| 1. |
Kana Hasegawa, Shinsuke Fujii, Shinji Matsumoto, Yudai Tajiri, Akira Kikuchi, Tamotsu Kiyoshima, YAP signaling induces PIEZO1 to promote oral squamous cell carcinoma cell proliferation, J Pathol, 10.1002/path.5553, 253, 1, 80-93, 2021.01, Most cancer cells are exposed to altered extracellular environments, such as an increase in extracellular matrix (ECM) stiffness and soluble signals consisting of growth factors and cytokines. It is therefore conceivable that changes in tumor extracellular environments affect tumor cell behavior. The Hippo pathway reportedly responds to the extracellular environment and regulates the nuclear localization of the transcription co-activator, yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ). Inactivation of the Hippo pathway with nuclear translocation of YAP/TAZ stimulates cell proliferation. Its pathway also regulates gene expression, but the precise molecule(s) meditating the cell-proliferating effect of YAP signaling on oral squamous cell carcinoma (OSCC) is unclear. First, we examined the effects of YAP signaling on OSCC tumorigenesis. Loss-of-function experiments using siRNA or an inhibitor, and immunohistochemical analyses of tissue specimens obtained from OSCC patients demonstrated that YAP signaling was involved in OSCC cell proliferation. Second, we identified Piezo-type mechanosensitive ion channel component 1 (PIEZO1), a Ca2+ channel, as a transcriptional target of YAP signaling and showed that elevated PIEZO1 was required for PIEZO1 agonist-dependent Ca2+ entry and cell proliferation in OSCC cells. Experiments using three-dimensional and suspension culture revealed that PIEZO1 was involved in OSCC cellular growth. Finally, YAP overexpression in the nucleus and/or cytoplasm was immunohistochemically detected in tumor lesions with frequent expression of both PIEZO1 and Ki-67, but not in non-tumor regions of OSCC specimens. These results suggest that the YAP/PIEZO1 axis promotes OSCC cell growth.
.  |
| 2. |
Shinsuke Fujii, Yudai Tajiri, Kana Hasegawa, Shinji Matsumoto, Reiko U. Yoshimoto, Hiroko Wada, Shosei Kishida, Mizuho A. Kido, Hiromasa Yoshikawa, Satoru Ozeki, Tamotsu Kiyoshima, The TRPV4-AKT axis promotes oral squamous cell carcinoma cell proliferation via CaMKII activation., Laboratory Investigation, 10.1038/s41374-019-0357-z., 100, 2, 311-323, 2020.02, Most human malignant tumor cells arise from epithelial tissues, which show distinctive characteristics, such as polarization, cell-to-cell contact between neighboring cells, and anchoring to a basement membrane. When tumor cells invaginate into the stroma, the cells are exposed to extracellular environments, including the extracellular matrix (ECM). Increased ECM stiffness has been reported to promote cellular biological activities, such as excessive cellular growth and enhanced migration capability. Therefore, tumorous ECM stiffness is not only an important clinical tumor feature but also plays a pivotal role in tumor cell behavior. Transient receptor potential vanilloid 4 (TRPV4), a Ca2+-permeable nonselective cation channel, has been reported to be mechano-sensitive and to regulate tumorigenesis, but the underlying molecular mechanism in tumorigenesis remains unclear. The function of TRPV4 in oral squamous cell carcinoma (OSCC) is also unknown. The current study was conducted to investigate whether or not TRPV4 might be involved in OSCC tumorigenesis. TRPV4 mRNA levels were elevated in OSCC cell lines compared with normal oral epithelial cells, and its expression was required for TRPV4 agonist-dependent Ca2+ entry. TRPV4-depleted tumor cells exhibited decreased proliferation capabilities in three-dimensional culture but not in a low-attachment plastic dish. A xenograft tumor model demonstrated that TRPV4 expression was involved in cancer cell proliferation in vivo. Furthermore, loss-of-function experiments using siRNA or an inhibitor revealed that the TRPV4 expression was required for CaMKII-mediated AKT activation. Immunohistochemical analyses of tissue specimens obtained from 36 OSCC patients showed that TRPV4 was weakly observed in non-tumor regions but was strongly expressed in tumor lesions at high frequencies where phosphorylated AKT expression was frequently detected. These results suggest that the TRPV4/CaMKII/AKT axis, which might be activated by extracellular environments, promotes OSCC tumor cell growth.. |
| 3. |
Shinsuke Fujii, Kengo Nagata, Shinji Matsumoto, Ken-ichi Kohashi, Akira Kikuchi, Yoshinao Oda, Tamotsu Kiyoshima, Naohisa Wada, Wnt/β-catenin signaling, which is activated in odontomas, reduces Sema3A expression to regulate odontogenic epithelial cell proliferation and tooth germ development., Scientific Reports., 10.1038/s41598-019-39686-1, 9, 2019.03, Odontomas, developmental anomalies of tooth germ, frequently occur in familial adenomatous polyposis patients with activated Wnt/β-catenin signaling. However, roles of Wnt/β-catenin signaling in odontomas or odontogenic cells are unclear. Herein, we investigated β-catenin expression in odontomas and functions of Wnt/β-catenin signaling in tooth germ development. β-catenin frequently accumulated in nucleus and/or cellular cytoplasm of odontogenic epithelial cells in human odontoma specimens, immunohistochemically. Wnt/β-catenin signaling inhibited odontogenic epithelial cell proliferation in both cell line and tooth germ development, while inducing immature epithelial bud formation. We identified Semaphorin 3A (Sema3A) as a downstream molecule of Wnt/β-catenin signaling and showed that Wnt/β-catenin signaling-dependent reduction of Sema3A expression resulted in suppressed odontogenic epithelial cell proliferation. Sema3A expression is required in appropriate epithelial budding morphogenesis. These results suggest that Wnt/β-catenin signaling negatively regulates odontogenic epithelial cell proliferation and tooth germ development through decreased-Sema3A expression, and aberrant activation of Wnt/β-catenin signaling may associate with odontoma formation.. |
| 4. |
Yurie Mikami, Shinsuke Fujii, Ken-Ichi Kohashi, Yuichi Yamada, Masafumi Moriyama, Shintaro Kawano, Seiji Nakamura, Yoshinao Oda, Tamotsu Kiyoshima, Low-grade myofibroblastic sarcoma arising in the tip of the tongue with intravascular invasion: A case report., Oncology letters., 10.3892/ol.2018.9115, 16, 3, 3889-3894, 2018.09, Low-grade myofibroblastic sarcoma (LGMS) is a rare intermediate tumor, which rarely metastasizes and has myofibroblastic differentiation in various sites. It is particularly associated with the tongue in the head and neck region. The lack of any pathological features means it is difficult to make a conclusive diagnosis of LGMS. The immunohistochemical features and genomic rearrangements, including SS18-SSXs and MYH9-USP6s and the genetic mutations of cancer-associated genes, including APC, CTNNB1, EGFR, KRAS, PIK3CA and p53 were examined in a case of LGMS arising in the tip of the tongue. Immunohistochemically, the tumor cells were positive for alpha-smooth muscle actin and vimentin, as in previous reports. They demonstrated neither genomic rearrangements nor point mutations of cancer-associated genes. Although several tumor cells demonstrated intravascular invasion, the MIB-l labeling index of the cells was the same as the original lesion. To the best of our knowledge, this is the first case report of LGMS arising in the tip of the tongue with intravascular invasion.. |
| 5. |
Yurie Mikami, Shinsuke Fujii, Kengo Nagata, Hiroko Wada, Kana Hasegawa, Misaki Abe, Reiko U Yoshimoto, Shintaro Kawano, Seiji Nakamura, Tamotsu Kiyoshima, GLI-mediated Keratin 17 expression promotes tumor cell growth through the anti-apoptotic function in oral squamous cell carcinomas., J Cancer Res Clin Oncol, 10.1007/s00432-017-2398-2, 2017.03, PURPOSE:Keratin 17 (KRT17) has been suggested as a potential diagnostic marker of squamous cell carcinoma including oral squamous cell carcinoma (OSCC). The current study was conducted to clarify the function of KRT17 and its expression mechanism in OSCC.METHODS:Immunohistochemical analyses were carried out to examine the expression of KRT17, GLI family zinc finger (GLI)-1, GLI-2, or cleaved caspase-3 in OSCCs. The expression of KRT17, GLI-1, or GLI-2 was investigated among OSCC cell lines, and the effects of loss-of-function of KRT17 or GLI, using siRNA or inhibitor, on the cell growth of the OSCC cell line HSC-2 particularly with respect to apoptosis were examined.RESULTS:Immunohistochemical analyses of tissue specimens obtained from 78 OSCC patients revealed that KRT17 was not observed in non-tumor regions but was strongly expressed at high frequencies in tumor regions. Knockdown of KRT17 increased the number of cleaved caspase-3-positive cells, leading to the reduction of cell number. Loss-of-function of GLI-1 or GLI-2 also increased the cell numbers of apoptotic cells positive for staining of Annexin-V and propidium iodide (PI) and the terminal deoxynucleotidyl transferase dUTP-biotin nick-end labeling (TUNEL) method, and induced DNA fragmentation. This inhibitory effect on cell growth was partially rescued by exogenous KRT17 expression. In the KRT17-positive regions in OSCCs, GLI-1 or GLI-2 was frequently detected, and the number of cells with cleaved caspase-3 positive was decreased.CONCLUSIONS:KRT17 promotes tumor cell growth, at least partially, through its anti-apoptotic effect as a result of the KRT17 overexpression by GLIs in OSCC.. |
| 6. |
Kana Hasegawa, Hiroko Wada, Kengo Nagata, Hiroaki Fujiwara, Naohisa Wada, Hirotaka Someya, Yurie Mikami, Hidetaka Sakai, Tamotsu Kiyoshima, Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) expression and possible function in mouse tooth germ development, Int. J. Mol. Med., 10.1007/s10735-016-9680-5, 47, 4, 375-387, 2016.08. |
