PMID- 31497348
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20211211
IS  - 2156-6976 (Print)
IS  - 2156-6976 (Electronic)
IS  - 2156-6976 (Linking)
VI  - 9
IP  - 8
DP  - 2019
TI  - LKB1 deficiency promotes proliferation and invasion of glioblastoma through 
      activation of mTOR and focal adhesion kinase signaling pathways.
PG  - 1650-1663
AB  - Liver kinase B1 (LKB1), a serine/threonine kinase, is frequently inactivated in 
      several types of human cancers. To date, inactivation of LKB1 tumor suppressor 
      has rarely been reported in glioblastoma. In this study, we investigated LKB1 
      status, biological significance, and therapeutic implications in glioblastoma. 
      Loss of LKB1 immunostaining was identified in 8.6% (5/58), while decrease of LKB1 
      immunostaining was found in 29.3% (17/58) of glioblastoma tissues. Notably, 
      mining TCGA database of LKB1 expression in glioblastoma revealed that lower mRNA 
      level of LKB1 was associated with shorter survival in glioblastoma. We found that 
      knockdown of LKB1 significantly promoted in vitro proliferation, adhesion, 
      invasion, and metformin-induced apoptosis, and simultaneously enhanced activation 
      of ERK and mammalian-target of rapamycin (mTOR) signaling pathways in 
      LKB1-compenent U87 and T98 glioblastoma cells. Moreover, global transcriptional 
      profiling revealed that adhesion and cytoskeletal proteins such as Vinculin, 
      Talin and signaling pathways including focal adhesion kinase (FAK), extracellular 
      martrix (ECM) receptor interaction, and cellular motility were significantly 
      enriched in U87 and T98 glioblastoma cells upon LKB1 knockdown. Additionally, we 
      demonstrated that the enhanced activation of FAK by LKB1 knockdown was dependent 
      on differentially expressed cytoskeletal proteins in these glioblastoma cells. 
      Importantly, we further found that mTOR1 inhibitor rapamycin dominantly inhibited 
      in vitro cellular proliferation, while FAK inhibitor PF-573288 drastically 
      decreased invasion of LKB1-attenuated glioblastoma cells. Therefore, 
      downregulation of LKB1 may contribute to the pathogenesis and malignancy of 
      glioblastoma and may have potential implications for stratification and treatment 
      of glioblastoma patients.
FAU - Zhang, Keqiang
AU  - Zhang K
AD  - Department of Surgery, City of Hope National Medical Center Duarte, CA, USA.
FAU - Wang, Jinghan
AU  - Wang J
AD  - The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital 
      Shanghai, China.
FAU - Wang, Jinhui
AU  - Wang J
AD  - The Integrative Genomics Core Lab, City of Hope National Medical Center Duarte, 
      CA, USA.
FAU - Luh, Frank
AU  - Luh F
AD  - Sino-American Cancer Foundation Temple City, CA, USA.
FAU - Liu, Xiyong
AU  - Liu X
AD  - Sino-American Cancer Foundation Temple City, CA, USA.
FAU - Yang, Lu
AU  - Yang L
AD  - Department of System Biology, City of Hope National Medical Center Duarte, CA, 
      USA.
FAU - Liu, Yun-Ru
AU  - Liu YR
AD  - Comprehensive Cancer Center, Taipei Medical University Taipei, Taiwan.
FAU - Su, Leila
AU  - Su L
AD  - Sino-American Cancer Foundation Temple City, CA, USA.
FAU - Yang, Yu-Chen Sh
AU  - Yang YS
AD  - PhD Program of Cancer Biology and Drug Discovery, College of Medical Science and 
      Technology, Taipei Medical University Taipei, Taiwan.
FAU - Chu, Peiguo
AU  - Chu P
AD  - Department of Pathology, City of Hope National Medical Center Duarte, CA, USA.
FAU - Yen, Yun
AU  - Yen Y
AD  - Comprehensive Cancer Center, Taipei Medical University Taipei, Taiwan.
AD  - PhD Program of Cancer Biology and Drug Discovery, College of Medical Science and 
      Technology, Taipei Medical University Taipei, Taiwan.
AD  - Research Center of Cancer Translational Medicine, Taipei Medical University 
      Taipei, Taiwan.
AD  - Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical 
      University Taipei, Taiwan.
LA  - eng
GR  - P30 CA033572/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20190801
PL  - United States
TA  - Am J Cancer Res
JT  - American journal of cancer research
JID - 101549944
PMC - PMC6726989
OTO - NOTNLM
OT  - Glioblastoma
OT  - LKB1
OT  - cytoskeletal proteins
OT  - focal adhesion kinase
OT  - mTOR
COIS- None.
EDAT- 2019/09/10 06:00
MHDA- 2019/09/10 06:01
PMCR- 2019/08/01
CRDT- 2019/09/10 06:00
PHST- 2019/05/30 00:00 [received]
PHST- 2019/07/28 00:00 [accepted]
PHST- 2019/09/10 06:00 [entrez]
PHST- 2019/09/10 06:00 [pubmed]
PHST- 2019/09/10 06:01 [medline]
PHST- 2019/08/01 00:00 [pmc-release]
PST - epublish
SO  - Am J Cancer Res. 2019 Aug 1;9(8):1650-1663. eCollection 2019.