Emergence of anticancer drug resistance of ANXA1 for gastrointestinal tract cancers

• Project/Area Number: 19K09099
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Fukushima Medical University
• Principal Investigator: ONOZAWA Hisashi 福島県立医科大学, 医学部, 助教 (50622338)
• Co-Investigator(Kenkyū-buntansha): 齋藤 元伸 福島県立医科大学, 医学部, 講師 (90611749)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 消化器癌 / ANXA1 / 抗癌剤耐性 / 消化管癌 / 薬剤耐性 / 化学療法

Outline of Research at the Start

アネキシン遺伝子群の１つであるANXA1（アネキシンA1）を用いて、胃癌や大腸癌といった消化管癌に対する化学療法選択の最適化を目指す。ANXA1はCa2+/リン脂質結合タンパク質であり、胃癌・大腸癌切除検体におけるその発現と抗癌剤治療効果の検討、抗癌剤治療中の血中循環ANXA1濃度と治療効果の検討、ANXA1の抗癌剤に対する耐性の機序の解明を目的とする。

Outline of Final Research Achievements

The family of Annexin is Ca2+/phospholipid-binding proteins that corporates with p53 on cancer development, progression, and metastasis. We found that elevated expression of Annexin A1, one of the annexin gene family, confers resistance to anticancer drugs. Because Annexin A1 expression is induced by ARID1A gene truncating mutations in breast cancer, we investigated the expression of both Annexin A1 and ARID1A to confirm their correlations in gastrointestinal cancer cells (gastric cancer). In addition, we performed immunohistochemical staining for Annexin A1 and ARID1a in surgically resected gastric cancer specimens. However, no correlation between Annexin A1 and ARID1A expressions was observed in cell experiment and gastric cancer tumor.

Academic Significance and Societal Importance of the Research Achievements

アネキシンA１の高発現が抗癌剤耐性をもたらすことから、抗癌剤の治療を長く継続できるためにはアネキシンA1が発現誘導されないほうが良い。そのため、アネキシンA1の発現を誘導する上流の因子であるARID1Aとの関連の解明を試みた。その理由は、乳癌でARID1A遺伝子の失活型変異がアネキシンA1の発現を誘導するためである。胃癌細胞株でARID1Aをノックダウンすると、目的としたアネキシンA１は発現誘導されず、他のアネキシンA6などが発現誘導されていた。本研究ではアネキシンA1は抗癌剤の耐性に寄与するが、その経路を明らかにすることはできなかったので、さらなる検討が必要である。

