Elevated Na + /H + exchanger-1 expression enhances the metastatic collective migration of head and neck squamous cell carcinoma cells

Kaminota, Teppei; Yano, Hajime; Shiota, Kohei; Nomura, Noriko; Yaguchi, Haruna; Kirino, Yui; Ohara, Kentaro; Tetsumura, Issei; Sanada, Tomoyoshi; Ugumori, Toru; Tanaka, Junya; Hato, Naohito

doi:10.1016/j.bbrc.2017.03.007

Cited by 18 publications

(18 citation statements)

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“…A role of NHE1 in collective migration of head and neck squamous cell carcinoma cells was recently suggested, albeit in cell clusters and without detailed analysis (Kaminota et al . ). We therefore hypothesized that NHE1 upregulation may stimulate collective epithelial cell migration and, in this way, contribute to kidney epithelial morphogenesis and other processes involving epithelial collective cell migration.…”

Section: Discussionmentioning

confidence: 97%

“…NHE1 is a major driver of single cell migration in many cell types (Lagana et al 2000;Schneider et al 2008;Martin et al 2011), has been assigned a role in mammary epithelial morphogenesis (Jenkins et al 2012) and is developmentally regulated in the kidney (Rieder & Fliegel, 2002). A role of NHE1 in collective migration of head and neck squamous cell carcinoma cells was recently suggested, albeit in cell clusters and without detailed analysis (Kaminota et al 2017). We therefore hypothesized that NHE1 upregulation may stimulate collective epithelial cell migration and, in this way, contribute to kidney epithelial morphogenesis and other processes involving epithelial collective cell migration.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, movement of clusters of head and neck squamous cell carcinoma cells was decreased upon NHE1 knockdown (Kaminota et al . ). Expression of NHE1 is developmentally regulated; NHE1 levels are particularly high in murine kidney at postnatal week 2, which is the time when normal kidney function is established, compared to both prenatal and adult stages (Rieder & Fliegel, ).…”

Section: Introductionmentioning

confidence: 97%

“…In a Drosophila model, NHE1 overexpression led to cell proliferation and tissue expansion, and overexpressed NHE1 co-operated with Ras to reduce cell-cell coordination (Grillo-Hill et al 2015). Finally, movement of clusters of head and neck squamous cell carcinoma cells was decreased upon NHE1 knockdown (Kaminota et al 2017). Expression of NHE1 is developmentally regulated; NHE1 levels are particularly high in murine kidney at postnatal week 2, which is the time when normal kidney function is established, compared to both prenatal and adult stages (Rieder & Fliegel, 2002).…”

Section: Introductionmentioning

confidence: 99%

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The Na⁺/H⁺ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration

Jensen

Pedersen

Morgen

et al. 2018

The Journal of Physiology

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Key points Exogenous Na+/H+ exchanger 1 (NHE1) expression stimulated the collective migration of epithelial cell sheets Stimulation with epidermal growth factor, a key morphogen, primarily increased migration of the front row of cells, whereas NHE1 increased that of submarginal cell rows, and the two stimuli were additive Accordingly, NHE1 localized not only to the leading edges of leader cells, but also in cryptic lamellipodia in submarginal cell rows NHE1 expression disrupted the morphology of epithelial cell sheets and three‐dimensional cysts Abstract Collective cell migration plays essential roles in embryonic development, in normal epithelial repair processes, and in many diseases including cancer. The Na+/H+ exchanger 1 (NHE1, SLC9A1) is an important regulator of motility in many cells and has been widely studied for its roles in cancer, although its possible role in collective migration of normal epithelial cells has remained unresolved. In the present study, we show that NHE1 expression in MDCK‐II kidney epithelial cells accelerated collective cell migration. NHE1 localized to the leading edges of leader cells, as well as to cryptic lamellipodia in submarginal cell rows. Epidermal growth factor, a kidney morphogen, increased displacement of the front row of collectively migrating cells and reduced the number of migration fingers. NHE1 expression increased the number of migration fingers and increased displacement of submarginal cell rows, resulting in additive effects of NHE1 and epidermal growth factor. Finally, NHE1 expression resulted in disorganized development of MDCK‐II cell cysts. Thus, NHE1 contributes to collective migration and epithelial morphogenesis, suggesting roles for the transporter in embryonic and early postnatal development.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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The Na⁺/H⁺ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration

Jensen

Pedersen

Morgen

et al. 2018

The Journal of Physiology

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“…Immunoblotting analyses were performed according to a previously described study . Equal amounts of protein (9 μg serum or 3 μg supernatant and exosome protein) were separated by SDS‐PAGE, transferred to a nitrocellulose membrane, and immunoblotted with anti‐LOXL2 antibody.…”

Section: Methodsmentioning

confidence: 99%

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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Pharmacological interventions part II

Koltai¹,

Reshkin²,

Harguindey³

2020

An Innovative Approach to Understanding and Treating Cancer: Targeting pH

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Elevated Na + /H + exchanger-1 expression enhances the metastatic collective migration of head and neck squamous cell carcinoma cells

Cited by 18 publications

References 31 publications

The Na⁺/H⁺ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration

The Na⁺/H⁺ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration

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

Pharmacological interventions part II

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Elevated Na + /H + exchanger-1 expression enhances the metastatic collective migration of head and neck squamous cell carcinoma cells

Cited by 18 publications

References 31 publications

The Na+/H+ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration

The Na+/H+ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration

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

Pharmacological interventions part II

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The Na⁺/H⁺ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration

The Na⁺/H⁺ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration