呼吸臨床

【特集】呼吸器科医に役立つ最先端のメカノバイオロジー研究

企画：寺崎泰弘，ゲストエディター：伊藤理


　生体は常に重力，圧力，ずり応力といった機械的刺激（メカニカルストレス）を受けています。これらメカニカルストレスがどのようにして細胞機能や生体の応答を制御するか，疾患の病態生理に関与するかを追究する研究が「メカノバイオロジー」です。呼吸器は多様なメカニカルストレスにさらされていることから，呼吸器の細胞機能・生理機能や呼吸器疾患の病態機序を解明するうえで，呼吸器メカノバイオロジー研究の果たすべき役割は大きいと期待されています。今回の特集では，メカノバイオロジーを紹介し，研究の魅力と課題をお伝えすることを企画しています。

（伊藤理）

2）各論：3．肺癌・悪性中皮腫のメカノバイオロジーとYAP/TAZの役割

田中一大*

*名古屋大学医学部附属病院呼吸器内科（〒466-8560　愛知県名古屋市昭和区鶴舞町65）


Mechanobiology and functional role of YAP/TAZ in lung cancer and malignant mesothelioma

Ichidai Tanaka*
*Department of Respiratory Medicine, Nagoya University Hospital, Nagoya


Keywords：メカノバイオロジー，YAP/TAZ，Hippoシグナル経路，肺癌，悪性中皮腫／mechanobiology，YAP/TAZ，hippo signal pathway，lung cancer，malignant mesothelioma


呼吸臨床 2017年1巻2号　論文No.e00020
Jpn Open J Respir Med 2017 Vol. 1 No. 2 Article No.e00020

DOI: 10.24557/kokyurinsho.1.e00020


掲載日：2017年11月21日


©️Ichidai Tanaka. 本論文の複製権，翻訳権，上映権，譲渡権，貸与権，公衆送信権（送信可能化権を含む）は弊社に帰属し，それらの利用ならびに許諾等の管理は弊社が行います。


要旨

　生体を構成する細胞は，さまざまな物理的刺激（メカニカルストレス）に応答して，増殖・分化・形態形成を制御する。近年，物理的刺激が感知された後の応答分子として，Hippoシグナル経路およびその標的因子である転写共役因子YAP/TAZが同定された。Hippoシグナル経路・YAP/TAZは，発生過程で臓器サイズを決定する重要な役割を担う一方で，腫瘍の悪性化にも深く関連している。肺癌においては，YAP/TAZが細胞外基質の硬度に応答して細胞増殖に寄与している可能性が高い。それに対し，悪性中皮腫においてはHippoシグナル経路の破綻が基軸となり，YAPの恒常的活性化を引き起こしている。YAP/TAZの活性化は，細胞外基質の再構築にも関与し腫瘍進展を促進している。

