Impacts of circLRP6 on cisplatin resistance to esophageal squamous cell carcinoma by regulating miR⁃125a⁃5p/MCL1 axis
Received date: 2022-12-22
Online published: 2023-09-27
目的 探讨环状RNA脂蛋白受体6（circLRP6）对食管鳞癌（ESCC）顺铂（CDDP）耐药性的影响及潜在分子机制。 方法 建立KYSE30的CDDP抗性细胞株（KYSE30/CDDP-R），分为对照（Control）组、si-NC组、si-circLRP6组、si-circLRP6+anti-NC组、si-circLRP6+anti-miR-125a-5p组。采用RT-qPCR和Western blot检测组织/细胞中circLRP6、miR-125a-5p和髓样细胞白血病-1（MCL-1）的表达水平；CCK-8法检测KYSE30/CDDP-R细胞的CDDP敏感性；流式细胞术检测细胞凋亡。 结果 ESCC癌组织/细胞和CDDP耐药癌组织中circLRP6、MCL-1 mRNA水平升高，miR-125a-5p水平降低（P < 0.001）；circLRP6沉默可上调miR-125a-5p，抑制MCL-1表达，增强体内外CDDP抗性ESCC细胞对CDDP的敏感性，促进CDDP抗性ESCC细胞凋亡；抑制miR-125a-5p可减弱circLRP6沉默对CDDP抗性ESCC细胞中CDDP耐药性和细胞凋亡的影响。circLRP6可靶向负调控miR-125a-5p表达，MCL-1是miR-125a-5p的靶标。 结论 circLRP6沉默可能通过miR-125a-5p/MCL-1轴增强CDDP抗性ESCC细胞对CDDP的敏感性。
关键词： 环状RNA脂蛋白受体6; 食管鳞癌; 顺铂耐药; miR-125a-5p/MCL-1轴
林萍萍 , 李富博 , 王东娟 , 郭研 , 董怡 . CircLRP6调节miR-125a-5p/MCL1轴对食管鳞癌顺铂耐药性的影响[J]. 实用医学杂志, 2023 , 39(17) : 2183 -2189 . DOI: 10.3969/j.issn.1006-5725.2023.17.006
Objective To investigate the impacts of circular RNA lipoprotein receptor 6 （circLRP6） on cisplatin （CDDP） resistance to esophageal squamous cell carcinoma （ESCC） and its relevant potential molecular mechanism. Methods CDDP?resistant cell lines of KYSE30 （KYSE30/CDDP?R） were established and divided into a control group， si?NC group， si?circLRP6 group， si?circLRP6 plus anti?NC group， and si?circLRP6 plus anti?miR?125a?5p group. The expression levels of circLRP6， miR?125a?5p and myeloid leukemia?1 （MCL?1） in tissues/cells were detected by RT?qPCR and Western blot. CCK?8 assay was applied to detect the CDDP sensitivity of KYSE30/CDDP?R cells， so was flow cytometry to detect apoptosis. Results mRNA levels of circLRP6 and MCL?1 were increased， while level of miR?125a?5p was decreased in ESCC cancer tissues/cells and CDDP?resistant cancer tissues （P < 0.001）. CircLRP6 silencing was able to up?regulate miR?125a?5p， inhibit the expression of MCL?1， enhance the sensitivity of CDDP?resistant ESCC cells to CDDP in vitro and in vivo， and promote the apoptosis of CDDP?resistant ESCC cells. Inhibition of miR?125a?5p weakened the effects of circLRP6 silencing on CDDP resistance and apoptosis in CDDP?resistant ESCC cells （P < 0.05）. circLRP6 could target and negatively regulate the expression of miR?125a?5p， and MCL?1 was the target of miR?125a?5p. Conclusion CircLRP6 silencing may enhance the sensitivity of CDDP?resistant ESCC cells to CDDP through the miR?125a?5p/MCL?1 axis.
