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Dopamine Pathway Mediated by DRD5 Facilitates Tumor Growth via Enhancing Warburg Effect in Esophageal Cancer.

ABSTRACT: Esophageal cancer (EC) is among the most malignant cancers globally due to its aggressiveness and poor survival. To set off from the inflammatory tumor immune microenvironment, we analyzed tumor tissues of EC patients with or without lymphatic metastasis to explore the importance of cancer cell derived neurotransmitters. Results have emphasized that the accumulation of dopamine but not other neurotransmitters could be observed in EC tumor tissue of patients, especially those who are bearing lymphatic metastasis. Transcriptional analysis of mentioned tissues was also performed to filter out key enzymes involved in dopamine pathway including tyrosine hydroxylase (TH), DOPA decarboxylase (DCC), monoamine oxidase (MAO), etc. Further analysis on tumor tissues of patients indicated that dopamine receptor D5 was aberrantly upregulated and co-located with TH. Both in vitro and in vivo tests have demonstrated that dopamine could stimulate the proliferation and outgrowth of EC tumor cells via the DRD5 mediated pathway. The exploration of mechanism has unveiled that activation of the dopamine pathway significantly enhanced the uptake of glucose and production of lactate of EC tumor cells. It can also facilitate the extracellular acid rate (ECAR), dedicating that DRD5-mediated activated dopamine pathway could effectively form and trigger Warburg effect, which is modulated by the cross-talk of mTOR and AKT pathway. Our results would unveil the relationship between cancer derived neurotransmitters and inflammatory tumor immune microenvironment, thus provide potential therapeutic targets and novel clinical strategy towards metastatic EC.

SUBMITTER: Qian X

PROVIDER: S-EPMC8061419 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common aggressive tumors in the world. m6A modification has been implicated to play an important role in many biological progressions. METTL3 as the main methyltransferase has been found in many cancers, including ESCC. Here, we investigated the underlying mechanism of METTL3 in the development of ESCC. Methods: Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) and western blot were used to detect METTL3 expression. To evaluate the function of METTL3, MTS, colony formation, scratch wound healing assay, and transwell and invasion assays were performed. To find out the downstream target of METTL3, mRNA sequencing (mRNA-seq) was conducted. GO and KEGG functional enrichment analyses were carried out to predict possible biological processes and signaling pathways. qRT-PCR and western blot were performed to identify the expression of COL12A1 and the phosphorylation status of RAF, MRK and ERK. Cotransfection of small interfering RNA (for METTL3 silence) with plasmid (for overexpression of COL12A1) and the following gain- and loss-of-function experiments were performed to detect the target gene function of COL12A1 in progression of ESCC mediated by METTL3. Results: Using TCGA database, higher METTL3 expression was found in ESCC tissues. Moreover, we found that METTL3 was significantly increased in ESCC patient tissues compared with normal tissues and correlated with poor prognosis. The expression of METTL3 in ESCC cell lines was assessed. The gain- and loss-of-function indicates that METTL3 promotes cell proliferation, migration and invasion. Additionally, we confirmed that METTL3 can promote the expression of COL12A1 and upregulate the phosphorylation of RAF, MER and ERK, and moreover COL12A1 can restrain siMETTL3-mediated inhibition of proliferation, migration and invasion in ESCC. Conclusion: Our study revealed that METTL3 may have an oncogenic role, facilitating the ESCC progression and metastasis by COL12A1/MAPK signaling pathway.

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Dopamine Pathway Mediated by DRD5 Facilitates Tumor Growth via Enhancing Warburg Effect in Esophageal Cancer.

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