ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia

Lin, Tao-Yan1,2; Jia, Jun-Shuang1,3; Luo, Wei-Ren4; Lin, Xiao-Lin1,5; Xiao, Sheng-Jun6; Yang, Jie1,7; Xia, Jia-Wei8; Zhou, Chen6; Zhou, Zhi-Hao1; Lin, Shu-Jun1; Li, Qi-Wen1; Yang, Zhi-Zhi1; Lei, Ye1; Yang, Wen-Qing9; Shen, Hong-Fen1; Huang, Shi-Hao1; Wang, Sheng-Chun1,10; Chen, Lin-Bei9; Yang, Yu-Lin9; Xue, Shu-Wen1; Li, Yong-Long1; Dai, Guan-Qi1; Zhou, Ying1; Li, Ying-Chun1; Wei, Fang1; Rong, Xiao-Xiang11; Luo, Xiao-Jun5; Zhao, Bing-Xia1; Huang, Wen-Hua12,13,14; Xiao, Dong1,3,15,16,17; Sun, Yan1,3

2024-02-29

10.1186/s13046-024-02983-3

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH   影响因子和分区

1756-9966

BackgroundIn recent years, the development of adjunctive therapeutic hyperthermia for cancer therapy has received considerable attention. However, the mechanisms underlying hyperthermia resistance are still poorly understood. In this study, we investigated the roles of cold-inducible RNA binding protein (Cirbp) in regulating hyperthermia resistance and underlying mechanisms in nasopharyngeal carcinoma (NPC).MethodsCCK-8 assay, colony formation assay, tumor sphere formation assay, qRT-PCR, Western blot were employed to examine the effects of hyperthermia (HT), HT + oridonin(Ori) or HT + radiotherapy (RT) on the proliferation and stemness of NPC cells. RNA sequencing was applied to gain differentially expressed genes upon hyperthermia. Gain-of-function and loss-of-function experiments were used to evaluate the effects of RNAi-mediated Cirbp silencing or Cirbp overexpression on the sensitivity or resistance of NPC cells and cancer stem-like cells to hyperthermia by CCK-8 assay, colony formation assay, tumorsphere formation assay and apoptosis assay, and in subcutaneous xenograft animal model. miRNA transient transfection and luciferase reporter assay were used to demonstrate that Cirbp is a direct target of miR-377-3p. The phosphorylation levels of key members in ATM-Chk2 and ATR-Chk1 pathways were detected by Western blot.ResultsOur results firstly revealed that hyperthermia significantly attenuated the stemness of NPC cells, while combination treatment of hyperthermia and oridonin dramatically increased the killing effect on NPC cells and cancer stem cell (CSC)-like population. Moreover, hyperthermia substantially improved the sensitivity of radiation-resistant NPC cells and CSC-like cells to radiotherapy. Hyperthermia noticeably suppressed Cirbp expression in NPC cells and xenograft tumor tissues. Furthermore, Cirbp inhibition remarkably boosted anti-tumor-killing activity of hyperthermia against NPC cells and CSC-like cells, whereas ectopic expression of Cirbp compromised tumor-killing effect of hyperthermia on these cells, indicating that Cirbp overexpression induces hyperthermia resistance. ThermomiR-377-3p improved the sensitivity of NPC cells and CSC-like cells to hyperthermia in vitro by directly suppressing Cirbp expression. More importantly, our results displayed the significantly boosted sensitization of tumor xenografts to hyperthermia by Cirbp silencing in vivo, but ectopic expression of Cirbp almost completely counteracted hyperthermia-mediated tumor cell-killing effect against tumor xenografts in vivo. Mechanistically, Cirbp silencing-induced inhibition of DNA damage repair by inactivating ATM-Chk2 and ATR-Chk1 pathways, decrease in stemness and increase in cell death contributed to hyperthermic sensitization; conversely, Cirbp overexpression-induced promotion of DNA damage repair, increase in stemness and decrease in cell apoptosis contributed to hyperthermia resistance.ConclusionTaken together, these findings reveal a previously unrecognized role for Cirbp in positively regulating hyperthermia resistance and suggest that thermomiR-377-3p and its target gene Cirbp represent promising targets for therapeutic hyperthermia.

Hyperthermia Nasopharyngeal carcinoma (NPC) Cold-inducible RNA-binding protein (Cirbp) Temperature-sensitive miRNA-377-3p (termed thermomiR-377-3p) Cancer stem cells (CSCs) Chemotherapy Radiotherapy Therapy resistance DNA damage Apoptosis Thermosensitivity Near-infrared (NIR) laser

SCI

英语

其他

Oncology

Oncology

WOS:001177062700001

BMC

CLINICAL MEDICINE

Web of Science

1.Southern Med Univ, Canc Res Inst, Lab Anim Management Ctr, Sch Basic Med Sci, Guangzhou 510515, Peoples R China
2.Southern Med Univ, Nanfang Hosp, Dept Pharm, Guangzhou 510515, Peoples R China
3.Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Med Res Inst, Guangzhou 510080, Peoples R China
4.Southern Univ Sci & Technol, Affiliated Hosp 2, Shenzhen Peoples Hosp 3, Canc Res Inst, Shenzhen 518112, Peoples R China
5.Southern Med Univ, Integrated Hosp Tradit Chinese Med, Canc Ctr, Guangzhou 510315, Peoples R China
6.Guilin Med Univ, Affiliated Hosp 2, Dept Pathol, Guilin 541199, Peoples R China
7.Cent Hosp Shaoyang, Dept Imaging, Shaoyang 422000, Peoples R China
8.Dali Univ, Affiliated Hosp 6, Peoples Hosp Kunming 3, Kunming 650041, Peoples R China
9.Southern Med Univ, Sch Lab Med & Biotechnol, Guangzhou 510515, Peoples R China
10.Guangdong Med Univ, Sch Basic Med, Dept Pathol, Dongguan 523808, Peoples R China
11.Southern Med Univ, Nanfang Hosp, Dept Oncol, Guangzhou 510515, Peoples R China
12.Southern Med Univ, Guangdong Engn Res Ctr Translat Med Printing Appli, Sch Basic Med Sci, Guangdong Prov Key Lab Med Biomech,Natl Key Discip, Guangzhou 510515, Peoples R China
13.Southern Med Univ, Affiliated Hosp 3, Guangdong Med Innovat Platform Translat Printing A, Guangzhou 510000, Peoples R China
14.Guangdong Med Univ, Affiliated Hosp, Orthopaed Ctr, Zhanjiang 524001, Peoples R China
15.Guangzhou Southern Med Lab Anim Sci &Tech Co Ltd, Guangzhou 510515, Peoples R China
16.Southern Med Univ, Natl Demonstrat Ctr Expt Educ Basic Med Sci, Guangzhou 510515, Peoples R China
17.Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Dept Stomatol, Guangzhou 510080, Peoples R China

Lin, Tao-Yan,Jia, Jun-Shuang,Luo, Wei-Ren,et al. ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia[J]. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,2024,43(1).

Lin, Tao-Yan.,Jia, Jun-Shuang.,Luo, Wei-Ren.,Lin, Xiao-Lin.,Xiao, Sheng-Jun.,...&Sun, Yan.(2024).ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia.JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,43(1).

Lin, Tao-Yan,et al."ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia".JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 43.1(2024).