Characterization of Alternative Splicing Events in HPV-Negative Head and Neck Squamous Cell Carcinoma Identifies an Oncogenic DOCK5 Variant

Liu, Chao; Guo, Theresa; Xu, Guiyin; Sakai, Akihiro; Fukusumi, Takahito; Ando, Mizuo; Sadat, Sayed; Saito, Yuki; Khan, Zubair; Fisch, Kathleen; Califano, Joseph A.

doi:10.1158/1078-0432.ccr-18-0752

Cited by 33 publications

(56 citation statements)

References 54 publications

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“…16,23 All tissue samples were obtained from the Johns Hopkins University Oncology Tissue Services (formerly the Tissue Microarray Core) and approved by the institutional review board under the research protocol #NA_00036235. 16,23 All tissue samples were obtained from the Johns Hopkins University Oncology Tissue Services (formerly the Tissue Microarray Core) and approved by the institutional review board under the research protocol #NA_00036235.…”

Section: Patient Samplesmentioning

confidence: 99%

“…TCGA data regarding the LOXL2 variant were obtained and analyzed as previously described, 16 and included 407 HPV-negative HNSCC samples and 38 normal samples. The mRNA expression of the LOXL2 gene (RNA sequencing [RNA-Seq] by expectation maximization normalized) and corresponding clinical data were downloaded from the TCGA data portal (available at: https :// cance rgeno me.nih.gov/).…”

Section: Tcga Data Setmentioning

confidence: 99%

“…16 Briefly, different groups of cells were plated into 6-well culture plates and maintained to at least 95% confluence. 16 Briefly, different groups of cells were plated into 6-well culture plates and maintained to at least 95% confluence.…”

Section: Cell Scratch Assaymentioning

confidence: 99%

“…17,18 In patients with esophageal squamous cell carcinoma, several alternative splicing isoforms of LOXL2 also have been discovered to exert cell functions distinct from those of canonical-type LOXL2. 16 However, to the best of our knowledge, the function and downstream effects of this specific LOXL2 variant have not been described to date. 16 However, to the best of our knowledge, the function and downstream effects of this specific LOXL2 variant have not been described to date.…”

Section: Introductionmentioning

confidence: 98%

“…As examples, proangiogenic and antiangiogenic isoforms of VEGFA undergo switching among tumor and normal samples in several types of cancer. 15,16 These differential expression patterns of ASEs greatly broaden and deepen our knowledge of the role of alternative spicing in regulating the initiation and progression of HNSCC. 10 With the development of next-generation sequencing technologies and computational analysis, more cancer-specific ASEs have been proposed by large-scale screening and confirmed to Cancer February 15, 2020 play critical roles in the initiation and progression of cancer.…”

Section: Introductionmentioning

confidence: 99%

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A novel splice variant of LOXL2 promotes progression of human papillomavirus–negative head and neck squamous cell carcinoma

Liu

Guo

Sakai

et al. 2019

Cancer

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BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently diagnosed cancers worldwide. LOXlike (LOXL) 2 (LOXL2) demonstrates alternative splicing events in patients with human papillomavirus (HPV)-negative HNSCC. The current study explored the role of a dominant LOXL2 variant in HPV-negative HNSCC. METHODS: Expression of the LOXL2 variant was analyzed using The Cancer Genome Atlas cohorts and validated using quantitative reverse transcriptase-polymerase chain reaction in a separate primary tumor set. The authors defined the effect of LOXL2 splice variants in assays for cell proliferation using a cell viability assay and colony formation assay. Cell migration and invasion were examined using a cell scratch assay and transwell cell migration and invasion assay in LOXL2 splice variant gain and loss of expression cells. Western blot analysis and gene set enrichment analysis were used to explore the potential mechanism of the LOXL2 splice variant in HPV-negative HNSCC. RESULTS: Expression of a novel LOXL2 variant was found to be upregulated in The Cancer Genome Atlas HPV-negative HNSCC, and confirmed in the separate primary tumor validation set. Analyses of loss and gain of function demonstrated that this LOXL2 variant enhanced proliferation, migration, and invasion in HPV-negative HNSCC cells and activated the FAK/AKT pathway. A total of 837 upregulated and 820 downregulated genes and 526 upregulated and 124 downregulated pathways associated with LOXL2 variant expression were identified using gene set enrichment analysis, which helped in developing a better understanding of the networks activated by this LOXL2 variant in patients with HPV-negative HNSCC. CONCLUSIONS: The novel LOXL2 variant can promote the progression of HPV-negative HNSCC, in part through FAK/AKT pathway activation, which may provide a new potential therapeutic target among patients with HPV-negative HNSCC. Cancer 2020;126:737-748.

