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Int J Biol Sci 2024; 20(7):2640-2657. doi:10.7150/ijbs.95595 This issue Cite

Research Paper

HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis

Jin-Rong Guo#, Kai-Yue He#, Jia-Li Yuan#, Wang An, Wei-Tao Yin, Qiu-Tong Li, Li-Yuan Lu, Jing-Yu Yang, Meng-Jie Liu, Yu-Jia Li, Yuan Zhao, Qi Yang, Xin-Yuan Lei, Fan Gao, Lei Zhang, Dan-Hui Wu, Jun-Qi Li, Zi-Long Zhao, Huai Liu, Ling-Jun Zhu, Xiong-Yan Xiang, Qian-Hui Sun, Yong-Ping Jian✉, Zhi-Xiang Xu✉

School of Life Sciences, Henan University, Kaifeng, Henan Province, China.
# These authors contributed equally.

✉ Corresponding authors: Zhi-Xiang Xu (zhixiangxu08com) or Yong-Ping Jian (yongpingjian123com).

Citation:
Guo JR, He KY, Yuan JL, An W, Yin WT, Li QT, Lu LY, Yang JY, Liu MJ, Li YJ, Zhao Y, Yang Q, Lei XY, Gao F, Zhang L, Wu DH, Li JQ, Zhao ZL, Liu H, Zhu LJ, Xiang XY, Sun QH, Jian YP, Xu ZX. HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis. Int J Biol Sci 2024; 20(7):2640-2657. doi:10.7150/ijbs.95595. https://www.ijbs.com/v20p2640.htm
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Abstract

Graphic abstract

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

Keywords: ESCC, HMGA1, FKBP12, ETS1, mTOR inhibitor, Rapamycin, resistance

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APA
Guo, J.R., He, K.Y., Yuan, J.L., An, W., Yin, W.T., Li, Q.T., Lu, L.Y., Yang, J.Y., Liu, M.J., Li, Y.J., Zhao, Y., Yang, Q., Lei, X.Y., Gao, F., Zhang, L., Wu, D.H., Li, J.Q., Zhao, Z.L., Liu, H., Zhu, L.J., Xiang, X.Y., Sun, Q.H., Jian, Y.P., Xu, Z.X. (2024). HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis. International Journal of Biological Sciences, 20(7), 2640-2657. https://doi.org/10.7150/ijbs.95595.

ACS
Guo, J.R.; He, K.Y.; Yuan, J.L.; An, W.; Yin, W.T.; Li, Q.T.; Lu, L.Y.; Yang, J.Y.; Liu, M.J.; Li, Y.J.; Zhao, Y.; Yang, Q.; Lei, X.Y.; Gao, F.; Zhang, L.; Wu, D.H.; Li, J.Q.; Zhao, Z.L.; Liu, H.; Zhu, L.J.; Xiang, X.Y.; Sun, Q.H.; Jian, Y.P.; Xu, Z.X. HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis. Int. J. Biol. Sci. 2024, 20 (7), 2640-2657. DOI: 10.7150/ijbs.95595.

NLM
Guo JR, He KY, Yuan JL, An W, Yin WT, Li QT, Lu LY, Yang JY, Liu MJ, Li YJ, Zhao Y, Yang Q, Lei XY, Gao F, Zhang L, Wu DH, Li JQ, Zhao ZL, Liu H, Zhu LJ, Xiang XY, Sun QH, Jian YP, Xu ZX. HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis. Int J Biol Sci 2024; 20(7):2640-2657. doi:10.7150/ijbs.95595. https://www.ijbs.com/v20p2640.htm

CSE
Guo JR, He KY, Yuan JL, An W, Yin WT, Li QT, Lu LY, Yang JY, Liu MJ, Li YJ, Zhao Y, Yang Q, Lei XY, Gao F, Zhang L, Wu DH, Li JQ, Zhao ZL, Liu H, Zhu LJ, Xiang XY, Sun QH, Jian YP, Xu ZX. 2024. HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis. Int J Biol Sci. 20(7):2640-2657.

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