The Study Of The Effects And Mechanisms Of HPIP Protein On Gastric Carcinoma

The mortality rate of gastric cancer(GC)is among the top three of the most common cancers.The main therapies for GC therapy include surgery,radiotherapy and chemotherapy.However,even with triple therapy,the prognosis of patients with advanced GC is still poor.Therefore,elucidating the pathogenesis of GC is crucial for the development of new diagnostic and therapeutic strategies for this disease.Cap-dependent translation can regulate the process of cell proliferation,survival,metastasis and angiogenesis by enhancing the translation initiation of many carcinogenic mRNAs,which in turn influence the occurrence and development of tumors.The cap-dependent translational rate-limiting factor eIF4E is over-expressed in gastric cancer tissues and it was found that silencing eIF4E can inhibit GC cell proliferation.Studies have shown that the AKT/mTORC1 pathway is often activated in GC and GC progression is closely related.In GC tissues,the expression of Hematopoietic PBX Interacting Protein(HPIP)was significantly up-regulated compared with the observed adjacent normal tissues,and was positively correlated with tumor size and metastasis,but how was HPIP?It is still not clear how these enhancements will be made.Since the AKT/mTORCl signaling pathway plays an important role in regulating phosphorylation of 4E-BP1,we hypothesized that HPIP may increase GC cell proliferation by activating cap-dependent translation.To verify the above assumptions,we designed a series of experiments:First,we used a bicistronic luciferase reporter system that can monitor the cap-dependent(renilla luciferase)and non-hat-dependent(firefly luciferase)translation initiation to detect the control and HPIP-overexpressing cells.Cap-dependent translation rate.The results showed that cap-dependent translation was significantly enhanced in GC cells overexpressing HPIP.In addition,the AKT signaling pathway in HPIP-overexpressing cells was significantly activated,and the expression of cap-dependent translation-related proteins was significantly increased,indicating that HPIP can activate cap-dependent translation through the AKT/mTORC1 signaling pathway.Second,we need to prove whether HPIP needs to promote GC cell proliferation through cap-dependent translation.The results showed that the expression level of cyclin D1,the proportion of cells in S phase,and the activity of cells in HPIP overexpressed cells were all increased.However,treatment with 4EGI-1,an eIF4E/eIF4G selective interaction inhibitor,eliminated the effect of HPIP on the proportion of cyclin D1,S phase cells and cell proliferation.This indicates that HPIP can enhance GC cell proliferation by activating cap-dependent translation.Finally,we demonstrated that inhibiting the function of HPIP can inhibit GC cell proliferation and tumor growth in xenograft mice.The results showed that HPIP overexpression significantly promoted tumor growth in nude mice;4EGI-1 treatment inhibited HPIP function and inhibited tumor growth.In addition,Cyclin D1 expression was increased in HPIP-overexpressed nude mouse tumors,but this effect of HPIP was reversed by 4EGI-1.These results indicate that HPIP promotes GC cell proliferation by activating cap-dependent translation in vivo.In summary,we have found that HPIP activates cap-dependent translation in a manner that activates the AKT/mTORC1 signaling pathway.In addition,we demonstrated that inhibiting the activity of the eIF4F complex abolished the ability of HPIP to enhance GC cell proliferation in mouse models in vitro and in xenografts,while silencing 4E-BP1 expression enhanced the activity of the eIF4F complex,which in turn reversed knockdown.HPIP inhibition of GC cells.Our study showed that HPIP promotes GC cell proliferation by enhancing cap-dependent translation.