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Section: Patient Samplesmentioning

confidence: 99%

Section: Tcga Data Setmentioning

confidence: 99%

Section: Cell Scratch Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A novel splice variant of LOXL2 promotes progression of human papillomavirus–negative head and neck squamous cell carcinoma

Liu

Guo

Sakai

et al. 2019

Cancer

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Liraglutide Promotes Diabetic Wound Healing via Myo1c/Dock5

Zhang,

Kang

et al. 2024

Advanced Science

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Non‐healing diabetic wounds and ulcer complications, with persistent cell dysfunction and obstructed cellular processes, are leading causes of disability and death in patients with diabetes. Currently, there is a lack of guideline‐recommended hypoglycemic drugs in clinical practice, likely due to limited research and unclear mechanisms. In this study, it is demonstrated that liraglutide significantly accelerates wound closure in diabetic mouse models (db/db mice and streptozotocin‐induced mice) by improving re‐epithelialization, collagen deposition, and extracellular matrix remodeling, and enhancing the proliferation, migration, and adhesion functions of keratinocytes. However, these effects of improved healing by liraglutide are abrogated in dedicator of cytokinesis 5 (Dock5) keratinocyte‐specific knockout mice. Mechanistically, liraglutide induces cellular function through stabilization of unconventional myosin 1c (Myo1c). Liraglutide directly binds to Myo1c at arginine 93, enhancing the Myo1c/Dock5 interaction by targeting Dock5 promoter and thus promoting the proliferation, migration, and adhesion of keratinocytes. Therefore, this study provides insights into liraglutide biology and suggests it may be an effective treatment for diabetic patients with wound‐healing pathologies.

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Bicarbonate transporter SLC4A7 promotes EMT and metastasis of HNSCC by activating the PI3K/AKT/mTOR signaling pathway

Guo

Liu

et al. 2023

Molecular Carcinogenesis

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Currently, therapeutic modalities such as surgery, chemotherapy, radiotherapy, and immunotherapy are being used to treat HNSCC.However, the treatment outcomes of most patients are dismal because they are already in middle or advanced stage by the time of diagnosis and poorly responsive to treatments. It is therefore of great interest to clarify mechanisms that contribute to the metastasis of cells to identify possible targets for therapy.In this study, we identified the Na + -coupled bicarbonate transporter, SLC4A7, play essential roles in the metastasis of HNSCC. Our results showed that the relative expression of SLC4A7 messenger RNA was highly expressed in HNSCCs samples from TCGA, and compared with precancerous cells of human oral mucosa (DOK), SLC4A7 was highly expressed in HNSCC cell lines. In vitro and in vivo experiments showed that dysregulation of SLC4A7 had minor influence on the proliferation of HNSCC but impacted HNSCC's migration and invasion.Meanwhile, SLC4A7 could promote epithelial-mesenchymal transition (EMT) in HNSCC. RNA-seq, KEGG pathway enrichment analysis and Western blot further revealed that downregulation of SLC4A7 in HNSCC cells inhibited the PI3K/AKT pathway. These findings were further validated via rescue experiments using a small molecule inhibitor of PI3K/mTOR (GDC-0980). Our findings suggest that SLC4A7 promotes EMT and metastasis of HNSCC through the PI3K/AKT/mTOR signaling pathway, which may be a valuable predictive biomarker and potential therapeutic target in HNSCC.

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Characterization of Alternative Splicing Events in HPV-Negative Head and Neck Squamous Cell Carcinoma Identifies an Oncogenic DOCK5 Variant

Cited by 33 publications

References 54 publications

A novel splice variant of LOXL2 promotes progression of human papillomavirus–negative head and neck squamous cell carcinoma

A novel splice variant of LOXL2 promotes progression of human papillomavirus–negative head and neck squamous cell carcinoma

Liraglutide Promotes Diabetic Wound Healing via Myo1c/Dock5

Bicarbonate transporter SLC4A7 promotes EMT and metastasis of HNSCC by activating the PI3K/AKT/mTOR signaling pathway

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