Research Products

• [Journal Article] Long-term Outcomes of Lower Rectal Cancer Patients Treated with Total Mesorectal Excision and Lateral Pelvic Lymph Node Dissection after Preoperative Radiotherapy or Chemoradiotherapy (2021)
  • Author(s): Sakamoto Wataru、Ohki Shinji、Onozawa Hisashi、Okayama Hirokazu、Endo Hisahito、Fujita Shotaro、Saito Motonobu、Saze Zenichiro、Momma Tomoyuki、Takenoshita Seiichi、Kono Koji
  • Journal Title: Journal of the Anus, Rectum and Colon Volume: 5 Issue: 2 Pages: 129-136
  • DOI: 10.23922/jarc.2020-054
  • NAID: 130008031068
  • ISSN: 2432-3853
  • Year and Date: 2021-04-28
  • Peer Reviewed / Open Access
• [Journal Article] PD-L1 overexpression in EBV-positive gastric cancer is caused by unique genomic or epigenomic mechanisms (2021)
  • Author(s): Nakano Hiroshi、Saito Motonobu、Nakajima Shotaro、Saito Katsuharu、Nakayama Yuko、Kase Koji、Yamada Leo、Kanke Yasuyuki、Hanayama Hiroyuki、Onozawa Hisashi、Okayama Hirokazu、Fujita Shotaro、Sakamoto Wataru、Saze Zenichiro、Momma Tomoyuki、Mimura Kosaku、Ohki Shinji、Goto Akiteru、Kono Koji
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 1982-1982
  • DOI: 10.1038/s41598-021-81667-w
  • Peer Reviewed / Open Access
• [Journal Article] Downregulation of PAICS due to loss of chromosome 4q is associated with poor survival in stage III colorectal cancer (2021)
  • Author(s): Kobayashi Yusuke、Kumamoto Kensuke、Okayama Hirokazu、Matsumoto Takuro、Nakano Hiroshi、Saito Katsuharu、Matsumoto Yoshiko、Endo Eisei、Kanke Yasuyuki、Watanabe Yohei、Onozawa Hisashi、Fujita Shotaro、Sakamoto Wataru、Saito Motonobu、Momma Tomoyuki、Takenoshita Seiichi、Kono Koji
  • Journal Title: PLOS ONE Volume: 16 Issue: 2 Pages: e0247169-e0247169
  • DOI: 10.1371/journal.pone.0247169
  • Peer Reviewed / Open Access
• [Journal Article] Validation of Gene Expression-Based Predictive Biomarkers for Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer (2021)
  • Author(s): Momma Tomoyuki、Okayama Hirokazu、Kanke Yasuyuki、Fukai Satoshi、Onozawa Hisashi、Fujita Shotaro、Sakamoto Wataru、Saito Motonobu、Ohki Shinji、Kono Koji
  • Journal Title: Cancers Volume: 13 Issue: 18 Pages: 4642-4642
  • DOI: 10.3390/cancers13184642
  • Peer Reviewed / Open Access
• [Journal Article] The Expression of Immune Checkpoint Receptors and Ligands in the Colorectal Cancer Tumor Microenvironment (2021)
  • Author(s): NEUPANE PRAJWAL、MIMURA KOSAKU、NAKAJIMA SHOTARO、OKAYAMA HIROKAZU、ITO MISATO、THAR MIN AUNG KYI、SAITO KATSUHARU、ONOZAWA HISASHI、FUJITA SHOTARO、SAKAMOTO WATARU、SAITO MOTONOBU、SAZE ZENICHIRO、MOMMA TOMOYUKI、KONO KOJI
  • Journal Title: Anticancer Research Volume: 41 Issue: 10 Pages: 4895-4905
  • DOI: 10.21873/anticanres.15303
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] SH2D4A downregulation due to loss of chromosome 8p is associated with poor prognosis and low T cell infiltration in colorectal cancer (2021)
  • Author(s): Matsumoto Takuro、Okayama Hirokazu、Nakajima Shotaro、Saito Katsuharu、Ito Misato、Kaneta Akinao、Kanke Yasuyuki、Onozawa Hisashi、Hayase Suguru、Fujita Shotaro、Sakamoto Wataru、Saito Motonobu、Seze Zenichiro、Momma Tomoyuki、Mimura Kosaku、Kono Koji
  • Journal Title: British Journal of Cancer Volume: 126 Issue: 6 Pages: 917-926
  • DOI: 10.1038/s41416-021-01660-y
  • Peer Reviewed / Open Access
• [Journal Article] Selective sensitivity of EZH2 inhibitors based on synthetic lethality in ARID1A-deficient gastric cancer (2020)
  • Author(s): Yamada Leo、Saito Motonobu、Thar Min Aung Kyi、Saito Katsuharu、Ashizawa Mai、Kase Koji、Nakajima Shotaro、Onozawa Hisashi、Okayama Hirokazu、Endo Hisahito、Fujita Shotaro、Sakamoto Wataru、Saze Zenichiro、Momma Tomoyuki、Mimura Kosaku、Ohki Shinji、Kono Koji
  • Journal Title: Gastric Cancer Volume: 24 Issue: 1 Pages: 60-71
  • DOI: 10.1007/s10120-020-01094-0
  • NAID: 40022454373
  • Peer Reviewed / Open Access
• [Journal Article] ARID1A deficiency in EBV-positive gastric cancer is partially regulated by EBV-encoded miRNAs, but not by DNA promotor hypermethylation (2020)
  • Author(s): Kase Koji、Saito Motonobu、Nakajima Shotaro、Takayanagi Daisuke、Saito Katsuharu、Yamada Leo、Ashizawa Mai、Nakano Hiroshi、Hanayama Hiroyuki、Onozawa Hisashi、Kono Koji, et al.
  • Journal Title: Carcinogenesis Volume: 42 Issue: 1 Pages: 21-30
  • DOI: 10.1093/carcin/bgaa123
  • Peer Reviewed / Open Access
• [Journal Article] Explore the correlation between ARID1A and ANXA1 expressions in gastric cancer (2019)
  • Author(s): Leo Yamada, Motonobu Saito, Aung Kyi Thar Min, Katsuharu Saito, Koji Kase, Hisashi Onozawa, Hirokazu Okayama, Shotaro Fujita, Hisahito Endo, Wataru Sakamoto, Zenichiro Saze, Tomoyuki Momma, Shinji Ohki, Kosaku Mimura, Koji Kono
  • Journal Title: Ann. Cancer Res. Ther Volume: 27 Pages: 46-51
  • NAID: 130007739091
  • Peer Reviewed / Open Access