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A novel stromal lncRNA signature reprograms fibroblasts to promote the growth of oral squamous cell carcinoma via LncRNA-CAF/interleukin-33
- Source :
- Carcinogenesis. 39:397-406
- Publication Year :
- 2018
- Publisher :
- Oxford University Press (OUP), 2018.
-
Abstract
- Stromal carcinoma-related fibroblasts (CAFs) are the main type of non-immune cells in the tumor microenvironment (TME). CAFs interact with cancer cells to promote tumor proliferation. Long non-coding RNAs (lncRNAs) are known to regulate cell growth, apoptosis and metastasis of cancer cells, but their role in stromal cells is unclear. Using RNA sequencing, we identified a stromal lncRNA signature during the transformation of CAFs from normal fibroblasts (NFs) in oral squamous cell carcinoma (OSCC). We uncovered an uncharacterized lncRNA, FLJ22447, which was remarkably up-regulated in CAFs, referred to LncRNA-CAF (Lnc-CAF) hereafter. Interleukin-33 (IL-33) was mainly located in the stroma and positively co-expressed with Lnc-CAF to elevate the expression of CAF markers (α-SMA, vimentin and N-cadherin) in fibroblasts. In a co-culture system, IL-33 knockdown impaired Lnc-CAF-mediated stromal fibroblast activation, leading to decreased proliferation of tumor cells. Mechanistically, Lnc-CAF up-regulated IL-33 levels and prevented p62-dependent autophagy-lysosome degradation of IL-33, which was independent of LncRNA-protein scaffold effects. Treatment with the autophagy inducer, rapamycin, impaired the proliferative effect of Lnc-CAF/IL-33 by promoting IL-33 degradation. In turn, tumor cells further increased Lnc-CAF levels in stromal fibroblasts via exosomal Lnc-CAF. In patients with OSCC, high Lnc-CAF/IL-33 expression correlated with high TNM stage (n = 140). Moreover, high Lnc-CAF expression predicted poor prognosis. In vivo, Lnc-CAF knockdown restricted tumor growth and was associated with decreased Ki-67 expression and α-SMA+ CAF in the stroma. In conclusion, we identified a stromal lncRNA signature, which reprograms NFs to CAFs via Lnc-CAF/IL-33 and promotes OSCC development.
- Subjects :
- Male
0301 basic medicine
Cancer Research
Stromal cell
Vimentin
Metastasis
03 medical and health sciences
Stroma
Tumor Microenvironment
medicine
Humans
Fibroblast
Aged
Tumor microenvironment
biology
Squamous Cell Carcinoma of Head and Neck
Chemistry
Cell growth
General Medicine
Fibroblasts
Middle Aged
Cellular Reprogramming
Interleukin-33
medicine.disease
Gene Expression Regulation, Neoplastic
030104 developmental biology
medicine.anatomical_structure
Head and Neck Neoplasms
Cancer cell
Carcinoma, Squamous Cell
biology.protein
Cancer research
Female
Mouth Neoplasms
RNA, Long Noncoding
Subjects
Details
- ISSN :
- 14602180 and 01433334
- Volume :
- 39
- Database :
- OpenAIRE
- Journal :
- Carcinogenesis
- Accession number :
- edsair.doi.dedup.....b2b05804789ee5b14e422cb31883322b