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한빛사논문
- 조회211
J. Biomed. Sci., May 19 2025, 32 (1) | https://doi.org/10.1186/s12929-025-01140-y
Gemcitabine resistance by CITED4 upregulation via the regulation of BIRC2 expression in pancreatic cancer
Eun‑Jeong Jeong1,3,5, Yuna Roh1,2, Eunsun Jung1, Jin‑Seong Hwang1,2, Taesang Son1,2, Hyun Seung Ban1,2, Tae‑Su Han1,2,4* , Young‑Kug Choo3* and Jang‑Seong Kim1,2*
1Biotherapeutics Translational Research Center, Division of Biomedical Science, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak‑Ro, Yuseong‑Gu, Daejeon 34141, Republic of Korea.
2University of Science and Technology (UST), Daejeon 34141, Republic of Korea.
3Department of Biological Science, College of Health Sciences, Wonkwang University, Iksan 54538, Republic of Korea.
4School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea.
5Department of Otorhinolaryngology, College of Medicine, Konyang University Hospital, Konyang University Myunggok Medical Research Institute, Daejeon 35365, Republic of Korea.
Corresponding authors
Correspondence to Tae-Su Han, Young-Kug Choo or Jang-Seong Kim.
1Biotherapeutics Translational Research Center, Division of Biomedical Science, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak‑Ro, Yuseong‑Gu, Daejeon 34141, Republic of Korea.
2University of Science and Technology (UST), Daejeon 34141, Republic of Korea.
3Department of Biological Science, College of Health Sciences, Wonkwang University, Iksan 54538, Republic of Korea.
4School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea.
5Department of Otorhinolaryngology, College of Medicine, Konyang University Hospital, Konyang University Myunggok Medical Research Institute, Daejeon 35365, Republic of Korea.
Corresponding authors
Correspondence to Tae-Su Han, Young-Kug Choo or Jang-Seong Kim.
Abstract
Background: Gemcitabine (GEM) is used as a first-line therapy for patients diagnosed with any stage of pancreatic cancer (PC); however, patient survival is poor because of GEM resistance. Thus, new approaches to overcome GEM resistance in PC are urgently needed. Here, we aimed to establish an in vivo drug-resistant PC model and identify genes involved in GEM resistance. We focused on one of these factors, CITED4, and elucidated its mechanisms of action in GEM resistance in PC.
Methods: L3.6pl, a GEM-sensitive PC cell line, was orthotopically injected into the pancreas of BALB/c nude mice to establish a GEM-resistant PC animal model. Transcriptomic data from control or GEM-resistant tumor-derived cells were analyzed. GEM resistance was evaluated using cell viability, clonogenicity, and apoptosis assays. An apoptosis array was used to identify genes downstream of CITED4. A CITED4 knockout-mediated GEM sensitivity assay was performed in an orthotopic xenograft mouse model using PANC-1 cells, which are GEM-resistant cells.
Results: From the RNA sequencing data of isolated GEM-resistant PC cells and The Cancer Genome Atlas dataset, 15 GEM resistance-related genes were found to be upregulated, including CITED4, the gene encoding a type of CBP/p300-interacting transactivator implicated in several cancers. CITED4 knockdown in drug-resistant cells reduced cell proliferation and migration but increased apoptosis. To identify the molecular mechanism underlying CITED4-mediated induction of GEM resistance, alterations in Baculoviral IAP Repeat Containing 2 (BIRC2) levels were observed using an apoptosis array. BIRC2 expression was downregulated following CITED4 knockdown in GEM-resistant PC cell lines. Furthermore, chromatin immunoprecipitation and promoter assays showed that BIRC2 was directly regulated by CITED4. Consistent with the CITED-knockdown experiments, silencing of BIRC2 increased the sensitivity of L3.6pl-GEM-resistant and PANC-1 cell lines to GEM. Furthermore, CITED4 knockout using the CRISPR-Cas9 system in PANC-1 cells increased the sensitivity to GEM in orthotopic mice. Moreover, elevated CITED4 and BIRC2 expression levels were associated with poorer outcomes in human PC clinical samples.
Conclusions: Collectively, these results indicate that CITED4 regulates GEM resistance via inhibition of apoptosis by upregulating BIRC2 expression in PC cells. Therefore, CITED4 may serve as a valuable diagnostic marker and therapeutic target for GEM-resistant PC.
Methods: L3.6pl, a GEM-sensitive PC cell line, was orthotopically injected into the pancreas of BALB/c nude mice to establish a GEM-resistant PC animal model. Transcriptomic data from control or GEM-resistant tumor-derived cells were analyzed. GEM resistance was evaluated using cell viability, clonogenicity, and apoptosis assays. An apoptosis array was used to identify genes downstream of CITED4. A CITED4 knockout-mediated GEM sensitivity assay was performed in an orthotopic xenograft mouse model using PANC-1 cells, which are GEM-resistant cells.
Results: From the RNA sequencing data of isolated GEM-resistant PC cells and The Cancer Genome Atlas dataset, 15 GEM resistance-related genes were found to be upregulated, including CITED4, the gene encoding a type of CBP/p300-interacting transactivator implicated in several cancers. CITED4 knockdown in drug-resistant cells reduced cell proliferation and migration but increased apoptosis. To identify the molecular mechanism underlying CITED4-mediated induction of GEM resistance, alterations in Baculoviral IAP Repeat Containing 2 (BIRC2) levels were observed using an apoptosis array. BIRC2 expression was downregulated following CITED4 knockdown in GEM-resistant PC cell lines. Furthermore, chromatin immunoprecipitation and promoter assays showed that BIRC2 was directly regulated by CITED4. Consistent with the CITED-knockdown experiments, silencing of BIRC2 increased the sensitivity of L3.6pl-GEM-resistant and PANC-1 cell lines to GEM. Furthermore, CITED4 knockout using the CRISPR-Cas9 system in PANC-1 cells increased the sensitivity to GEM in orthotopic mice. Moreover, elevated CITED4 and BIRC2 expression levels were associated with poorer outcomes in human PC clinical samples.
Conclusions: Collectively, these results indicate that CITED4 regulates GEM resistance via inhibition of apoptosis by upregulating BIRC2 expression in PC cells. Therefore, CITED4 may serve as a valuable diagnostic marker and therapeutic target for GEM-resistant PC.
논문정보
- Research article
- 2025년 05월 (BRIC 등록일 2025-05-20)
- 국내 연구진
- 의약학 > 종양의학
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