Novel K6-K14 keratin fusion enhances cancer stemness and aggressiveness in oral squamous cell carcinoma

Tsai, Fuu‐Jen; Lai, Ming‐Tsung; Cheng, Jack; Chao, Stev Chun-Chin; Korla, Praveen Kumar; Chen, Hui-Jye; Lin, Chung-Ming; Tsai, Ming‐Hsui; Hua, Chun‐Hung; Jan, Chia-Ing; Jinawath, Natini; Wu, Chia-Hung; Chen, Chih-Mei; Kuo, Brian Yu-Ting; Chen, Liwen; Yang, Jacky; Hwang, Tritium; Sheu, Jim Jinn‐Chyuan

doi:10.1038/s41388-019-0781-y

Cited by 14 publications

(13 citation statements)

References 49 publications

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“…Cell proliferation was carried out by MTT assay for four days, as previously described [62]. Colony formation assay .…”

Section: Methodsmentioning

confidence: 99%

“…Sphere number and size were determined by microscopy at 10X magnification under DIC. Wound healing, in vitro cell migration, and invasion and anti‐anoikis assay were done as described previously [62,64]. Modification in detecting of invading cells was done.…”

Section: Methodsmentioning

confidence: 99%

“…Normal and tumor (tissues array), and mouse xenograft were processed for IHC and H&E staining, according to the protocol as described previously [62].…”

Section: Immunohistochemistry (Ihc) Hande Staining and Western Blottingmentioning

confidence: 99%

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Overexpression of wild type or a Q311E mutant MB21D2 promotes a pro‐oncogenic phenotype in HNSCC

et al. 2020

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Cadherin-mediated cell-cell contacts regulated by intracellular binders play critical roles in tissue homeostasis and tumorigenesis. Here, we screened mutational profiles of 312 annotated genes involved in cadherin binding in human squamous cell carcinomas and found MB21D2 to carry a unique recurrent Q311E mutation. MB21D2 overexpression was also frequently found in head and neck cancer (HNSCC) and was associated with poor clinical outcomes. Cell-based characterizations revealed pro-oncogenic roles for MB21D2 wild-type (WT) and its Q311E mutant (Q311E) in cell proliferation, colony formation, sphere growth, and migration/invasion by promoting epithelial-mesenchymal transition. Conversely, MB21D2 knockdown in MB21D2-overexpressing cells resulted in cell growth arrest and apoptosis. Xenograft tumor models with Q311E-expressing cells formed larger and more aggressive lesions, compared to models with WT-MB21D2-expressing cells or an empty vector. Transcriptome and protein interactome analyses revealed enrichment of KRAS signaling by MB21D2 expression. Immunoblotting confirmed RAS elevation, along with upregulation/phosphorylation of PI3K, AKT, and CREB. Blocking RAS signaling in MB21D2-expressing cells by manumycin significantly reduced cell growth and survival. Our study thus defined RAS signaling-dependent prooncogenic roles for MB21D2 overexpression and Q311E MB21D2 expression in HNSCC development. Abbreviations GEPIA, gene expression profiling interactive analysis; HNSCC, head and neck squamous cell carcinoma; KRAS, Kirsten rat sarcoma viral oncogene homolog (KRAS proto-oncogene, GTPase); MB21D2, Mab-21-containing domain 2; PI3K, phospho-inositol kinase 3; Q311E, change in glutamine at the position 311 to glutamic acid; SCCs, squamous cell carcinoma(s; TCGA, The Cancer Genome Atlas; WT, in this study, wild-type MB21D2.

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“…Cell proliferation was carried out by MTT assay for four days, as previously described [62]. Colony formation assay .…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Overexpression of wild type or a Q311E mutant MB21D2 promotes a pro‐oncogenic phenotype in HNSCC

et al. 2020

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“…Defects in keratin cytoskeleton have been reported to be involved in some squamous cancers (13) but no dynamics analysis and migratory assays were reported so far. To determine whether defects in keratin impair motion in confined spaces, we used oral squamous epithelial cells CAL27, expressing wild type keratin tagged with GFP.…”

Section: Resultsmentioning

confidence: 99%

“…These types of situations can be found in small veins and in venules where microscopic venous valves (MVV) are present (12) introducing ‘bottlenecks’ in the migratory path. In addition, in some squamous cancers, cells are known to be defective for keratin, an intermediate filament essential to shape the scaffold surrounding the nucleus (13). Defects in these structures and their implications in motility in confined spaces have not been reported.…”

Section: Introductionmentioning

confidence: 99%

Ratchetaxisin channels: cells move directionally by pushing walls asymmetrically

Maout

Vecchio

Korla

et al. 2020

Preprint

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Cell motility is essential in a variety of biological phenomena ranging from early development to organ homeostasis and diseases. This phenomenon was so far mainly studied and characterized on flat surfaces in vitro whereas this situation is rarely seen in vivo. Recently, cell motion in 3D microfabricated channels was reported to be possible, and it was shown that confined cells push on walls. However, rules setting cell directions in this context were not characterized yet. Here, we show by using assays that ratchetaxis operates in 3D ratchets on fibroblasts and on epithelial cancerous cells. Open ratchets rectify cell motion, whereas closed ratchets impose a direct cell migration along channels set by the cell orientation at the channel entry point. We also show that nuclei are pressed at constrictions zones through mechanisms involving dynamic asymmetries of focal contacts, stress fibers, and intermediate filaments. Interestingly, cells do not pass these constricting zones when defective in the keratin fusion implicated in squamous cancer. By combining ratchetaxis with chemical gradients, we finally report that cells are sensitive to local asymmetries in confinement and that topological and chemical cues may be encoded differently by cells. Altogether our ratchet channels could mimic small blood vessels where cells are confined: cells would probe local asymmetries which would determine their entry into tissues and direction. Our results could shed light on invasions mechanisms in cancer.

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Susceptibility of cytoskeletal-associated proteins for tumor progression

Ayanlaja

Hong

Cheng

et al. 2021

Cell. Mol. Life Sci.

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Novel K6-K14 keratin fusion enhances cancer stemness and aggressiveness in oral squamous cell carcinoma

Cited by 14 publications

References 49 publications

Overexpression of wild type or a Q311E mutant MB21D2 promotes a pro‐oncogenic phenotype in HNSCC

Overexpression of wild type or a Q311E mutant MB21D2 promotes a pro‐oncogenic phenotype in HNSCC

Ratchetaxisin channels: cells move directionally by pushing walls asymmetrically

Susceptibility of cytoskeletal-associated proteins for tumor progression

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