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SHMT2 promotes tumor growth through VEGF and MAPK signaling pathway in breast cancer.

ABSTRACT: Cancer cells modulate their metabolic activities to adapt to their growth and proliferation. Despite advances in breast cancer biology having led to the widespread use of molecular targeted therapy and hormonal drugs, the molecular mechanisms in metabolism related to the regulation of breast cancer cell proliferation are still poorly understood. Here, we investigate the possible role of SHMT2, a key enzyme in serine metabolism, in breast cancer. Firstly, SHMT2 is found highly expressed in both breast cancer cells and tissues, and patients with high expression of SHMT2 have a worse prognosis. Moreover, the intervention of SHMT2 by either knockdown or over-expression in vitro induces the effect on breast cancer proliferation. Mechanistically, RNA-seq shows that over-expression of SHMT2 affect multiple signaling pathways and biological process in breast cancer cells. Furthermore, we confirm that SHMT2 promotes breast cancer cell growth through MAPK and VEGF signaling pathways. Finally, we verify the role of SHMT2 in promoting breast cancer growth in the xenograft tumor model. Our results indicate that SHMT2 plays a critical role in regulating breast cancer growth through MAPK, and VEGF signaling pathways, and maybe serve as a therapeutic target for breast cancer therapy.

SUBMITTER: Xie SY

PROVIDER: S-EPMC9360240 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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SHMT2 promotes tumor growth through VEGF and MAPK signaling pathway in breast cancer.

Xie Shuang-Yan SY Shi Ding-Bo DB Ouyang Yi Y Lin Fei F Chen Xiao-Yu XY Jiang Tong-Chao TC Xia Wen W Guo Ling L Lin Huan-Xin HX

American journal of cancer research 20220715 7

Cancer cells modulate their metabolic activities to adapt to their growth and proliferation. Despite advances in breast cancer biology having led to the widespread use of molecular targeted therapy and hormonal drugs, the molecular mechanisms in metabolism related to the regulation of breast cancer cell proliferation are still poorly understood. Here, we investigate the possible role of SHMT2, a key enzyme in serine metabolism, in breast cancer. Firstly, SHMT2 is found highly expressed in both b ...[more]

PMID: 35968337

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Project description:BackgroundAngiogenesis strongly reflects poor breast cancer outcome and an important contributor to breast cancer (BC) metastasis; therefore, anti-angiogenic intervention is a potential tool for cancer treatment. However, currently used antibodies against vascular endothelial growth factor A (VEGFA) or inhibitors that target the VEGFA receptor are not effective due to weak penetration and low efficiency. Herein, we assessed the anti-BC angiogenic role of muscone, a natural bioactive musk constituent, and explored possible anti-cancer mechanisms of this compound.MethodsCCK-8, EdU, scratch and Transwell assessments were employed to detect the muscone-mediated regulation of breast cancer (BC) and human umbilical vein endothelial cells (HUVECs) proliferation and migration. Tube formation, matrigel plug assay and zebrafish assay were employed for assessment of regulation of tumor angiogenesis by muscone. In vivo xenograft mouse model was constructed to compare microvessel density (MVD), vascular leakage, vascular maturation and function in muscone-treated or untreated mice. RNA sequencing was performed for gene screening, and Western blot verified the effect of the VEGFA-VEGFR2 pathway on BC angiogenic inhibition by muscone.ResultsBased on our findings, muscone suppressed BC progression via tumor angiogenic inhibition in cellular and animal models. Functionally, muscone inhibited BC cell proliferation and migration as well as tumor cell-conditioned medium-based endothelial cell proliferation and migration. Muscone exhibited a strong suppressive influence on tumor vasculature in cellular and animal models. It abrogated tumor cell growth in a xenograft BC mouse model and minimized tumor microvessel density and hypoxia, and increased vascular wall cell coverage and perfusion. Regarding the mechanism of action, we found that muscone suppressed phosphorylation of members of the VEGF/PI3K/Akt/MAPK axis, and it worked synergistically with a VEGFR2 inhibitor, an Akt inhibitor, and a MAPK inhibitor to further inhibit tube formation.ConclusionOverall, our results demonstrate that muscone may proficiently suppress tumor angiogenesis via modulation of the VEGF/PI3K/Akt/MAPK axis, facilitating its candidacy as a natural small molecule drug for BC treatment.

Project description:BackgroundGlioma is the most frequent and lethal primary brain malignancy. Amounting evidence has highlighted the importance of exosomal microRNAs (miRNAs or miRs) in this malignancy. This study aimed to investigate the regulatory role of exosomal miR-148a-3p in glioma.MethodsBioinformatics analysis was firstly used to predict the target genes of miR-148a-3p. Exosomes were then extracted from normal human astrocytes and glioma cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was applied to determine the expression patterns of miR-148a-3p and ERBB receptor feedback inhibitor 1 (ERRFI1). Dual-luciferase reporter gene assay was applied to verify the direct binding between miR-148a-3p and ERRFI1. Cell counting kit-8 and tube formation assays were further conducted to assess the proliferation and angiogenic properties of human umbilical vein endothelial cells (HUVECs) in the co-culture system with exosomes. Lastly, glioma tumor models were established in BALB/c nude mice to study the role of exosomal miR-148a-3p in vivo.ResultsmiR-148a-3p was highly expressed, while ERRFI1 was poorly expressed in glioma. miR-148a-3p was found to be enriched in glioma cells-derived exosomes and could be transferred to HUVECs via exosomes to promote their proliferation and angiogenesis. ERRFI1 was identified as a target gene of miR-148a-3p. In addition, miR-148a-3p activated the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signaling pathway by inhibiting ERRFI1. In the co-culture system, our data demonstrated that glioma cells-derived exosomal miR-148a-3p down-regulated ERRFI1 and activated the EGFR/MAPK signaling pathway, so as to promote cell proliferation and angiogenesis. In vivo experimentation further demonstrated that this mechanism was responsible for the promotive role of exosomal miR-148a-3p in tumorigenesis and angiogenesis.ConclusionTaken together, glioma-derived exosomal miR-148a-3p promoted tumor angiogenesis through activation of the EGFR/MAPK signaling pathway by ERRFI1 inhibition.

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SHMT2 promotes tumor growth through VEGF and MAPK signaling pathway in breast cancer.

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SHMT2 promotes tumor growth through VEGF and MAPK signaling pathway in breast cancer.

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