Exosomal Mir-210-3p Promotes Chemoresistance and Stem Cell Properties in Cervical Cancer by Targeting FBXO31
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摘要:
目的 探讨外泌体中的microRNA（miRNA）miR-210-3p在宫颈癌（cervical cancer，CC）化疗耐药及干细胞特性形成中的作用，并揭示其靶向F-盒蛋白31（F-box protein 31，FBXO31）蛋白的潜在机制。 方法 以顺铂敏感Hela细胞和顺铂耐药HeLa/DDP细胞为对象，通过超速离心法提取HeLa外泌体，并通过PKH26红色荧光探针验证HeLa/DDP细胞对外泌体的摄取。将NC inhibitor、miR-210-3p inhibitor单独或联合si-NC、si-FBXO31转入HeLa细胞。转染24 h后，提取外泌体，并与HeLa/DDP细胞共培养48 h。然后将HeLa/DDP细胞分为五组：Ctrl组（PBS空白对照）、NC inhibitor组、miR-210-3p inhibitor组、miR-210-3p inhibitor+si-NC组和miR-210-3p inhibitor+si-FBXO31组。RT-qPCR检测miR-210-3p 和FBXO31表达水平；采用MTT法检测IC50；瘤球形成实验检测干细胞特性；Western Blot检测FBXO31和干细胞标志物的表达水平；双荧光素酶检测miR-210-3p 与FBXO31靶向关系；裸鼠移植瘤检测外泌体miR-210-3p对宫颈癌体内转移的影响。 结果 与人正常宫颈上皮细胞HCeEpiC相比，miR-210-3p在宫颈癌细胞系HeLa、HT3、C33A和Caski显著高表达（P < 0.05），而FBXO31显著低表达（P < 0.05）。与HeLa细胞相比，HeLa/DDP细胞IC50和miR-210-3p的表达水平显著增加（P < 0.05），且HeLa的外泌体可被HeLa/DDP细胞摄取。与NC inhibitor组相比，miR-210-3p inhibitor组的miR-210-3p、Oct-4、SOX2和NANOG表达水平、IC50显著降低（P < 0.05），而FBXO31表达显著增加（P < 0.05）。与miR-210-3p inhibitor+si-NC组相比，miR-210-3p inhibitor+si-FBXO31组的FBXO31表达显著降低（P < 0.05），IC50、Oct-4、SOX2和NANOG表达水平显著增加（P < 0.05）。与对照组和空载组相比，miR-210-3p干扰组的肿瘤重量和肿瘤体积显著降低（P < 0.05）。 结论 外泌体miR-210-3p通过靶向抑制FBXO3，从而促进CC细胞的对化疗药物DDP耐药性和干细胞特性。 Abstract:Objective To investigate the role of exosomal microRNA （miRNA） miR-210-3p in chemoresistance and stem cell property formation in cervical cancer, and to elucidate its underlying mechanism through targeting of F-box protein 31 （FBXO31）. Methods Exosomes were isolated from cisplatin-sensitive HeLa cells and cisplatin-resistant HeLa/DDP cells via ultracentrifugation, and their uptake by HeLa/DDP cells was verified using the PKH26 red fluorescent labeling method. HeLa cells were transfected with NC inhibitor, miR-210-3p inhibitor alone, or in combination with si-NC and si-FBXO31. After 24 hours of transfection, exosomes were extracted and co-cultured with HeLa/DDP cells for 48 hours. Consequently, HeLa/DDP cells were divided into five groups: the Ctrl group （PBS blank control）, the NC inhibitor group, the miR-210-3p inhibitor group, the miR-210-3p inhibitor+si-NC group and the miR-210-3p inhibitor+si-FBXO31 group. RT-qPCR was used to measure miR-210-3p and FBXO31 expression levels. The half-maximal inhibitory concentration （IC50） of cisplatin was determined using the MTT assay. Stem cell properties were assessed via tumor sphere formation assays. Western blot analysis was performed to detect the protein expression of FBXO31 and stem cell markers （e.g., SOX2, OCT4, NANOG）. The targeting relationship between miR-210-3p and FBXO31 was validated using dual-luciferase reporter assays. The effect of exosomal miR-210-3p on the metastasis of cervical cancer