PMID- 29228674
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20191120
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 8
IP  - 58
DP  - 2017 Nov 17
TI  - The regulatory role of aberrant Phosphatase and Tensin Homologue and Liver Kinase 
      B1 on AKT/mTOR/c-Myc axis in pancreatic neuroendocrine tumors.
PG  - 98068-98083
LID - 10.18632/oncotarget.20956 [doi]
AB  - Pancreatic neuroendocrine tumor (pNET) is an uncommon type of pancreatic 
      neoplasm. Low Phosphatase and Tensin Homologue (PTEN) expression and activation 
      of the mechanistic target of rapamycin (mTOR) pathway have been noted in pNETs, 
      and the former is associated with poor survival in pNET patients. Based on the 
      results of the RADIANT-3 study, everolimus, an oral mTOR inhibitor, has been 
      approved to treat advanced pNETs. However, the exact regulatory mechanism for the 
      mTOR pathway in pNETs remains largely unknown. PTEN and liver kinase B1 (LKB1) 
      are well-known for their regulatory role in the mTOR pathway. We evaluated the 
      expression of PTEN and LKB1 in 21 pNET patients, and low PTEN and LKB1 expression 
      levels were noted in 48% and 24% of the patients, respectively. Loss of PTEN and 
      LKB1 synergistically promoted cell proliferation of pNET, attenuated the 
      sensitivity of cells to mTOR inhibitors and enhanced c-Myc expression, which 
      back-regulated PTEN, AKT, mTOR and its downstream effectors. For pNET cells with 
      low expression levels of PTEN and LKB1, silencing the expression of c-Myc by 
      shRNA reduced their proliferative rate, while adding either c-Myc inhibitor or 
      AMP-activated protein kinase activator reversed their resistance to mTOR 
      inhibitors in vitro and in vivo. Furthermore, high c-Myc expression was 
      subsequently identified in 81% of pNETs, suggesting that up-regulation of c-Myc 
      expression in pNETs may occur through PTEN/LKB1-dependent and 
      PTEN/LKB1-independent regulation. The results delineated the regulation of PTEN 
      and LKB1 on the AKT/mTOR/c-Myc axis and suggested that both c-Myc and mTOR are 
      potential therapeutic targets for pNET.
FAU - Chang, Tsung-Ming
AU  - Chang TM
AD  - National Institute of Cancer Research, National Health Research Institutes, 
      Tainan, Taiwan.
FAU - Shan, Yan-Shen
AU  - Shan YS
AD  - Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan.
AD  - Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan.
FAU - Chu, Pei-Yi
AU  - Chu PY
AD  - Department of Pathology, Show Chwan Memorial Hospital, Changhua, Taiwan.
AD  - National Institute of Cancer Research, National Health Research Institutes, 
      Tainan, Taiwan.
AD  - School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei 
      City, Taiwan.
FAU - Jiang, Shih Sheng
AU  - Jiang SS
AD  - National Institute of Cancer Research, National Health Research Institutes, 
      Tainan, Taiwan.
FAU - Hung, Wen-Chun
AU  - Hung WC
AD  - National Institute of Cancer Research, National Health Research Institutes, 
      Tainan, Taiwan.
FAU - Chen, Yu-Lin
AU  - Chen YL
AD  - National Institute of Cancer Research, National Health Research Institutes, 
      Tainan, Taiwan.
FAU - Tu, Hsiu-Chi
AU  - Tu HC
AD  - National Institute of Cancer Research, National Health Research Institutes, 
      Tainan, Taiwan.
FAU - Lin, Hui-You
AU  - Lin HY
AD  - National Institute of Cancer Research, National Health Research Institutes, 
      Tainan, Taiwan.
FAU - Tsai, Hui-Jen
AU  - Tsai HJ
AD  - National Institute of Cancer Research, National Health Research Institutes, 
      Tainan, Taiwan.
AD  - Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, 
      Taiwan.
AD  - Department of Internal Medicine, Kaohsiung Medical University Hospital, 
      Kaohsiung, Taiwan.
FAU - Chen, Li-Tzong
AU  - Chen LT
AD  - National Institute of Cancer Research, National Health Research Institutes, 
      Tainan, Taiwan.
AD  - Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, 
      Taiwan.
AD  - Department of Internal Medicine, Kaohsiung Medical University Hospital, 
      Kaohsiung, Taiwan.
AD  - Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan.
LA  - eng
PT  - Journal Article
DEP - 20170916
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
PMC - PMC5716714
OTO - NOTNLM
OT  - LKB1
OT  - PTEN
OT  - c-Myc
OT  - mTOR
OT  - pancreatic neuroendocrine tumor
COIS- CONFLICTS OF INTEREST The authors declare no competing financial interests.
EDAT- 2017/12/13 06:00
MHDA- 2017/12/13 06:01
PMCR- 2017/11/17
CRDT- 2017/12/13 06:00
PHST- 2017/06/15 00:00 [received]
PHST- 2017/09/03 00:00 [accepted]
PHST- 2017/12/13 06:00 [entrez]
PHST- 2017/12/13 06:00 [pubmed]
PHST- 2017/12/13 06:01 [medline]
PHST- 2017/11/17 00:00 [pmc-release]
AID - 20956 [pii]
AID - 10.18632/oncotarget.20956 [doi]
PST - epublish
SO  - Oncotarget. 2017 Sep 16;8(58):98068-98083. doi: 10.18632/oncotarget.20956. 
      eCollection 2017 Nov 17.