PMID- 37381714
OWN - NLM
STAT- MEDLINE
DCOM- 20230908
LR  - 20240102
IS  - 2095-3941 (Print)
IS  - 2095-3941 (Linking)
VI  - 20
IP  - 8
DP  - 2023 Jun 27
TI  - Nuclear PLD1 combined with NPM1 induces gemcitabine resistance through 
      tumorigenic IL7R in pancreatic adenocarcinoma.
PG  - 599-626
LID - j.issn.2095-3941.2023.0039 [pii]
LID - 10.20892/j.issn.2095-3941.2023.0039 [doi]
AB  - OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant 
      gastrointestinal cancer with a 5-year survival rate of only 9%. Of PDAC patients, 
      15%-20% are eligible for radical surgery. Gemcitabine is an important 
      chemotherapeutic agent for patients with PDAC; however, the efficacy of 
      gemcitabine is limited due to resistance. Therefore, reducing gemcitabine 
      resistance is essential for improving survival of patients with PDAC. Identifying 
      the key target that determines gemcitabine resistance in PDAC and reversing 
      gemcitabine resistance using target inhibitors in combination with gemcitabine 
      are crucial steps in the quest to improve survival prognosis in patients with 
      PDAC. METHODS: We constructed a human genome-wide CRISPRa/dCas 9 overexpression 
      library in PDAC cell lines to screen key targets of drug resistance based on 
      sgRNA abundance and enrichment. Then, co-IP, ChIP, ChIP-seq, transcriptome 
      sequencing, and qPCR were used to determine the specific mechanism by which 
      phospholipase D1 (PLD1) confers resistance to gemcitabine. RESULTS: PLD1 combines 
      with nucleophosmin 1 (NPM1) and triggers NPM1 nuclear translocation, where NPM1 
      acts as a transcription factor to upregulate interleukin 7 receptor (IL7R) 
      expression. Upon interleukin 7 (IL-7) binding, IL7R activates the JAK1/STAT5 
      signaling pathway to increase the expression of the anti-apoptotic protein, 
      BCL-2, and induce gemcitabine resistance. The PLD1 inhibitor, Vu0155069, targets 
      PLD1 to induce apoptosis in gemcitabine-resistant PDAC cells. CONCLUSIONS: PLD1 
      is an enzyme that has a critical role in PDAC-associated gemcitabine resistance 
      through a non-enzymatic interaction with NPM1, further promoting the downstream 
      JAK1/STAT5/Bcl-2 pathway. Inhibiting any of the participants of this pathway can 
      increase gemcitabine sensitivity.
CI  - Copyright (c) 2023 Cancer Biology & Medicine.
FAU - Fu, Danqi
AU  - Fu D
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Yan, Jingrui
AU  - Yan J
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Zhang, Zhaoyu
AU  - Zhang Z
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Liu, Yang
AU  - Liu Y
AD  - Department of General Surgery, Changzheng Hospital, Naval Medical University 
      (Second Military Medical University), Shanghai 200003, China.
FAU - Ma, Xiaoqing
AU  - Ma X
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Ding, Jinsheng
AU  - Ding J
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Yang, Shengyu
AU  - Yang S
AD  - Department of Cellular and Molecular Physiology, Penn State College of Medicine, 
      Hershey, Pennsylvania 17033, USA.
FAU - Zhao, Ran
AU  - Zhao R
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Chang, Antao
AU  - Chang A
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Gao, Chuntao
AU  - Gao C
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Liu, Jing
AU  - Liu J
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Zhao, Tiansuo
AU  - Zhao T
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Wang, Xiuchao
AU  - Wang X
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Huang, Chongbiao
AU  - Huang C
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Gao, Song
AU  - Gao S
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Ma, Ying
AU  - Ma Y
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Tang, Bo
AU  - Tang B
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Feng, Yukuan
AU  - Feng Y
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Wang, Hongwei
AU  - Wang H
AUID- ORCID: 0000-0001-8198-0677
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
FAU - Hao, Jihui
AU  - Hao J
AUID- ORCID: 0000-0002-1607-1730
AD  - Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and 
      Hospital, National Clinical Research Centre for Cancer, Key Laboratory of Cancer 
      Prevention and Therapy, Tianjin 300060, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - China
TA  - Cancer Biol Med
JT  - Cancer biology & medicine
JID - 101588850
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0W860991D6 (Deoxycytidine)
RN  - 0 (Gemcitabine)
RN  - 0 (IL7R protein, human)
RN  - 0 (Nuclear Proteins)
RN  - EC 3.1.4.4 (phospholipase D1)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Receptors, Interleukin-7)
RN  - 0 (RNA, Guide, CRISPR-Cas Systems)
RN  - 0 (STAT5 Transcription Factor)
RN  - 0 (NPM1 protein, human)
SB  - IM
MH  - Humans
MH  - *Adenocarcinoma/drug therapy/genetics
MH  - Antimetabolites, Antineoplastic/pharmacology/therapeutic use
MH  - *Carcinoma, Pancreatic Ductal/drug therapy/genetics/pathology
MH  - Deoxycytidine/pharmacology/therapeutic use
MH  - Drug Resistance, Neoplasm/genetics
MH  - Gemcitabine
MH  - Nuclear Proteins/genetics/metabolism
MH  - *Pancreatic Neoplasms/drug therapy/genetics
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - Receptors, Interleukin-7/metabolism
MH  - RNA, Guide, CRISPR-Cas Systems
MH  - STAT5 Transcription Factor/metabolism/pharmacology
PMC - PMC10476466
OTO - NOTNLM
OT  - CRISPRa library
OT  - Gemcitabine resistance
OT  - nucleophosmin 1
OT  - pancreatic ductal adenocarcinoma
OT  - phospholipase D1
COIS- No potential conflicts of interest are disclosed.
EDAT- 2023/06/29 06:43
MHDA- 2023/09/05 06:42
PMCR- 2023/08/15
CRDT- 2023/06/29 03:18
PHST- 2023/09/05 06:42 [medline]
PHST- 2023/06/29 06:43 [pubmed]
PHST- 2023/06/29 03:18 [entrez]
PHST- 2023/08/15 00:00 [pmc-release]
AID - j.issn.2095-3941.2023.0039 [pii]
AID - 10.20892/j.issn.2095-3941.2023.0039 [doi]
PST - ppublish
SO  - Cancer Biol Med. 2023 Jun 27;20(8):599-626. doi: 
      10.20892/j.issn.2095-3941.2023.0039.