| 1 | 王静， 杨雅阁， 郑晓永， 等. 安罗替尼单药在晚期食管鳞癌患者后线治疗中的疗效及安全性［J］. 实用医学杂志， 2022， 38（7）：893-899. |
| 2 | ZHOU T， FU H， DONG B， et al. HOXB7 mediates cisplatin resistance in esophageal squamous cell carcinoma through involvement of DNA damage repair［J］. Thorac Cancer， 2020， 11（11）：3071-3085. |
| 3 | YAJIMA S， SUZUKI T， NANAMI T， et al. Randomized phase II study to comparing docetaxel/nedaplatin versus docetaxel for 5-fluorouracil/cisplatin resistant esophageal squamous cell carcinoma［J］. Ann Thorac Cardiovasc Surg， 2021， 27（4）：219-224. |
| 4 | MU Q， LV Y， LUO C， et al. Research progress on the functions and mechanism of circRNA in cisplatin resistance in tumors［J］. Front Pharmacol， 2021， 12：709324. |
| 5 | WANG J， ZHU W， TAO G， et al. Circular RNA circ-LRP6 facilitates Myc-driven tumorigenesis in esophageal squamous cell cancer［J］. Bioengineered， 2020， 11（1）：932-938. |
| 6 | XU Y， ZHENG Y， DUAN Y， et al. MicroRNA-125a-5p targets LIM kinase 1 to inhibit cisplatin resistance of cervical cancer cells［J］. Oncol Lett， 2021， 21（5）：392. |
| 7 | LIU X， ZHAO T， YUAN Z， et al. MIR600HG sponges miR-125a-5p to regulate glycometabolism and cisplatin resistance of oral squamous cell carcinoma cells via mediating RNF44［J］. Cell Death Discov， 2022， 8（1）：216. |
| 8 | ZHAO Y， MA K， YANG S， et al. MicroRNA-125a-5p enhances the sensitivity of esophageal squamous cell carcinoma cells to cisplatin by suppressing the activation of the STAT3 signaling pathway［J］. Int J Oncol， 2018， 53（2）：644-658. |
| 9 | QI Y， DING Z， YAO Y， et al. Apigenin induces apoptosis and counteracts cisplatin-induced chemoresistance via Mcl-1 in ovarian cancer cells［J］. Exp Ther Med， 2020， 20（2）：1329-1336. |
| 10 | MICHELS J， OBRIST F， VITALE I， et al. MCL-1 dependency of cisplatin-resistant cancer cells［J］. Biochem Pharmacol， 2014， 92（1）：55-61. |
| 11 | YU X， LI W， XIA Z， et al. Targeting MCL-1 sensitizes human esophageal squamous cell carcinoma cells to cisplatin-induced apoptosis［J］. BMC Cancer， 2017， 17（1）：449-461. |
| 12 | JIA Y， TIAN C， WANG H， et al. Long non-coding RNA NORAD/miR-224-3p/MTDH axis contributes to CDDP resistance of esophageal squamous cell carcinoma by promoting nuclear accumulation of β-catenin［J］. Mol Cancer， 2021， 20（1）：162. |
| 13 | WANG Y， MO Y， PENG M， et al. The influence of circular RNAs on autophagy and disease progression［J］. Autophagy， 2022， 18（2）：240-253. |
| 14 | YU Y， DONG G， LI Z， et al. Circ-LRP6 contributes to osteosarcoma progression by regulating the miR-141-3p/HDAC4/HMGB1 axis［J］. Int J Oncol， 2022， 60（4）：38. |
| 15 | MISIR S， WU N， YANG B B. Specific expression and functions of circular RNAs［J］. Cell Death Differ， 2022， 29（3）：481-491. |
| 16 | CHANG N， GE N， ZHAO Y， et al. Hsa_circ_0007142 contributes to cisplatin resistance in esophageal squamous cell carcinoma via miR-494-3p/LASP1 axis［J］. J Clin Lab Anal， 2022， 36（5）：e24304. |
| 17 | TANG Y， YANG P， ZHU Y， et al. LncRNA TUG1 contributes to ESCC progression via regulating miR-148a-3p/MCL-1/Wnt/β- catenin axis in vitro［J］. Thorac Cancer， 2020， 11（1）：82-94. |
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