Evidence for AJUBA-catenin-CDH4-linked differentiation resistance of mesenchymal stem cells implies tumorigenesis and progression of head and neck squamous cell carcinoma: a single-cell transcriptome approach
Received:February 26, 2021  Revised:April 25, 2021
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DOI:10.46701/BG.2021012021106
KeyWord:mesenchymal stem cells  AJUBA  β-catenin  CDH4  head and neck squamous cell carcinoma  differentiation resistance  tumorigenesis  cancer progression  CTNNB1
                                
AuthorInstitution
Andres Stucky Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Li Gao Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Lan Sun Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Shengwen Calvin Li Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;Neuro-Oncology and Stem Cell Research Laboratory, Center for Neuroscience Research, CHOC Children's Research Institute, Children's Hospital of Orange County CHOC, Orange, CA 92868, USA;Department of Neurology, University of California - Irvine School of Medicine, Orange, CA 92868, USA
Xuelian Chen Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Tiffany H. Park Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Jin Cai Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Mustafa H. Kabeer Division of Pediatric General and Thoracic Surgery, Children's Hospital of Orange County, Orange, CA 92868, USA;Department of Surgery, University of California - Irvine School of Medicine, Orange, CA 92868, USA
Xi Zhang Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Uttam K. Sinha Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Jiang F. Zhong Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Abstract:
      An increasing number of reports indicate that mesenchymal stem cells (MSCs) play an essential role in promoting tumorigenesis and progression of head and neck squamous cell carcinoma (HNSCC). However, the molecular mechanisms underlying this process remain unclear. Using the MSC model system, this study analyzes the molecular pathway by which differentiation resistant MSCs promote HNSCC. MSCs were cultured in osteogenic differentiation media and harvested on days 12 and 19. Cells were stained for cell differentiation analysis using Alizarin Red. The osteogenesis-resistant MSCs (OR-MSCs) and MSC-differentiation-derived osteoblasts (D-OSTBs) were identified and subjected to the single-cell transcriptome analysis. Gene-specific analyses of these two sub-populations were performed for the patterns of differential expression. A total of 1780 differentially expressed genes were determined to distinguish OR-MSCs significantly from D-OSTB. Notably, AJUBA, β-catenin, and CDH4 expression levels were upregulated considerably within the OR-MSCs compared to D-OSTBs. To confirm their clinical relevance, a survey of a clinical cohort revealed a high correlation among the expression levels of AJUBA, β-catenin and CDH4. The results shed new light that OR-MSCs participate in the development of HNSCC via a pathway mediated by AJUBA, β-catenin, CDH4, and CTNNB1, thereby implying that MSC-based therapy is a promising therapeutic approach in the management of HNSCC.
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