Thoracic Cancer (Sep 2022)

Downregulation of fibulin‐4 inhibits autophagy and promotes the sensitivity of esophageal squamous cell carcinoma cells to apatinib by activating the Akt‐mTOR signaling pathway

  • Xiangyu Chen,
  • Jianyu Wang,
  • Liang Song,
  • Yang Yu,
  • Mo Shi,
  • Wenpeng Jiang,
  • Xiangyan Liu,
  • Xiaopeng He

DOI
https://doi.org/10.1111/1759-7714.14595
Journal volume & issue
Vol. 13, no. 18
pp. 2592 – 2605

Abstract

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Abstract Background Fibulin‐4, namely, EFEMP2, is an essential matricellular protein associated with a variety of malignancies. The aim of this study was to explore the role of fibulin‐4 in the progression of esophageal squamous cell carcinoma (ESCC), as well as its effect on ESCC sensitivity to apatinib treatment. Methods The expression of fibulin‐4 in ESCC tissues and cell lines was detected. Stably transfected ESCC cells were established by transducing lentiviral vectors for silencing or overexpressing the fibulin‐4 gene into ESCC cells, and a subcutaneous xenograft tumor model of ESCC in mice was successfully established. IHC, RT–qPCR and western blotting were used to detect the expression of related genes and proteins. The CCK8 assay, EdU cell proliferation assay, wound healing assay, transwell assay and flow cytometry were used to evaluate the proliferation, invasion, migration and apoptosis of ESCC cells. After mice were sacrificed, the transplanted tumors were resected, and their volumes were measured. Results The expression of fibulin‐4 was significantly increased in both ESCC tissues and cell lines, and the high expression was closely related to the poor clinicopathological features. Downregulation of fibulin‐4 inhibited the proliferation, invasion and migration of ESCC cells in vitro and in vivo. Meanwhile, fibulin‐4 knockdown inhibited autophagy of tumor cells by activating the Akt–mTOR signaling pathway and significantly promoted apatinib‐induced apoptosis of ESCC cells. Conclusion Our study showed that fibulin‐4 is an oncogene that can promote ESCC progression and inhibit apoptosis. Downregulation of fibulin‐4 enhances the sensitivity of ESCC cells to apatinib by inhibiting cellular protective autophagy through activating the Akt–mTOR signaling pathway.

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