Decreased activity of PP6 phosphatase is a switch in oncogenesis-mouse carcinogenesis experiment

• Project/Area Number: 21K15425
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Miyagi Prefectural Hospital Organization Miyagi Cancer Center
• Principal Investigator: Kanazawa Kousuke 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), がん薬物療法研究部, 共同研究員 (60898279)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2022: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2021: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 舌癌 / マウス発がん実験 / PP6 / KRAS / マウス膵癌モデル / 悪液質 / がん抑制遺伝子 / 膵癌 / Kras

Outline of Research at the Start

申請者らは、PP6ホスファターゼ(PP6)が変異型KRASの腫瘍形成能を抑える機能をもつことを、マウス皮膚・頭頸部発がん実験で明らかにしてきた。難治がんである膵臓がん（膵管腺がん/PDAC）は90%以上がKRAS変異をもつ。本研究は、PP6が膵臓がんにおいても、変異型KRAS依存性の腫瘍形成を抑える機能があるかを検証する研究である。それが同定された場合、PP6がKRAS依存性膵臓がん発症を抑える機構解明を行う。

Outline of Final Research Achievements

Here, we report that Ppp6c loss in pancreas of cKP (K-rasG12D + Trp53-deficient) mice promotes death from cancer within 150 days of induction of the mutation. Ppp6c-deficient mice showed accelerated cancer development and progression, and wasting with cachexia. We conclude that Ppp6c is a novel pancreatic tumor suppressor gene. To the best of our knowledge, ours is the first demonstration that a serine/threonine phosphatase functions as a tumor suppressor gene in mouse pancreatic carcinogenesis. Phenotypes seen in cKP(F/F) mice at the 80 day time point included weight loss, low serum albumin, muscle atrophy, loss of adipose tissue, and increased levels of inflammatory cytokines in serum, which is indicative of cachexia. High serum IL-6 levels also likely account for reduction in muscle and adipose tissue in these mice, as has been reported. cKP(F/F) mice exhibited symptoms of cachexia similar to those seen in human pancreatic cancer.

Academic Significance and Societal Importance of the Research Achievements

膵がんは、初期にKRAS変異が起こり、次にp53の遺伝子異常が起こり、引き続いていくつかの遺伝子異常が重なることで発症すると考えられている。一方で、KRAS変異やp53異常は、それを標的とする治療薬がないのが治療上の課題となっている。
本研究により（１）膵がんの新規抑制遺伝子としてPP6を同定した。（２）悪液質を呈するヒトの膵癌の発生のモデルとなるマウスを作製した。(３)本マウスを用いて、新規の治療法のスクリーニングをすることが可能となった。（４）NFkBの阻害剤、ERKの阻害剤、およびPP6の活性化剤が、新しい治療法になる可能性を提示した。

Research Products

• [Journal Article] PP6 deficiency in mice with KRAS mutation and Trp53 loss promotes early death by PDAC with cachexia-like features. (2022)
  • Author(s): Fukui K, Nomura M, Kishimoto K, Tanuma N, Kurosawa K, Kanazawa K, Kato H, Sato T, Miura S, Miura K, Sato I, Tsuji H, Yamashita Y, Tamai K, Watanabe T, Yasuda J, Tanaka T, Satoh K, Furukawa T, Jingu K, Shima H.
  • Journal Title: Cancer Sci. Volume: 印刷中 Issue: 5 Pages: 1613-1624
  • DOI: 10.1111/cas.15315
  • Peer Reviewed / Open Access
• [Journal Article] Ppp6c haploinsufficiency accelerates UV-induced BRAF(V600E)-initiated melanomagenesis. (2021)
  • Author(s): Kanazawa K, Kishimoto K, Nomura M, Kurosawa K, Kato H, Inoue Y, Miura K, Fukui K, Yamashita Y, Sato I, Tsuji H, Watanabe T, Tanaka T, Yasuda J, Tanuma N, Shima H
  • Journal Title: Cancer Sci. Volume: in press Issue: 6 Pages: 2233-2244
  • DOI: 10.1111/cas.14895
  • Peer Reviewed / Open Access
• [Journal Article] Ppp6c deficiency accelerates K-rasG12D -induced tongue carcinogenesis. (2021)
  • Author(s): Kishimoto K, Kanazawa K, Nomura M, Tanaka T, Shigemoto-Kuroda T, Fukui K, Miura K, Kurosawa K, Kawai M, Kato H, Terasaki K, Sakamoto Y, Yamashita Y, Sato I, Tanuma N, Tamai K, Kitabayashi I, Matsuura K, Watanabe T, Yasuda J, Tsuji H, Shima H.
  • Journal Title: Cancer Med. Volume: 10(13) Issue: 13 Pages: 4451-4464
  • DOI: 10.1002/cam4.3962
  • Peer Reviewed / Open Access