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Metabolomic Analysis Reveals that SPHK1 Promotes Oral Squamous Cell Carcinoma Progression through NF-κB Activation

  • Translational Research
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Metabolic disorders are significant in the occurrence and development of malignant tumors. Changes of specific metabolites and metabolic pathways are molecular therapeutic targets. This study aims to determine the metabolic differences between oral squamous cell carcinoma (OSCC) tissues and paired adjacent noncancerous tissues (ANT) through liquid chromatography-mass spectrometry (LC-MS). SPHK1 is a key enzyme in sphingolipid metabolism. This study also investigates the potential role of SPHK1 in OSCC.

Materials and Methods

This study used LC-MS to analyze metabolic differences between OSCC tissues and paired ANT. Principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) were applied to explain the significance of phospholipid metabolism pathways in the occurrence and development of OSCC. Through further experiments, we confirmed the oncogenic phenotypes of SPHK1 in vitro and in vivo, including proliferation, migration, and invasion.

Results

The sphingolipid metabolic pathway was significantly activated in OSCC, and the key enzyme SPHK1 was significantly upregulated in oral cancer tissues, predicting poor OSCC prognosis. In this study, SPHK1 overexpression was associated with high-grade malignancy and poor OSCC prognosis. SPHK1 targeted NF-κB by facilitating p65 expression to regulate OSCC tumor progression and promote metastasis.

Conclusions

This study identified metabolic differences between OSCC and paired ANT, explored the carcinogenic role of overexpressed SPHK1, and revealed the association of SPHK1 with poor OSCC prognosis. SPHK1 targets NF-κB signaling by facilitating p65 expression to regulate tumor progression and promote tumor metastasis, providing potential therapeutic targets for diagnosing and treating oral tumors.

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Availability of Data and Materials

All data generated or analyzed during this study are included in this published article.

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Acknowledgement

The authors thank Dr. Wei Zhang and Prof. Xiao-Ling Song for their excellent pathological technical support. This research was funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions: PAPD, 2018-87; Jiangsu Provincial Medical Key Talent Project: ZDRCA2016087; Southeast University-Nanjing Medical University Cooperative Research Project: 2017DN03.\

Author information

Author notes

  1. Chen-xing Hou, Guang-yan Mao and Qiu-wangyue Sun contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Key Laboratory of Oral Disease, & Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China

    Chen-xing Hou MD, Guang-yan Mao MD, Qiu-wangyue Sun MD, Ying Meng MD, Qing-hai Zhu MD, Yu-ting Tang MD, Wei Han MD, Nan-nan Sun MD, Xiao-meng Song MD, PhD, Chen-xing Wang MD, PhD & Jin-hai Ye MD, PhD

  2. Depatment of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China

    Chen-xing Hou MD, Ying Meng MD, Qing-hai Zhu MD, Yu-ting Tang MD, Wei Han MD, Nan-nan Sun MD, Xiao-meng Song MD, PhD, Chen-xing Wang MD, PhD & Jin-hai Ye MD, PhD

  3. Department of Stomatology, School of Medicine, Nanjing Tongren Hospital, Southeast University, Nanjing, China

    Guang-yan Mao MD

  4. Department of Stomatology, Affiliated Huaian Number 1 People’s Hospital of Nanjing Medical University, Huai’an, China

    Qiu-wangyue Sun MD

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  1. Chen-xing Hou MD
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Corresponding authors

Correspondence to Chen-xing Wang MD, PhD or Jin-hai Ye MD, PhD.

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Ethics Approval

The study was approved by the Research Ethics Committee of Nanjing Medical University, China.

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Supplementary Information

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10434_2022_12098_MOESM1_ESM.docx

Supplementary Fig. 1. (A) Statistics of SPHK1 positive areas in different clinical stages; (B, C) TUNEL staining for apoptosis analysis of cells (DOCX 17 KB)

Supplementary Fig. 2 (A, B) immunofluorescence expression of E-cadherin and vimentin in Cal 27 cells (TIF 14768 KB)

10434_2022_12098_MOESM3_ESM.tif

Supplementary Fig. 3. (A) total and phosphorylated p65 levels in HN6 cells; (B, C) QNZ treatment significantly reduced the enhanced proliferation ability of cells caused by SPHK1 overexpressed; (D, E, F) QNZ significantly inhibited the migration and invasion in HN6 cells (TIF 10924 KB)

10434_2022_12098_MOESM4_ESM.tif

Supplementary Fig. 4. (A) Total and phosphorylated p65 levels in mouse xenograft specimens; (B–D) statistics of the invasion and migration ability of Cal 27 cells after QNZ intervention (TIF 5157 KB)

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Hou, Cx., Mao, Gy., Sun, Qw. et al. Metabolomic Analysis Reveals that SPHK1 Promotes Oral Squamous Cell Carcinoma Progression through NF-κB Activation. Ann Surg Oncol 29, 7386–7399 (2022). https://doi.org/10.1245/s10434-022-12098-8

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  • DOI: https://doi.org/10.1245/s10434-022-12098-8

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