文献

  1. Tkach M, et al. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016; 164: 1226-32. 
  2. Becker A, et al. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell. 2016; 30: 836-48.
  3. Schedin P, et al. Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression. Cold Spring Harb Perspect Biol. 2011; 3: a003228.
  4. Jung HY, et al. Molecular pathways: linking tumor microenvironment to epithelial-mesenchymal transition in metastasis. Clin Cancer Res. 2015; 21: 962-8.
  5. Luo J, et al. Solid predominant histologic subtype and early recurrence predict poor postrecurrence survival in patients with stage I lung adenocarcinoma. Oncotarget. 2017; 8: 7050-8.
  6. Low BC, et al. YAP/TAZ as mechanosensors and mechanotransducers in regulating organ size and tumor growth. FEBS Lett. 2014; 588: 2663-70.
  7. Dupont S. Role of YAP/TAZ in cell-matrix adhesion-mediated signalling and mechanotransduction. Exp Cell Res. 2016; 343: 42-53.
  8. Wu S, et al. Hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts.  Cell. 2003; 114: 445-56.
  9. Udan RS, et al. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat Cell Biol. 2003; 5: 914-20.
  10. Harvey K, et al. The Salvador-Warts-Hippo pathway-an emerging tumour-suppressor network. Nat Rev Cancer. 2007; 7: 182-91.
  11. Yu FX, et al. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. 2015; 163: 811-28.
  12. Halder G, et al. Transduction of mechanical and cytoskeletal cues by YAP and TAZ.  Nat Rev Mol Cell Biol. 2012; 13: 591-600.
  13. Hao J, et al. Role of extracellular matrix and YAP/TAZ in cell fate determination. Cell Signal. 2014; 26: 186-91.
  14. Low BC, et al. YAP/TAZ as mechanosensors and mechanotransducers in regulating organ size and tumor growth. FEBS Lett. 2014; 588: 2663-70.
  15. Rauskolb C, et al. Cytoskeletal tension inhibits Hippo signaling through an Ajuba-Warts complex. Cell. 2014; 158: 143-56.
  16. Wang L, et al. Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature. 2016 Dec 7. doi: 10.1038/nature20602. [Epub ahead of print]
  17. Nardone G, et al. YAP regulates cell mechanics by controlling focal adhesion assembly. Nat Commun. 2017; 8: 15321.
  18. Urtasun R, et al. Connective tissue growth factor autocriny in human hepatocellular carcinoma: oncogenic role and regulation by epidermal growth factor receptor/yes-associated protein-mediated activation. Hepatology. 2011; 54: 2149-58.
  19. Reddy P, et al. Actin cytoskeleton regulates Hippo signaling. PLoS One. 2013 ; 8: e73763.
  20. Fujii M, et al. Convergent signaling in the regulation of connective tissue growth factor in malignant mesothelioma: TGFβ signaling and defects in the Hippo signaling cascade. Cell Cycle. 2012; 11: 3373-9.
  21. Tilghman RW, et al. Matrix rigidity regulates cancer cell growth and cellular phenotype. PLoS One. 2010; 5: e12905.
  22. Yuan Y, et al. Yes-associated protein regulates the growth of human non-small cell lung cancer in response to matrix stiffness. Mol Med Rep. 2015; 11: 4267-72.
  23. Ito T, et al. Loss of YAP1 defines neuroendocrine differentiation of lung tumors. Cancer Sci. 2016; 107: 1527-38.
  24. Horie M, et al. YAP and TAZ modulate cell phenotype in a subset of small cell lung cancer. Cancer Sci. 2016; 107: 1755-66.
  25. Lee JE, et al. Hippo pathway effector YAP inhibition restores the sensitivity of EGFR-TKI in lung adenocarcinoma having primary or acquired EGFR-TKI resistance. Biochem Biophys Res Commun. 2016; 474: 154-60.
  26. Hsu PC, et al. YAP promotes erlotinib resistance in human non-small cell lung cancer cells. Oncotarget. 2016; 7: 51922-33.
  27. Chaib I, et al. Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC. J Natl Cancer Inst. 2017;109. doi: 10.1093/jnci/djx014.
  28. Gregorieff A, et al. Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer. Nature. 2015; 526: 715-8.
  29. Shackelford DB, et al. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009; 9: 563-75.
  30. Hemminki A, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.Nature. 1998; 391: 184-7.
  31. Ji H, et al. LKB1 modulates lung cancer differentiation and metastasis.  Nature. 2007; 448: 807-10.
  32. Mohseni M, et al. A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway. Nat Cell Biol. 2014; 16: 108-17.
  33. Gao Y, et al. YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression. Nat Commun. 2014; 5: 4629.
  34. Sekido Y. Genomic abnormalities and signal transduction dysregulation in malignant mesothelioma cells. Cancer Sci. 2010; 101: 1-6.
  35. Li W, et al. Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus. Cell. 2010; 140: 477-90.
  36. Sekido Y. Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation. Pathol Int. 2011; 61: 331-44.
  37. Tranchant R, et al. Co-occurring Mutations of Tumor Suppressor Genes, LATS2 and NF2, in Malignant Pleural Mesothelioma. Clin Cancer Res. 2017; 23: 3191-202.
  38. Murakami H, et al. LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer Res. 2011; 71: 873-83.
  39. Tanaka I, et al. LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade. Oncogene. 2015; 34: 73-83.
  40. Mizuno T, et al. YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes. Oncogene. 2012; 31: 5117-22.
  41. Jiang L, et al. Connective tissue growth factor and β-catenin constitute an autocrine loop for activation in rat sarcomatoid mesothelioma. J Pathol. 2014; 233: 402-14.
  42. Fujii M, et al. TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth. J Exp Med. 2012; 209: 479-94.

続きを見る

ログイン

新規登録

会員登録





※ご登録の前に個人情報保護方針をご一読ください。

登録

パスワードを忘れた方


送信