PMID- 35252056
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220502
IS  - 2253-5969 (Print)
IS  - 2253-5969 (Electronic)
IS  - 2253-5969 (Linking)
VI  - 9
DP  - 2022
TI  - MicroRNA-128-3p Mediates Lenvatinib Resistance of Hepatocellular Carcinoma Cells 
      by Downregulating c-Met.
PG  - 113-126
LID - 10.2147/JHC.S349369 [doi]
AB  - OBJECTIVE: Lenvatinib is a first-line multikinase inhibitor for advanced 
      hepatocellular carcinoma (HCC), but resistance to the drug remains a major hurdle 
      for its long-term anti-cancer activity. This resistance is thought to be due to 
      overexpression of c-Met. This study aims to identify potential upstream microRNAs 
      (miRNAs) that regulate c-Met, investigate the underlying mechanisms, and seek 
      potential strategies that may reverse such resistance. METHODS: 
      Lenvatinib-resistant HCC (LR-HCC) cells were established from human HCC Huh7 and 
      SMMC-7721 cells. Assays of cell proliferation, cell cycle distribution, 
      apoptosis, RT-qPCR, Western blot analysis and immunohistochemistry were employed. 
      Potential miRNAs were screened by miRNA-target prediction tools and their 
      regulatory effects were evaluated by luciferase reporter assays. Xenograft tumor 
      models were used to evaluate the therapeutic effects. RESULTS: LR-HCC cells were 
      refractory to lenvatinib-induced growth inhibition and apoptosis in vitro and in 
      vivo. Sustained exposure of cells to lenvatinib resulted in increased expression 
      and phosphorylation of c-Met, and c-Met inhibition enhanced the effects of 
      lenvatinib in suppressing LR-HCC cells. Among eleven miRNA candidates, miR-128-3p 
      displayed the most vigorous activity to negatively regulate c-Met and was 
      downregulated in LR-HCC cells. MiR-128-3p mimics inhibited proliferation and 
      induced apoptosis of LR-HCC cells, and enhanced the effects of lenvatinib in cell 
      culture and animal models. MiR-128-3p and c-Met participate in the mechanisms 
      underlying lenvatinib resistance through regulating Akt that mediates the 
      apoptotic pathway and ERK (extracellular-signal-regulated kinase) modulating cell 
      cycle progression. CONCLUSION: The present results indicate that the 
      miR-128-3p/c-Met axis may be potential therapeutic targets for circumventing 
      lenvatinib resistance in HCC and warrant further investigation.
CI  - (c) 2022 Xu et al.
FAU - Xu, Xin
AU  - Xu X
AD  - Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical 
      University, Harbin, 150001, People's Republic of China.
AD  - Department of General Surgery, Daqing Oil Field General Hospital, Daqing, 163000, 
      People's Republic of China.
FAU - Jiang, Wenjing
AU  - Jiang W
AD  - Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical 
      University, Harbin, 150001, People's Republic of China.
FAU - Han, Peng
AU  - Han P
AD  - Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical 
      University, Harbin, 150001, People's Republic of China.
FAU - Zhang, Jingyan
AU  - Zhang J
AD  - Department of General Surgery, The Fifth Affiliated Hospital of Harbin Medical 
      University, Daqing, 163316, People's Republic of China.
FAU - Tong, Liquan
AU  - Tong L
AUID- ORCID: 0000-0002-1970-6674
AD  - Department of General Surgery, The Fifth Affiliated Hospital of Harbin Medical 
      University, Daqing, 163316, People's Republic of China.
FAU - Sun, Xueying
AU  - Sun X
AUID- ORCID: 0000-0002-8065-8747
AD  - Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical 
      University, Harbin, 150001, People's Republic of China.
LA  - eng
PT  - Journal Article
DEP - 20220227
PL  - New Zealand
TA  - J Hepatocell Carcinoma
JT  - Journal of hepatocellular carcinoma
JID - 101674775
PMC - PMC8894104
OTO - NOTNLM
OT  - c-Met
OT  - drug resistance
OT  - hepatocellular carcinoma
OT  - lenvatinib
OT  - microRNA-128-3p
COIS- The authors report no conflicts of interest in this work.
EDAT- 2022/03/08 06:00
MHDA- 2022/03/08 06:01
PMCR- 2022/02/27
CRDT- 2022/03/07 06:07
PHST- 2021/11/17 00:00 [received]
PHST- 2022/02/12 00:00 [accepted]
PHST- 2022/03/07 06:07 [entrez]
PHST- 2022/03/08 06:00 [pubmed]
PHST- 2022/03/08 06:01 [medline]
PHST- 2022/02/27 00:00 [pmc-release]
AID - 349369 [pii]
AID - 10.2147/JHC.S349369 [doi]
PST - epublish
SO  - J Hepatocell Carcinoma. 2022 Feb 27;9:113-126. doi: 10.2147/JHC.S349369. 
      eCollection 2022.