in vivo was evaluated by nude mice xenograft tumor. Resuts Compared with human normal cervical epithelial cells （HCeEpiC）, miR-210-3p expression was significantly upregulated in cervical cancer cell lines （HeLa, HT3, C33A, and CaSki）, while FBXO31 expression was significantly downregulated （P < 0.05）. HeLa/DDP cells （cisplatin-resistant） exhibited significantly higher miR-210-3p expression levels and IC50 values for cisplatin compared with parental HeLa cells （P < 0.05）, and HeLa exosomes were efficiently taken up by HeLa/DDP cells. Compared with the NC inhibitor groupThe miR-210-3p inhibitor group showed significantly reduced expression levels of miR-210-3p, OCT4, SOX2, and NANOG, as well as a significantly lower IC50 （P < 0.05）, while FBXO31 expression was significantly increased （P < 0.05）. Compared with the miR-210-3p inhibitor + si-NC group, the miR-210-3p inhibitor + si-FBXO31 group exhibited significantly decreased FBXO31 expression （P < 0.05） and increased IC50, Oct-4, SOX2, and NANOG expression （P < 0.05）. Compared with the control group and the empty vector group, the tumor weight and volume were significantly lower in the miR-210-3p than in the control and empty vector groups （P < 0.05）. Conclusion Exosomal miR-210-3p promotes chemoresistance to DDP and enhances stem cell-like properties in CC cells by directly targeting and inhibiting FBXO31. -
Key words:
- Exosome /
- MiR-210-3p /
- Chemoresistance /
- Stem cell properties /
- FBXO31 /
- Cervical cancer
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图 1 FBXO31在CC细胞系中的表达（n = 3，$\bar x \pm s $）
Figure 1. Expression of FBXO31 in CC cell lines （n = 3，$\bar x \pm s $）
图 2 外泌体的提取、鉴定和摄取（n = 3，$\bar x \pm s $）
A：透射电子显微镜观察外泌体形状；B： 纳米颗粒示踪分析外泌体粒径；C：CD9和CD81蛋白表达水平；D：HeLa/DDP细胞对HeLa细胞的外泌体摄取作用（×
2000 ，标尺：100 nm）。Figure 2. Isolation，identification and uptake of exosomes （n = 3，$\bar x \pm s $）
图 3 外泌体来源miR-210-3p对 HeLa/DDP细胞干细胞特性的影响（n = 3，$\bar x \pm s $）
A：各组干细胞标志物Oct-4、SOX2和NANOG的表达水平；B：瘤球形成实验（×400，标尺：25 µm）。
Figure 3. Effects of exosomal miR-210-3p on stem cell properties of HeLa/DDP cells （n = 3，$\bar x \pm s $）
图 4 FBXO31是miR-210-3p的靶标（n = 3，$\bar x \pm s $）
A：miR-210-3p和FBXO31预测靶点；B：各组FBXO31的表达水平。
Figure 4. FBXO31 is a target of miR-210-3p （n = 3，$\bar x \pm s $）
图 5 外泌体来源miR-210-3p对 HeLa/DDP细胞干细胞特性的影响（n = 3，$\bar x \pm s $）
A：各组干细胞标志物Oct-4、SOX2和NANOG的表达水平；B：瘤球形成实验（×800，标尺：25 µm）。
Figure 5. Effects of exosomal miR-210-3p on stem cell properties of HeLa/DDP cells （n = 3，$\bar x \pm s $）
图 6 各组裸鼠移植瘤（n = 5，$\bar x \pm s $）
Figure 6. Transplanted tumor of nude mice in each group （n = 5，$\bar x \pm s $）
表 1 引物序列信息
Table 1. Primer sequence information