| 7. |
Hirotaka Someya, Fujiwara Hiroaki, Kengo Nagata, Hiroko Wada, Kana Hasegawa, Yurie Mikami, Akiko Jinno, Hidetaka Sakai, Kiyoshi Koyano, Tamotsu Kiyoshima, Thymosin beta 4 is associated with RUNX2 expression via the Smad and Akt signaling pathways in mouse dental epithelial cells., Int. J. Mol. Med., doi: 10.3892/ijmm.2015.2118., 35, 5, 1169-1178, 2015.05. |
| 8. |
Makiko Kihara, Tamotsu Kiyoshima, Kengo Nagata, Hiroko Wada, Fujiwara Hiroaki, Kana Hasegawa, Hirotaka Someya, Ichiro Takahashi, Hidetaka Sakai, Itm2a expression in the developing mouse first lower molar, and the subcellular localization of itm2a in mouse dental epithelial cells., PLoS One., doi: 10.1371/journal.pone.0103928., 9, 7, e103928, 2014.07. |
| 9. |
Tamotsu Kiyoshima, Fujiwara Hiroaki, Kengo Nagata, Hiroko Wada, Yukiko Okuma, Maho Shiotsuka, Makiko Kihara, Kana Hasegawa, Hirotaka Someya, Hidetaka Sakai, Induction of dental epithelial cell differentiation marker gene expression in non-odontogenic human keratinocytes by transfection with thymosin beta 4., Stem Cell Research, doi: 10.1016/j.scr.2013.11.006., 12, 1, 309-322, 2014.01. |
| 10. |
Maho Shiotsuka, Hiroko Wada, Tamotsu Kiyoshima, Kengo Nagata, Fujiwara Hiroaki, Makiko Kihara, Kana Hasegawa, Hirotaka Someya, Ichiro Takahashi, Hidetaka Sakai, The expression and function of thymosin beta 10 in tooth germ development., Int J Dev Biol, doi: 10.1387/ijdb.120240hs., 57, 11-12, 873-883, 2013.12. |
| 11. |
Tamotsu Kiyoshima, Hisato Yoshida, Hiroko Wada, Kengo Nagata, Fujiwara Hiroaki, Makiko Kihara, Kana Hasegawa, Hirotaka Someya, Hidetaka Sakai, Chemoresistance to Concanamycin A1 in Human Oral Squamous Cell Carcinoma Is Attenuated by an HDAC Inhibitor Partly via Suppression of Bcl-2 Expression, PLOS ONE, 10.1371/journal.pone.0080998, 8, 11, 2013.11. |
| 12. |
Tamotsu Kiyoshima, Kengo Nagata, Hiroko Wada, Fujiwara Hiroaki, Maho Shiotsuka, Makiko Kihara, Kana Hasegawa, Hirotaka Someya, Hidetaka Sakai, Immunohistochemical Expression of Thymosin β4 in Ameloblastomas and Odontomas., Histol. Histopathol., doi: 10.3892/ijo.2012.1594., 28, 6, 775-786, 2013.06. |
| 13. |
Yukiko Okuma, Tamotsu Kiyoshima, Ieyoshi Kobayashi, Kengo Nagata, Hiroko Wada, Fujiwara Hiroaki, Haruyoshi Yamaza, Kazuaki Nonaka, Hidetaka Sakai, Multiple functional involvement of Thymosin beta-4 in tooth germ development, HISTOCHEMISTRY AND CELL BIOLOGY, 10.1007/s00418-012-1033-1, 139, 2, 355-370, 2013.02. |
| 14. |
Tamotsu Kiyoshima, Norio Enoki, Ieyoshi Kobayashi, Takako Sakai, Kengo Nagata, Hiroko Wada, Fujiwara Hiroaki, 大隈 由紀子, Hidetaka Sakai, Oxidative stress caused by a low concentration of hydrogen peroxide induces senescence-like changes in mouse gingival fibroblasts., Int. J. Mol. Med., doi: 10.3892/ijmm.2012.1102., 30, 5, 1007-1012, 2012.11. |
| 15. |
Lutfun Naher, Tamotsu Kiyoshima, Ieyoshi Kobayashi, Hiroko Wada, Kengo Nagata, Fujiwara Hiroaki, 大隈 由紀子, Satoru Ozeki, Seiji Nakamura, Hidetaka Sakai, STAT3 signal transduction through interleukin-22 in oral squamous cell carcinoma., Int. J. Oncol., doi: 10.3892/ijo.2012.1594., 41, 5, 1577-1586, 2012.11. |
| 16. |
Takahashi KF, Kiyoshima T, Kobayashi I, Xie M, Yamaza H, Fujiwara H, Ookuma Y, Nagata K, Wada H, Sakai T, Terada Y, Sakai H., Protogenin, a new member of the immunoglobulin superfamily, is implicated in the development of the mouse lower first molar., BMC Dev Biol., 10:115-129, 2010.11. |
