Xun Wu1,2,3, Yi-Shing Lisa Cheng4, Mathew Matthen5, Angela Yoon6, Gary K Schwartz5, Shashi Bala7, Alison M Taylor8,9, Fatemeh Momen-Heravi10,11,12. 1. Cancer Biology and Immunology Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA. 2. Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, Columbia University College of Dental Medicine, New York, NY, USA. 3. Department of Maxillofacial Surgery, Guangxi Medical University College of Stomatology, Nanning, Guangxi, China. 4. Department of Diagnostic Sciences, Texas A&M University College of Dentistry, Dallas, TX, USA. 5. Department of Medicine Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA. 6. Division of Pathology, Columbia University College of Dental Medicine, New York, NY, USA. 7. Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA. 8. Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. at3488@cumc.columbia.edu. 9. Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. at3488@cumc.columbia.edu. 10. Cancer Biology and Immunology Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA. fm2540@cumc.columbia.edu. 11. Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, Columbia University College of Dental Medicine, New York, NY, USA. fm2540@cumc.columbia.edu. 12. Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. fm2540@cumc.columbia.edu.
Abstract
BACKGROUND: MicroRNAs (miRs) have been shown to play an important role in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). The miR-34 family is thought to play a role in tumor suppression, but the exact mechanism of their action in HNSCC is not well understood. Moreover, the impact of chromosomal changes and mutation status on miR-34a expression remains unknown. METHODS: Differential expression of miR-34a, MET, and genomic alterations were assessed in the Cancer Genome Atlas (TCGA) datasets as well as in primary HNSCC and adjacent normal tissue. The biological functions of miR-34a in HNSCC were investigated in samples derived from primary human tumors and HNSCC cell lines. The expression of MET was evaluated using immunohistochemistry, and the molecular interaction of miR-34a and MET were demonstrated by RNA pulldown, RNA immunoprecipitation, luciferase reporter assay, and rescue experiments. Lastly, locked nucleic acid (LNA) miRs in mouse xenograft models were used to evaluate the clinical relevance of miR-34a in HNSCC tumor growth and modulation of the tumor microenvironment in vivo. RESULTS: Chromosome arm 1p loss and P53 mutations are both associated with lower levels of miR-34a. In HNSCC, miR-34a acts as a tumor suppressor and physically interacts with and functionally targets the proto-oncogene MET. Our studies found that miR-34a suppresses HNSCC carcinogenesis, at least in part, by downregulating MET, consequently inhibiting HNSCC proliferation. Consistent with these findings, administration of LNA-miR-34a in an in vivo model of HNSCC leads to diminished HNSCC cell proliferation and tumor burden in vitro and in vivo, represses expression of genes involved in epithelial-mesenchymal transition, and negates the oncogenic effect of MET in mouse tumors. Consistently, LNA-miR-34a induced a decreased number of immunosuppressive PDL1-expressing tumor-associated macrophages in the tumor microenvironment. In HNSCC patient samples, higher levels of miR-34a are significantly associated with a higher frequency of Th1 cells and CD8 naïve T cells. CONCLUSIONS: Our results demonstrate that miR-34a directly targets MET and maintains anti-tumor immune activity. We propose miR-34a as a potential new therapeutic approach for HNSCC.
BACKGROUND: MicroRNAs (miRs) have been shown to play an important role in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). The miR-34 family is thought to play a role in tumor suppression, but the exact mechanism of their action in HNSCC is not well understood. Moreover, the impact of chromosomal changes and mutation status on miR-34a expression remains unknown. METHODS: Differential expression of miR-34a, MET, and genomic alterations were assessed in the Cancer Genome Atlas (TCGA) datasets as well as in primary HNSCC and adjacent normal tissue. The biological functions of miR-34a in HNSCC were investigated in samples derived from primary humantumors and HNSCC cell lines. The expression of MET was evaluated using immunohistochemistry, and the molecular interaction of miR-34a and MET were demonstrated by RNA pulldown, RNA immunoprecipitation, luciferase reporter assay, and rescue experiments. Lastly, locked nucleic acid (LNA) miRs in mouse xenograft models were used to evaluate the clinical relevance of miR-34a in HNSCC tumor growth and modulation of the tumor microenvironment in vivo. RESULTS: Chromosome arm 1p loss and P53 mutations are both associated with lower levels of miR-34a. In HNSCC, miR-34a acts as a tumor suppressor and physically interacts with and functionally targets the proto-oncogene MET. Our studies found that miR-34a suppresses HNSCC carcinogenesis, at least in part, by downregulating MET, consequently inhibiting HNSCC proliferation. Consistent with these findings, administration of LNA-miR-34a in an in vivo model of HNSCC leads to diminished HNSCC cell proliferation and tumor burden in vitro and in vivo, represses expression of genes involved in epithelial-mesenchymal transition, and negates the oncogenic effect of MET in mousetumors. Consistently, LNA-miR-34a induced a decreased number of immunosuppressive PDL1-expressing tumor-associated macrophages in the tumor microenvironment. In HNSCC patient samples, higher levels of miR-34a are significantly associated with a higher frequency of Th1 cells and CD8 naïve T cells. CONCLUSIONS: Our results demonstrate that miR-34a directly targets MET and maintains anti-tumor immune activity. We propose miR-34a as a potential new therapeutic approach for HNSCC.
Entities:
Keywords:
Aneuploidy; Head and neck cancer; MET; P53; miR-34a; micoRNA
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