeted Drugs

Ruszkowska-Ciastek,

Kwiatkowska,

Marques-da-Silva

et al. 2024

IJMS

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Cancers remain the second leading cause of mortality in the world. Preclinical and clinical studies point an important role of cancer/leukaemia stem cells (CSCs/LSCs) in the colonisation at secondary organ sites upon metastatic spreading, although the precise mechanisms for specific actions are still not fully understood. Reviewing the present knowledge on the crucial role of CSCs/LSCs, their plasticity, and population heterogeneity in treatment failures in cancer patients is timely. Standard chemotherapy, which acts mainly on rapidly dividing cells, is unable to adequately affect CSCs with a low proliferation rate. One of the proposed mechanisms of CSC resistance to anticancer agents is the fact that these cells can easily shift between different phases of the cell cycle in response to typical cell stimuli induced by anticancer drugs. In this work, we reviewed the recent studies on CSC/LSC alterations associated with disease recurrence, and we systematised the functional assays, markers, and novel methods for CSCs screening. This review emphasises CSCs’ involvement in cancer progression and metastasis, as well as CSC/LSC targeting by synthetic and natural compounds aiming at their elimination or modulation of stemness properties.

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“…E-cadherin/SOX9 axis regulated cell growth and self-renewal of cancer stem cells partially through Akt and MAPK signaling in multiple myeloma cells. 20 In addition, the activity of the SOX9-dependent collagen type II alpha 1 enhancer was increased upon the coexpression of a constitutively active MAPK kinase 1 mutant both in primary chondrocytes and C3H10T1/2 cells. 21 Therefore, we hypothesized that SOX9 might promote fibrosis via the MAPK pathways.…”

mentioning

confidence: 94%

SOX9 Induces Orbital Fibroblast Activation in Thyroid Eye Disease Via MAPK/ERK1/2 Pathway

Zhou,

Lin,

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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Purpose To evaluate the expression of sry-box transcription factor 9 (SOX9) in orbital fibroblasts (OFs) of thyroid eye disease (TED) and to find its potential role and underlying mechanism in orbital fibrosis. Methods OFs were cultured from orbital connective tissues obtained from patients with TED ( n = 10) and healthy controls ( n = 6). SOX9 was depleted by small interfering RNA or overexpressed through lentivirus transduction in OFs. Fibroblast contractile activity was measured by collagen gel contraction assay and proliferation was examined by EdU assay. Transcriptomic changes were assessed by RNA sequencing. Results The mRNA and protein levels of SOX9 were significantly higher in OFs cultured from patients with TED than those from healthy controls. Extracellular matrix-related genes were down-regulated by SOX9 knockdown and up-regulated by SOX9 overexpression in TED-OFs. SOX9 knockdown significantly decrease the contraction and the antiapoptotic ability of OFs, whereas the overexpression of SOX9 increased the ability of transformation, migration, and proliferation of OFs. SOX9 knockdown suppressed the expression of phosphorylated ERK1/2, whereas its overexpression showed the opposite effect. Epidermal growth factor receptor (EGFR) is one of the notably down-regulated genes screened out by RNA sequencing. Chromatin immunoprecipitation-qPCR demonstrated SOX9 binding to the EGFR promoter. Conclusions A high expression of SOX9 was found in TED-OFs. SOX9 can activate OFs via MAPK/ERK1/2 signaling pathway, which in turn promotes proliferation and differentiation of OFs. EGFR was a downstream target gene of SOX9. SOX9/EGFR can be considered as therapeutic targets for the treatment of orbital fibrosis in TED.

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A novel E-cadherin/SOX9 axis regulates cancer stem cells in multiple myeloma by activating Akt and MAPK pathways

Cited by 7 publications

References 12 publications

Single-cell RNA-Seq Elucidates the Crosstalk Between Cancer Stem Cells and the Tumor Microenvironment in Hepatocellular Carcinoma

Single-cell RNA-Seq Elucidates the Crosstalk Between Cancer Stem Cells and the Tumor Microenvironment in Hepatocellular Carcinoma

Cancer Stem Cells from Definition to Detection and Targeted Drugs

SOX9 Induces Orbital Fibroblast Activation in Thyroid Eye Disease Via MAPK/ERK1/2 Pathway

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