| 17. |
Hideaki Fukuzawa, Tamotsu Kiyoshima, Ieyoshi Kobayashi, Satoru Ozeki, Hidetaka Sakai, Transcription promoter activity of the human S100A7 gene in oral squamous cell carcinoma cell lines., Biochem, Biophys.Acta, 1759: 171-176,, 2006.04. |
| 18. |
Ken-ichiro Hashimoto, Tamotsu Kiyoshima, Kou Matsuo, Satoru Ozeki, Hidetaka Sakai, Effect of SCCA1 and SCCA2 on the suppression of TNF-a-induced cell death by impeding the release of mitochondrial cytochrome c in oral squamous cell carcinoma cell line., Tumor Biol., 10.1159/000086949, 26, 4, 165-172, 26:165-172, 2005.07. |
| 19. |
Ogasawara T, Yoshimine Y, Kiyoshima T, Kobayashi I, Matsuo K, Akamine A, Sakai H, In situ expression of RANKL, RANK, osteoprotegerin and cytokines in osteoclasts of rat periodontal tissue., J Periodontal Res., 10.1111/j.1600-0765.2004.00699.x, 39, 1, 42-49, Vol.39, pp.42-9., 2004.01. |
| 20. |
Kiyoshima T, Yamauchi M, Wong C, Jheon A, Ganss B, Sodek J., An L1 element disrupts human bone sialoprotein promoter: lack of tissue-specific regulation by distalless5 (Dlx5) and runt homeodomain protein2 (Runx2)/core binding factor a1 (Cbfa1) elements., Gene, Vol.299, pp.205-17., 2002.10. |
| 21. |
Okamura K, Kiyoshima T, Shima K, Kobayashi I, Matsuo K, Ishibashi H, Komatsu S, Rasul AM, Sakai H., Immunohistochemical expression of CA19-9 and CA125 in mucoepidermoid and adenoid cystic carcinomas of the salivary gland., Oral Oncol., 10.1016/S1368-8375(01)00049-5, 38, 3, 244-250, Vol.38, pp.244-50., 2002.04. |
| 22. |
Wada H, Kobayashi I, Yamaza H, Matsuo K, Kiyoshima T, Akhtar M, Sakai T, Koyano K, Sakai H., In situ expression of heat shock proteins, Hsc73, Hsj2 and Hsp86 in the developing tooth germ of mouse lower first molar., Histochem J., 10.1023/A:1020930228303, 34, 3-4, 105-109, Vol.34, pp.105-9., 2002.03. |
| 23. |
Yamaza H, Matsuo K, Kobayashi I, Wada H, Kiyoshima T, Akhtar M, Ishibashi Y, Sakai T, Akamine A, Sakai H., Expression of Set-alpha during morphogenesis of mouse lower first molar, Histochem J., 10.1023/A:1014491111628, 33, 8, 437-441, Vol.33,pp.437-41, 2001.08. |
| 24. |
Kiyoshima T, Shima K, Kobayashi I, Matsuo K, Okamura K, Komatsu S, Rasul AM, Sakai H., Expression of p53 tumor suppressor gene in adenoid cystic and mucoepidermoid carcinomas of the salivary glands, Oral Oncol., 10.1016/S1368-8375(00)00083-X, 37, 3, 315-322, Vol.37,pp.315-22, 2001.04. |
| 25. |
Shigemura N, Kiyoshima T, Sakai T, Matsuo K, Momoi T, Yamaza H, Kobayashi I, Wada H, Akamine A, Sakai H., Localization of activated caspase-3-positive and apoptotic cells in the developing tooth germ of the mouse lower first molar, Histochem J., 10.1023/A:1017900305661, 33, 5, 253-258, Vol.33,pp.253-8, 2001.03. |
| 26. |
Yamaza H, Matsuo K, Kiyoshima T, Shigemura N, Kobayashi I, Wada H, Akamime A, Sakai H., Detection of differentially expressed genes in the early developmental stage of the mouse mandible, Int J Dev Biol., 45, 4, 675-680, Vol.45,pp.675-80, 2001.01. |
| 27. |
Shima K, Kobayashi I, Saito I, Kiyoshima T, Matsuo K, Ozeki S, Ohishi M, Sakai H., Incidence of human papillomavirus 16 and 18 infection and p53 mutation in patients with oral squamous cell carcinoma in Japan, Br J Oral Maxillofac Surg., Vol.38,pp.445-50, 2000.10. |
