Dopamine Receptor D5 Facilitates Esophageal Cancer Progress Via Enhancing Warburg Effect Of Tumor Cells

Background:Gastrointestinal tumors are of high incidence rate and malignancy.Among them,esophageal cancer is usually difficult for diagnosis in early stage due to the lack of typical symptoms and perform lymphatic metastasis which leads to poor prognosis.Tumors are systemic disease with the destroy of homeostasis and dysfunction involved in whole body.The microenvironment involved in this progress is recognized as tumor microenvironment(TME).Considering that many studies have reported the close relationship between nerve system and cancers and tumor associated neurotransmitters are detected in TME,we find them obliged to be investigated.Methods:We set off from exploring the key molecular involved in EC progress via performing RNAseq analysis on EC tumor tissues from patients with(MT)or without(T)lymphatic metastasis compare with normal esophageal tissues(N).The expression of synthesis and degeneration enzymes in dopamine pathway was also measured for seeking the reason of tumor derived neurotransmitter accumulation.In the following-up,IHC-P,IF and real-time PCR were also performed to figure out the aberrant upregulated dopamine related receptors and CCK-8 assay was used to evaluate the alteration of proliferation ability of tumor cells affected by dopamine pathway.We also measured key enzymes involved in glycolysis and performing Seahorse assay to assess the effects dopamine pathway exerted on Warburg Effects.At last,we performed in vivo imaging and subcutaneous injection mouse model to measure lymphatic metastasis and in vivo proliferation ability.Results:Results have unveiled that dopamine accumulation has been detected in tumor tissues and a significant elevation could be detect in MT compared to N,which indicate the vital role dopamine played in metastatic EC progress.Further studies have pointed out the overexpression of dopamine synthesis enzymes and deficit of degeneration enzyme in EC cells.What’s more,dopamine receptor D5 was also found overexpressed in EC tissues and promotes the proliferation and survival ability both in vivo and in vitro.Further studies have revealed that the aberrantly activated dopamine pathway has facilitated the expression level of metabolism enzymes,glucose consumption,lactate production and extracellular acid rate of tumor cells.Mechanism studies have demonstrated that Warburg Effect was modulated by the cross-talk of mTOR and AKT signal pathway.Conclusions:Taken together,we have discovered the abnormality of dopamine pathway which could lead to Warburg Effect in EC thus facilitating its progress from clinical phenomena.These findings could provide potential therapeutic targets and clinical strategy in store.