Identification of a novel lysyl oxidase-like 2 alternative splicing isoform, LOXL2 Δe13, in esophageal squamous cell carcinoma

Lv, Guoqing; Zou, Hai-Ying; Liao, Lian‐Di; Cao, Hongxin; Zeng, Fa‐Min; Wu, Bing‐Li; Xie, Jian‐Jun; Fang, Wang‐Kai; Xu, Li‐Yan; Li, En‐Min

doi:10.1139/bcb-2014-0046

Cited by 38 publications

(32 citation statements)

References 34 publications

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“…Furthermore, a 50‐kDa band was also detected with an anti‐N‐terminus antibody (unpublished data), indicating that the 50‐kDa protein is unlikely to be a processed product of 92 kDa, but is most likely a splice variant. Indeed, a LOXL2 splice variant has been reported that skips exon 13 and splices out 24 amino acids; however, this deletion does not explain the 42‐kDa discrepancy, suggesting 50‐kDa product might be a splice variant which has not been identified and remains to be clarified.…”

Section: Discussionmentioning

confidence: 98%

Elevated exosomal lysyl oxidase like 2 is a potential biomarker for head and neck squamous cell carcinoma

et al. 2019

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Objectives: The secretory enzyme lysyl oxidase like 2 (LOXL2) is speculated to contribute to tumor progression through its functions in the remodeling of extracellular matrix and epithelial-mesenchymal transition. We previously identified elevated expression of LOXL2 in metastatic human head and neck squamous cell carcinoma (HNSCC) cells in a mouse lymph node metastases model. Here we performed a case series study examining LOXL2 expression levels in human serum from HNSCC patients to evaluate whether LOXL2 is worth evaluation in a large cohort study.Methods: LOXL2 protein levels in three serum samples from HNSCC patients were assessed by immunoblotting and LOXL2 tissue expression was examined in one human tongue squamous cell carcinoma (SCC) tissue by immunohistochemistry as a representative of HNSCC tissue. Serum samples were further fractionated in exosomes and supernatants by ultracentrifugation, which were then subjected to immunoblot and in vitro LOX activity analyses. Exosomal LOXL2 levels of 36 serum samples from HNSCC patients and seven healthy volunteers were measured using polymer sedimentation exosome preparation followed by ELISA measurement and subjected to statistical analyses.Results: Immunoblot analyses revealed that LOXL2 was present in serum exosomal fractions from three HNSCC patients, and we observed approximately threefold higher levels of LOXL2 in HNSCC patients compared with three healthy volunteers. Immunohistochemical LOXL2 staining was detected in HNSCC cells in addition to non-cancerous lipid tissues and some muscles in human tongue HNSCC tissue. Further measurements of exosomal LOXL2 by ELISA showed over ninefold higher mean LOXL2 levels in patients compared with controls. Statistical analysis revealed a correlation between elevated serum exosomal LOXL2 levels and low-grade, but not high-grade, HNSCC.Conclusions: Our case series study that elevated serum exosomal LOXL2 levels exhibited a correlation with low-grade HNSCCs. A follow-up large cohort clinical study will be required to determine the potential clinical utility of LOXL2 as a new biomarker and/or therapy target for HNSCCs.

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Section: Discussionmentioning

confidence: 98%

Elevated exosomal lysyl oxidase like 2 is a potential biomarker for head and neck squamous cell carcinoma

et al. 2019

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“…17 In previous studies, it has been demonstrated that LOXL2 was associated with poor prognosis in a variety of tumors and that overexpression of LOXL2 can promote the invasion and metastatic activity of cancer cells. 19,22 In the current study, we used the loss-of-function and gain-of-function experiments to elucidate the role of the novel LOXL2 variant identified from TCGA HPVnegative HNSCC data. 19,22 In the current study, we used the loss-of-function and gain-of-function experiments to elucidate the role of the novel LOXL2 variant identified from TCGA HPVnegative HNSCC data.…”

Section: Discussionmentioning

confidence: 99%

“…17,39,40 In addition, several LOXL2 splice variants have been found in esophageal squamous cell carcinoma, such as the variant lacking exon 13 and the variant with a deletion of 72 nucleotides, which contribute to tumor progression by a novel molecular mechanism distinct from canonical-type LOXL2. 19,22 In the current study, we used the loss-of-function and gain-of-function experiments to elucidate the role of the novel LOXL2 variant identified from TCGA HPVnegative HNSCC data. The tumor-specific LOXL2 variant could enhance the proliferative, migratory, and invasive capacities of HPV-negative HNSCC cells in vitro.…”

Section: Discussionmentioning

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. [19][20][21][22] In our previous study, a total of 580 significant ASEs related to HPV-negative HNSCC have been identified using outlier analysis, including a novel splice variant of LOXL2 with a unique inserted exon. 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: 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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“…Sources of oesophageal cancer cell lines have been described previously . KYSE150, KYSE510 and TE3 cells were maintained in RPMI‐1640 medium containing 10% foetal bovine serum.…”

Section: Methodsmentioning

confidence: 99%

Identification of lncRNA‐associated differential subnetworks in oesophageal squamous cell carcinoma by differential co‐expression analysis

Liu

Gan

Wang

et al. 2020

J Cellular Molecular Medi

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Differential expression analysis has led to the identification of important biomarkers in oesophageal squamous cell carcinoma (ESCC). Despite enormous contributions, it has not harnessed the full potential of gene expression data, such as interactions among genes. Differential co-expression analysis has emerged as an effective tool that complements differential expression analysis to provide better insight of dysregulated mechanisms and indicate key driver genes. Here, we analysed the differential co-expression of lncRNAs and protein-coding genes (PCGs) between normal oesophageal tissue and ESCC tissues, and constructed a lncRNA-PCG differential co-expression network (DCN). DCN was characterized as a scale-free, small-world network with modular organization. Focusing on lncRNAs, a total of 107 differential lncRNA-PCG subnetworks were identified from the DCN by integrating both differential expression and differential co-expression. These differential subnetworks provide a valuable source for revealing lncRNA functions and the associated dysfunctional regulatory networks in ESCC. Their consistent discrimination suggests that they may have important roles in ESCC and could serve as robust subnetwork biomarkers. In addition, two tumour suppressor genes (AL121899.1 and ELMO2), identified in the core modules, were validated by functional experiments. The proposed method can be easily used to investigate differential subnetworks of other molecules in other cancers. K E Y W O R D Sdifferential co-expression, differential subnetwork, lncRNA, oesophageal squamous cell carcinoma | 4805 LIU et aL.

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Identification of a novel lysyl oxidase-like 2 alternative splicing isoform, LOXL2 Δe13, in esophageal squamous cell carcinoma

Cited by 38 publications

References 34 publications

Elevated exosomal lysyl oxidase like 2 is a potential biomarker for head and neck squamous cell carcinoma

Elevated exosomal lysyl oxidase like 2 is a potential biomarker for head and neck squamous cell carcinoma

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

Identification of lncRNA‐associated differential subnetworks in oesophageal squamous cell carcinoma by differential co‐expression analysis

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