Anovel mechanism of tumor progression by the candidate tumor suppressor Proxl : RNA mutation in cancer

• Project/Area Number: 18390345
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: Kyoto University
• Principal Investigator: KUBO Hajime Kyoto University, Department of Surgery, Associate Professor (50362520)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥17,620,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥2,220,000); Fiscal Year 2007: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000); Fiscal Year 2006: ¥8,000,000 (Direct Cost: ¥8,000,000)
• Keywords: oncogene / homebox gene / RNA mutation / 癌 / RNA / ゲノム / Prox1 / 癌抑制遺伝子 / RNA編集

Research Abstract

1. Homeobox gene, Prox1 acts as tumor suppressor
We showed that the expression of Prox1 was associated with the differentiation grades in hepatocellular carcinoma using human samples. Transfection of prox1 gene in cancer cells suppressed the growth in vitro and in vivo. In contrast, siRNA for prox1 promoted the growth of cancer cells in vitro. These findings suggested that Prox1 may act as tumor suppressor.
[Significance]
Drosophila, Prospero, has been known to function during the asymmetric cell division of neural stem cells. The relationship between the disorder of asymmetric cell division and cancer could be confirmed in mammal.
2. RNA mutation of prox1 promotes cancer progression.
We found RNA mutation in 4 common sites of prox1 gene in cancer cells. On the other hand, genetic mutations in the sites were not found in the cells. These mutations were all A-I mutation, suggesting the involvement of RNA editing in cancer progression. The transfection of mutant form of prox1 did not show the suppressive function in cancer cells.
[Significance]
Classically, cancer is believed to be the product of the genomic mutation. However, here, we found that RNA mutations could promote the cancer formation. Surprisingly, these mutations were found in human samples. The novel concept may provide the new target of cancer therapy, ie. the molecular mechanism of RNA mutations.

Research Products

• [Journal Article] RNA mutations of proxl detected in human esophageal cancer cells by the shifted termination assay. (2007)
  • Author(s): Yoshimoto T, Takahashi M, Nagayama S, Watanabe G, Shimada Y, Sakai Y, Kubo H
  • Journal Title: BBRC 359 Pages: 258-262
  • Peer Reviewed
• [Journal Article] Thalidomide prevents bleomycin-induced pulmonary fibrosis in mice. (2007)
  • Author(s): Tabata C, Tabata R, Kadokawa Y, Hisamori S, Takahashi M, Mishima M, Nakano T, Kubo H
  • Journal Title: J Immunol. 179 Pages: 208-214
  • Peer Reviewed
• [Journal Article] Two populations of Thyl-positive mesenchymal cells regulate the in vitro maturation of hepaticprogenitor cells. (2007)
  • Author(s): Kamo N, Yasuchika K, Ishii T, Fujita N, Tsuruo T, Yamashita JK, Kubo H, Ikai I
  • Journal Title: Am J Physiol Gastr Liver Physiol. 292 Pages: 526-534
  • Peer Reviewed
• [Journal Article] Two populations of Thyl-positive mesenchymal cells regulate the in vitro maturation of hepatic progenitor cells. (2007)
  • Author(s): Kamo N, Yasuchika K, Fujii H, Hoppo T, Machimoto T, Ishii T, Fujita N, Tsuruo T, Yamashita JK, Kubo H, Ikai I
  • Journal Title: Am J Physiol Gastr Liver Physiol. 292
• [Journal Article] Loss of function of the candidate tumor suppressor prox1 by RNA mutation in human cancer cells. (2006)
  • Author(s): Takahashi, Meiko(高橋めい子)
  • Journal Title: Neoplasia 8 Pages: 1003-1010
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A homeobox protein prox1 is involved in the differentiation, proliferation and prognosis in hepatocellular carcinoma (2006)
  • Author(s): Sgimoda, Masayuki(霜田雅之)
  • Journal Title: Clin Can Res 12 Pages: 6005-6011
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Loss of function of the candidate tumor suppressor proxl by RNA mutation in human cancer cells (2006)
  • Author(s): Takahashi, Meiko
  • Journal Title: Neoplasia 8 Pages: 1003-1010
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A homeobox protein proxl is involved in the differentiation, proliferation and prognosis in hepatocellular carcinoma (2006)
  • Author(s): Shimoda, M
  • Journal Title: Clin Cancer Res 12 Pages: 6005-11
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Loss of function of the candidate tumor suppressor proxl by RNA mutation in human cancer cells. (2006)
  • Author(s): Takahashi, M., Yoshimoto.T., Shimoda.M., Kono.T., Koisumi, M., Yazumi, S., Shimada, Y., Doi, R., Chiba.T., Kubo, H
  • Journal Title: Neoplasia 8(12) Pages: 1003-1010
• [Journal Article] A homeobox protein proxl is involved in the differentiation, proliferation and prognosis in hepatocellular carcinoma (2006)
  • Author(s): Shimoda, M., Takahashi, M., Yoshimoto, T., Kono, T., Ikai, I., Kubo, H
  • Journal Title: Clin Can Res 12(20) Pages: 6005-6011
• [Journal Article] Differentiation of lymphatic endothelial cells from Embryonic Stem cells on OP9 stromal cells. (2006)
  • Author(s): Kono, T., Kubo.H., Shimazu, C., Ueda Y., Takahashi, M., Yanagi, K., Fujita.N., Tsuruo.T., Wada.H., Yamashita.JK
  • Journal Title: Arterioscler Thromb Vasc Biol Sep;26(9) Pages: 2070-2076
• [Journal Article] All-trans retinoic acid modulates proliferation of lung fibroblasts via IL-6/IL-6R system. (2006)
  • Author(s): Tabata C., Kubo H., Tabata R., Wada M., Sakuma K., Ichikawa M., Fujita S., Mio T, Mishima M
  • Journal Title: Am J Physiol Lung Cell Mol Physiol. 290
• [Journal Article] All-trans-retinoic acid prevents radiation- or bleomycin-induced pulmonary fibrosis. (2006)
  • Author(s): Tabata C, Kadokawa Y, Tabata R, Takahashi M, Okoshi K, Sakai Y, Mishima M, Kubo H
  • Journal Title: Am J Respir Crit Care Med. 174 Pages: 1352-1360
• [Presentation] Lymphangiogenesis and cancer (2006)
  • Author(s): Hajime, Kubo
  • Organizer: Lymphology meeting
  • Place of Presentation: Tokyo
  • Year and Date: 2006-06-30
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] リンパ管新生とがん転移 (2006)
  • Author(s): 久保肇
  • Organizer: 第30回日本リンパ学会
  • Place of Presentation: 東京
  • Year and Date: 2006-06-01
  • Description: 「研究成果報告書概要(和文)」より