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Src heterodimerically activates Lyn or Fyn to serve as targets for the diagnosis and treatment of esophageal squamous cell carcinoma

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Abstract

Although Src is one of the oldest and most investigated oncoproteins, its function in tumor malignancy remains to be defined further. In this study, we demonstrated that the inhibition of Src activity by ponatinib effectively suppressed several malignant phenotypes of esophageal squamous cell carcinoma (ESCC) both in vitro and in vivo, whereas it did not produce growth-inhibitory effects on normal esophageal epithelial cells (NEECs). Importantly, we combined phosphoproteomics and several cellular and molecular biologic strategies to identify that Src interacted with the members of Src-family kinases (SFKs), such as Fyn or Lyn, to form heterodimers. Src interactions with Fyn and Lyn phosphorylated the tyrosine sites in SH2 (Fyn Tyr185 or Lyn Tyr183) and kinase domains (Fyn Tyr420 or Lyn Tyr397), which critically contributed to ESCC development. By contrast, Src could not form heterodimers with Fyn or Lyn in NEECs. We used RNA sequencing to comprehensively demonstrate that the inhibition of Src activity effectively blocked several critical tumor-promoting pathways, such as JAK/STAT, mTOR, stemness-related, and metabolism-related pathways. Results of the real-time polymerase chain reaction (RT-PCR) assay confirmed that Lyn and Fyn were critical effectors for the Src-mediated expression of tumor growth or metastasis-related molecules. Furthermore, results of the clinical ESCC samples showed that the hyperactivation of pSrc Tyr419, Fyn Tyr185 or Tyr420, and Lyn Tyr183 or Tyr397 could be biomarkers of ESCC prognosis. This study illustrates that Src/Fyn and Src/Lyn heterodimers serve as targets for the treatment of ESCC.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81988101, 81830086 and 81972243), CAMS Innovation Fund for Medical Sciences (2019-I2M-5-081), Major Program of Shenzhen Bay Laboratory (S201101004), Guangdong Basic and Applied Basic Research Foundation (2019B030302012), the Fund of “San-ming” Project of Medicine in Shenzhen (SZSM201812088).

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Authors and Affiliations

  1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China

    Jing Zhang, Di Zhao, Lingyuan Zhang, Yuanfan Xiao, Qingnan Wu, Yan Wang, Jie Chen & Qimin Zhan

  2. Peking University International Cancer Institute, Peking University, Beijing, 100191, China

    Jing Zhang, Di Zhao, Lingyuan Zhang, Yuanfan Xiao, Qingnan Wu, Yan Wang, Jie Chen & Qimin Zhan

  3. Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100142, China

    Jing Zhang, Di Zhao, Lingyuan Zhang, Yuanfan Xiao, Qingnan Wu, Yan Wang, Jie Chen & Qimin Zhan

  4. Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518107, China

    Qimin Zhan

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  1. Jing Zhang
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  2. Di Zhao
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  3. Lingyuan Zhang
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  4. Yuanfan Xiao
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  6. Yan Wang
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Correspondence to Jie Chen or Qimin Zhan.

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Zhang, J., Zhao, D., Zhang, L. et al. Src heterodimerically activates Lyn or Fyn to serve as targets for the diagnosis and treatment of esophageal squamous cell carcinoma. Sci. China Life Sci. 66, 1245–1263 (2023). https://doi.org/10.1007/s11427-022-2216-x

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