| 28. |
Li C.Y., Shirasuna K., Ishibashi H., Nakayama H. and Kiyoshima T., Epithelial-myoepithelial carcinoma arising in pleomorphic adenoma of the palate., Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod., 10.1067/moe.2000.108099, 90, 4, 460-465, 2000.10. |
| 29. |
Sakai T, Kiyoshima T, Kobayashi I, Moroi R, Ibuki T, Nagadome M, Terada Y, Sakai H., Age-dependent changes in the distribution of BrdU- and TUNEL-positive cells in the murine gingival tissue, J Periodontol., 10.1902/jop.1999.70.9.973, 70, 9, 973-981, Vol.70,pp.973-81, 1999.09. |
| 30. |
Kobayashi I, Shima K, Saito I, Kiyoshima T, Matsuo K, Ozeki S, Ohishi M, Sakai H., Prevalence of Epstein-Barr virus in oral squamous cell carcinoma, J Pathol., 10.1002/(SICI)1096-9896(199909)189:1<34::AID-PATH391>3.0.CO;2-4, 189, 1, 34-39, Vol.189,pp.34-9, 1999.09. |
| 31. |
Shigemura N, Kiyoshima T, Kobayashi I, Matsuo K, Yamaza H, Akamine A, Sakai H., The distribution of BrdU- and TUNEL-positive cells during odontogenesis in mouse lower first molars, Histochem J., 10.1023/A:1003796023992, 31, 6, 367-377, Vol.31,pp.367-77, 1999.07. |
| 32. |
Kobayashi I., Kiyoshima T., Ozeki S., Shima K., Shigemura N., Matsuo K. and Sakai H., Immunohistochemical and ultrastructural study of a papillary cystadenocarcinoma arising from the sublingual gland., J. Oral Pathol. Med., 28, 6, 282-286, 1999.07. |
| 33. |
Kiyoshima T., Kobayashi, I., Matsuo K., Ishibashi Y., Miyoshi A., Akashi Y. and Sakai H., Immunohistochemical localization of laminin, collagen type IV and heparan sulfate proteoglycan in human colorectal adenocarcinoma: correlation with local invasive pattern and lymph node metastasis, Acta Histochemica et Cytochemica, 31, 1, 39-47, Vol.31,pp.39-47, 1998.01. |
| 34. |
Kazuhiko Okamura, Ieyoshi Kobayashi, Kou Matsuo, Tamotsu Kiyoshima, Kenji Yamamoto, Akira Miyoshi, Hidetaka Sakai, Immunohistochemical localization of cathepsin D, proliferating cell nuclear antigen and epidermal growth factor receptor in human breast carcinoma analysed by computer image analyser: correlation with histological grade and metastatic behaviour, HISTOPATHOLOGY, 31, 6, 540-548, 1997.12. |
| 35. |
Kobayashi I., Matsuo K., Kiyoshima T., Shinohara M. and Sakai H., Salivary Duct Carcinoma with Sebaceous Cell Differentiation arising from Parotid Gland: Histological, Immunohistochemical and Ultrastructural Analyses of a Case., Oral Med. Pathol., 2, 89-93, 1997.03. |
| 36. |
Okamura K., Kobayashi I., Matsuo K., Kiyoshima T., Yamamoto K., Miyoshi A. and Sakai H., Immunohistochemical localization of cathepsin D, proliferating cell nuclear antigen and epidermal growth factor receptor in human breast carcinoma analyzed by computor image analyzer: correlation with the histological grade and the metastatic activity of carcinoma., Histopathology, 31, 540-548, 1997.03. |
| 37. |
Kou Matsuo, Ieyoshi Kobayashi, Takayuki TSUKUBA, Tamotsu Kiyoshima, Yukiko Ishibashi, Akira Miyoshi, Kenji Yamamoto, Hidetaka Sakai, Immunohistochemical localization of cathepsins D and E in human gastric cancer: A possible correlation with local invasive and metastatic activities of carcinoma cells, HUMAN PATHOLOGY, 27, 2, 184-190, 1996.02. |