基因 引物类型 序列 5'→3' miR-210-3p F CTGTGCGTGTGACAG R GTGCAGGGTCCGAGGT FBXO31 F CCATACGGAGGACTGCTGA R GTACATCCACCCGATGATGA U6 F CAGCACATATACTAAAATGGAACG R ACGAATTTGCGTGTCATCC β-actin F CAGAAGGAGATTACTGCT R TACTCCTGCTTGCTGATCCAC 
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表 2 miR-210-3p和FBXO31在CC细胞系中的表达（n = 3，$ \bar x \pm s $）
Table 2. Expression of miR-210-3p and FBXO31 in CC cell lines （n = 3，$ \bar x \pm s $）
细胞系 miR-210-3p mRNA FBXO31 mRNA FBXO31蛋白 HCeEpiC 1.00 ± 0.04 1.01 ± 0.04 0.97 ± 0.08 HeLa 3.86 ± 0.24∆ 0.20 ± 0.03∆ 0.16 ± 0.02∆ HT3 2.04 ± 0.15∆ 0.32 ± 0.04∆ 0.25 ± 0.01∆ C33A 1.97 ± 0.09∆ 0.67 ± 0.06∆ 0.64 ± 0.05∆ Caski 2.13 ± 0.29∆ 0.65 ± 0.05∆ 0.60 ± 0.04∆ F 92.273 150.515 136.132 P <0.001* <0.001* <0.001* *P < 0.05；与HCeEpiC相比，∆P < 0.05。
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表 3 DDP对HeLa/DDP和HeLa细胞的抑制率（n = 3，$ \bar x \pm s $）
Table 3. Inhibition rate of DDP on HeLa/DDP and HeLa cells （n = 3，$ \bar x \pm s $）
组别 抑制率（%） IC50
（μg/mL）DDP
0 μg/mLDDP
2.0 μg/mLDDP
4.0 μg/mLDDP
8.0 μg/mLDDP
16.0 μg/mLDDP
32.0 μg/mLDDP
64.0 μg/mLF P HeLa 0.00 ± 0.00 15.49 ± 1.32a 27.03 ± 3.45b 46.04 ± 3.42c 65.32 ± 3.79d 82.62 ± 4.29e 97.98 ± 1.03f 474.235 <0.001* 8.59 ± 0.95 HeLa/DDP 0.00 ± 0.00 8.08 ± 1.15a 11.95 ± 2.12b 19.49 ± 2.91c 29.95 ± 3.35d 45.29 ± 3.16e 67.91 ± 4.28f 323.727 <0.001* 34.03 ± 2.95 t - 7.331 6.450 10.241 12.111 13.435 11.831 - - 14.218 P - 0.002* 0.003* 0.001* <0.001* <0.001* <0.001* - - <0.001* *P < 0.05；横向比较：与DDP 0 μg/mL相比，aP < 0.05；与DDP 2.0 μg/mL相比，bP < 0.05；与DDP 4.0 μg/mL相比，cP < 0.05；与DDP 8.0 μg/mL相比，dP < 0.05；与DDP 16.0 μg/mL相比，eP < 0.05；与DDP 32.0 μg/mL相比，fP < 0.05。
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表 4 miR-210-3p在HeLa/DDP和HeLa细胞的表达水平（n = 3，$ \bar x \pm s $）
Table 4. Expression levels of miR-210-3p in HeLa/DDP and HeLa cells （n = 3，$ \bar x \pm s $）
组别 miR-210-3p mRNA HeLa 0.39 ± 0.04 HeLa/DDP 1.02 ± 0.03 t 21.824 P <0.001* *P < 0.05。
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表 5 CD9和CD81在外泌体和细胞裂解液的表达水平（n = 3，$ \bar x \pm s $）
Table 5. Expression levels of CD9 and CD81 in exosomes and cell lysates （n = 3，$ \bar x \pm s $）
样本来源 CD9 CD81 Calnexin 外泌体 1.01 ± 0.08 0.83 ± 0.07 0.02 ± 0.01 细胞裂解液 0.20 ± 0.04 0.11 ± 0.01 1.09 ± 0.10 t 15.686 17.636 18.441 P <0.001* <0.001* <0.001* *P < 0.05。
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表 6 各组 miR-210-3p的表达水平（n = 3，$ \bar x \pm s $）
Table 6. Expression levels of miR-210-3p in each group （n = 3，$ \bar x \pm s $）
组别 miR-210-3p Ctrl组 1.00 ± 0.09 NC inhibitor组 0.99 ± 0.08 miR-210-3p inhibitor组 0.24 ± 0.03∆# F 11.058 P <0.001* *P < 0.05；与Ctrl组相比，∆P < 0.05；与NC inhibitor组相比，#P < 0.05。
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表 7 DDP对HeLa/DDP和HeLa细胞的抑制率（n = 3，$ \bar x \pm s $）
Table 7. Inhibitory rate of DDP on HeLa/DDP and HeLa cells （n = 3，$ \bar x \pm s $）
组别 抑制率（%） IC50
（μg/mL）DDP
0 μg/mLDDP
