2. Academic Validation
  3. Kremen2 drives the progression of non-small cell lung cancer by preventing SOCS3-mediated degradation of EGFR

Kremen2 drives the progression of non-small cell lung cancer by preventing SOCS3-mediated degradation of EGFR

  • J Exp Clin Cancer Res. 2023 Jun 3;42(1):140. doi: 10.1186/s13046-023-02692-3.
Yuxiao Sun 1,  Yu Gao 1,  Mingxin Dong 1,  Jiuzhen Li 2 3,  Xin Li 2 3,  Ningning He 1,  Huijuan Song 1,  Manman Zhang 1,  Kaihua Ji 1,  Jinhan Wang 1,  Yeqing Gu 1,  Yan Wang 1,  Liqing Du 1,  Yang Liu 1,  Qin Wang 1,  Hezheng Zhai 1 4,  Daqiang Sun 5 6,  Qiang Liu 7,  Chang Xu 8
Affiliations

Affiliations

  • 1 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300192, China.
  • 2 Graduate School, Tianjin Medical University, Tianjin, 300070, China.
  • 3 Department of Thoracic Surgery, Tianjin Chest Hospital of Tianjin University, Tianjin, 300222, China.
  • 4 School of Precision Instruments and OPTO-Electronics Engineering, Tianjin University, Tianjin, 300072, China.
  • 5 Graduate School, Tianjin Medical University, Tianjin, 300070, China. sdqmd@163.com.
  • 6 Department of Thoracic Surgery, Tianjin Chest Hospital of Tianjin University, Tianjin, 300222, China. sdqmd@163.com.
  • 7 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300192, China. liuqiang@irm-cams.ac.cn.
  • 8 Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300192, China. xuchang@irm-cams.ac.cn.
PMID: 37270563 DOI: 10.1186/s13046-023-02692-3
Abstract

Background: The transmembrane receptor Kremen2 has been reported to participate in the tumorigenesis and metastasis of gastric Cancer. However, the role of Kremen2 in non-small cell lung Cancer (NSCLC) and the underlying mechanism remain unclear. This study aimed to explore the biological function and regulatory mechanism of Kremen2 in NSCLC.

Methods: The correlation between Kremen2 expression and NSCLC was assessed by analyzing the public database and clinical tissue samples. Colony formation and EdU assays were performed to examine cell proliferation. Transwell and wound healing assays were used to observe cell migration ability. Tumor-bearing nude mice and metastatic tumor models were used to detect the in vivo tumorigenic and metastatic abilities of the NSCLC cells. An immunohistochemical assay was used to detect the expression of proliferation-related proteins in tissues. Western blot, immunoprecipitation and immunofluorescence were conducted to elucidate the Kremen2 regulatory mechanisms in NSCLC.

Results: Kremen2 was highly expressed in tumor tissues from NSCLC patients and was positively correlated with a poor patient prognosis. Knockout or knockdown of Kremen2 inhibited cell proliferation and migration ability of NSCLC cells. In vivo knockdown of Kremen2 inhibited the tumorigenicity and number of metastatic nodules of NSCLC cells in nude mice. Mechanistically, Kremen2 interacted with suppressor of cytokine signaling 3 (SOCS3) to maintain the epidermal growth factor receptor (EGFR) protein levels by preventing SOCS3-mediated ubiquitination and degradation of EGFR, which, in turn, promoted activation of the PI3K-AKT and JAK2-STAT3 signaling pathways.

Conclusions: Our study identified Kremen2 as a candidate oncogene in NSCLC and may provide a potential target for NSCLC treatment.

Keywords

EGFR; Kremen2; Non-small cell lung cancer; SOCS3; Ubiquitination.

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