Mechanisms Of Cyclin D1 On The Regulation Of Proliferation Of Gastrointestinal Stromal Tumors With Loss Of Oncoprotein KIT Expression

Gastrointestinal stromal tumors(GIST)are the most common tumors of mesenchymal tissue in the digestive.Most of GISTs(85%)have a tyrosine kinase receptor(RTK)--KIT oncogene mutation,and others(5%-10%)have another RTK--PDGFRA oncogene mutation.Currently studies have demonstrated that constitutively activated mutant KIT and PDGFRA oncoproteins are molecular targets for the treatment of GIST.The first-line treatment used clinically is imatinib(IM),which is a small molecule inhibitor for KIT and PRKCQ specifically.Although most patients with GIST have a good clinical response at the beginning of treatment with IM,they gradually developing resistance to IM after 2-3 years.Studies have shown that 5%-10%of GIST resistance in the IM resistance mechanism appears to be the loss of KIT oncoprotein expression.However,no new carcinogenic mechanism has been found to replace KIT.Therefore,this research has carried on this situation.In the early stage of transcriptome sequencing,we found that CCND1 was significantly increased in GIST with loss of KIT expression,accompanied by down-regulation of PRKCQ and increased expression ofJUN,and the Hippo/YAP pathway was also activated.Moreover,inhibition of cyclin D1 expression has a significant inhibitory effect on cell growth.Therefore,we hypothesize that cyclin D1 is an important mediator in GIST with loss of KIT expression.PRKCQ?JUN and Hippo/YAP pathway the regulat the GIST's proliferation coordinately.This paper clarifies the unique biological mechanism of KIT-independent GIST by western,fluorescence in situ hybridization,cell growth,cell apoptosis,cell cycle,dual fluorescein plum viability assay,qRT-PCR,Co-IP and other experiments.providing new therapeutic targets for IM-resistant GIST.The results showed that compared with GIST which has high expression of KIT mutation,the expression of cyclin D1 was increased in GIST with loss of KIT expression,and inhibit cyclin D1 has anti-proliferative and pro-apoptotic effection.PRKCQ,JUN and Hippo signaling pathways coordinate the regulation of cyclin D1 expression,PRKCQ,but not KIT,positive regulation of cyclin D1,JUN and Hippo signaling pathway effector proteins YAP and TAZ are positive regulators of cyclin D1.This provides a new theoretical basis and treatment strategy for the clinical management and treatment of patients with GIST:Cyclin D1 can be a new target for the treatment of drug-resistant GIST with loss of KIT expression,and the combination of PRKCQ,JUN and Hippo/YAP pathways may be new strategies for the treatment of such GIST subtypes.