دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis.
المؤلفون: Guo JR; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., He KY; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Yuan JL; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., An W; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Yin WT; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Li QT; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Lu LY; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Yang JY; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Liu MJ; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Li YJ; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Zhao Y; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Yang Q; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Lei XY; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Gao F; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Zhang L; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Wu DH; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Li JQ; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Zhao ZL; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Liu H; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Zhu LJ; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Xiang XY; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Sun QH; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Jian YP; School of Life Sciences, Henan University, Kaifeng, Henan Province, China., Xu ZX; School of Life Sciences, Henan University, Kaifeng, Henan Province, China.
المصدر: International journal of biological sciences [Int J Biol Sci] 2024 Apr 22; Vol. 20 (7), pp. 2640-2657. Date of Electronic Publication: 2024 Apr 22 (Print Publication: 2024).
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Ivyspring International Country of Publication: Australia NLM ID: 101235568 Publication Model: eCollection Cited Medium: Internet ISSN: 1449-2288 (Electronic) Linking ISSN: 14492288 NLM ISO Abbreviation: Int J Biol Sci Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Lake Haven, N.S.W., Australia : Ivyspring International, c2004-
مواضيع طبية MeSH: Esophageal Neoplasms*/metabolism , Esophageal Neoplasms*/drug therapy , Esophageal Neoplasms*/genetics , Esophageal Squamous Cell Carcinoma*/metabolism , Esophageal Squamous Cell Carcinoma*/drug therapy , Esophageal Squamous Cell Carcinoma*/genetics , Esophageal Squamous Cell Carcinoma*/pathology , HMGA1a Protein*/metabolism , HMGA1a Protein*/genetics , MTOR Inhibitors*/pharmacology , MTOR Inhibitors*/therapeutic use , Proto-Oncogene Protein c-ets-1*/metabolism , Proto-Oncogene Protein c-ets-1*/genetics , Tacrolimus Binding Protein 1A*/metabolism , Tacrolimus Binding Protein 1A*/genetics, Animals ; Humans ; Mice ; Cell Line, Tumor ; Mice, Nude ; Signal Transduction/drug effects ; Sirolimus/pharmacology ; Sirolimus/therapeutic use ; TOR Serine-Threonine Kinases/metabolism
مستخلص: 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.
Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
(© The author(s).)
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فهرسة مساهمة: Keywords: ESCC; ETS1; FKBP12; HMGA1; Rapamycin; mTOR inhibitor; resistance
المشرفين على المادة: 0 (ETS1 protein, human)
0 (HMGA1 protein, human)
124544-67-8 (HMGA1a Protein)
0 (MTOR Inhibitors)
EC 2.7.1.1 (MTOR protein, human)
0 (Proto-Oncogene Protein c-ets-1)
W36ZG6FT64 (Sirolimus)
EC 5.2.1.- (Tacrolimus Binding Protein 1A)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
تواريخ الأحداث: Date Created: 20240510 Date Completed: 20240510 Latest Revision: 20240613
رمز التحديث: 20240613
مُعرف محوري في PubMed: PMC11077367
DOI: 10.7150/ijbs.95595
PMID: 38725843
قاعدة البيانات: MEDLINE
الوصف
تدمد:1449-2288
DOI:10.7150/ijbs.95595