Abstract
Multidrug resistance (MDR) significantly restricts the clinical efficacy of gastric cancer (GC) chemotherapy, and it is critical to search novel targets to predict and overcome MDR. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) has been proved to be correlated with drug resistance in several cancers. The present study revealed that LRIG1 was overexpressed in chemo-sensitive GC tissues and decreased expression of LRIG1 predicted poor survival in GC patients. We observed that up-regulation of LRIG1 enhanced chemo-sensitivity in GC cells. Interestingly, miR-20a, which was overexpressed in GC MDR cell lines and tissues, was identified to regulate LRIG1 expression by directly targeting its 3′untranslated region. We also found that inhibition of miR-20a suppressed GC MDR, and up-regulation showed opposite effects. Moreover, we demonstrated that the miR-20a/LRIG1 axis regulated GC cell MDR through EGFR mediated PI3K/AKT and MAPK/ERK signaling pathways. Finally, LRIG1 expression in human GC tissues is inversely correlated with miR-20a and EGFR. Taken together, the newly identified miR-20a/LRIG1/EGFR link provides insight into the MDR process of GC, and targeting this axis represents a novel potential therapeutic strategy to block GC chemo-resistance.
Abbreviations
- 5-FU
- 5-fluorouracil
- ABCB1
- ATP-binding cassette, sub-family B member 1
- ABCG2
- ATP-binding cassette, sub-family G, member2
- ADR
- adriamycin
- AKT
- protein kinase B
- CDDP
- cisplatin
- EGFR
- epidermal growth factor receptor
- ERK
- extracellular signal-regulated kinase
- GAPDH
- glyceraldehyde 3-phosphate dehydrogenase
- GC
- gastric cancer
- HER2
- human epidermal growth factor receptor 2
- IHC
- immunohistochemistry
- LRIG1
- leucine-rich repeats and immunoglobulin-like domains 1
- MAPK
- mitogen-activated protein kinase
- MDR
- multidrug resistance
- miR
- microRNA
- miRNA
- microRNA
- mRNA
- messenger RNA
- PI3K
- phosphatidylinositol 3 kinase
- qRT-PCR
- quantitative reverse transcription–polymerase chain reaction
- siRNA
- silencing RNA
- TNFα
- tumor necrosis factor α
- UTR
- untranslated region
- VCR
- vincristine