2.0 μg/mLDDP
4.0 μg/mLDDP
8.0 μg/mLDDP
16.0 μg/mLDDP
32.0 μg/mLDDP
64.0 μg/mLF P Ctrl组 0.00±0.00 7.60±0.97a 12.27±2.17b 19.92±2.43c 31.24±3.55d 47.01±3.41e 67.59±3.63f 245.673 <0.001* 33.09±1.42 NC inhibitor组 0.00±0.00 7.57±0.87a 12.13±1.89b 20.07±2.74c 30.10±3.12d 46.32±2.99e 68.16±3.97f 260.926 <0.001* 33.27±1.51 miR-210-3p
inhibitor组0.00±0.00 10.24±0.94a△# 19.75±2.13b△# 30.26±2.86c△# 42.56±3.74d△# 58.93±4.13e△# 78.98±3.36f△# 291.249 <0.001* 20.10±1.36△# F - 8.379 13.345 14.642 11.756 12.023 9.215 - - 83.522 P - 0.019* 0.006* 0.005* 0.008* 0.008* 0.015* - - <0.001* *P < 0.05；横向比较：与DDP 0 μg/mL相比，aP < 0.05；与DDP 2.0 μg/mL相比，bP < 0.05；与DDP 4.0 μg/mL相比，cP < 0.05；与DDP 8.0 μg/mL相比，dP < 0.05；与DDP 16.0 μg/mL相比，eP < 0.05；与DDP 32.0 μg/mL相比，fP < 0.05。纵向比较：与Ctrl组相比，△P < 0.05；与NC inhibitor组相比，#P < 0.05。
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表 8 各组干细胞标志物Oct-4、SOX2和NANOG的表达水平（n = 3，$ \bar x \pm s $）
Table 8. Expression levels of stem cell markers Oct-4，SOX2 and NANOG in each group （n = 3，$ \bar x \pm s $）
组别 Oct-4 SOX2 NANOG Ctrl组 1.06 ± 0.07 0.96 ± 0.05 1.00 ± 0.07 NC inhibitor组 1.04 ± 0.08 0.98 ± 0.06 1.01 ± 0.06 miR-210-3p
inhibitor组0.43 ± 0.05△# 0.40 ± 0.03△# 0.31 ± 0.03△# F 83.630 139.371 154.181 P <0.001* <0.001* <0.001* *P < 0.05；与Ctrl组相比，△P < 0.05；与NC inhibitor组相比，#P < 0.05。
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表 9 双荧光素酶实验（n = 3，$ \bar x \pm s $）
Table 9. Dual-luciferase reporter assay （n = 3，$ \bar x \pm s $）
组别 FBXO31-WT FBXO31-MUT NC mimic组 1.00 ± 0.05 1.01 ± 0.03 miR-210-3p mimic组 0.42 ± 0.03 1.00 ± 0.02 t 17.229 0.480 P <0.001* 0.656 *P < 0.05。
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表 10 各组FBXO31的表达水平（n = 3，$ \bar x \pm s $）
Table 10. Expression levels of FBXO31 in each group （n = 3，$ \bar x \pm s $）
组别 FBXO31 mRNA FBXO31 蛋白 Ctrl组 0.99 ± 0.06 0.41 ± 0.02 NC inhibitor组 1.00 ± 0.07 0.39 ± 0.03 miR-210-3p inhibitor组 3.15 ± 0.24△# 1.10 ± 0.07△# miR-210-3p inhibitor+si-NC组 3.09 ± 0.20 1.07 ± 0.08 miR-210-3p inhibitor
+si-FBXO31组1.57 ± 0.11▽ 0.77 ± 0.06▽ F 149.353 108.907 P <0.001* <0.001* *P < 0.05；与Ctrl组相比，△P < 0.05；与NC inhibitor组相比，#P < 0.05；与miR-210-3p inhibitor+si-NC组相比，▽P < 0.05。
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表 11 DDP对HeLa/DDP和HeLa细胞的抑制率（n = 3，$ \bar x \pm s $）.
Table 11. Inhibitory rate of DDP on HeLa/DDP and HeLa cells （n = 3，$ \bar x \pm s $）
组别 抑制率（%） IC50
（μg/mL）DDP
0 μg/mLDDP
2.0 μg/mLDDP
4.0 μg/mlLDDP
8.0 μg/mLDDP
16.0 μg/mLDDP
32.0 μg/mLDDP
64.0 μg/mLF P miR-210-3p inhibitor+
si-NC组0.00 ± 0.00 10.33 ± 0.57a 19.32 ± 1.75b 31.06 ± 2.51c 42.99 ± 3.25d 55.34 ± 1.91e 78.23 ± 1.67f 329.076 <0.001* 20.64 ± 1.30 miR-210-3p inhibitor+
si-FBXO31组0.00 ± 0.00 8.61 ± 0.44a 14.26 ± 1.35b 23.47 ± 1.75c 32.62 ± 2.13d 50.03 ± 1.64e 70.45 ± 1.19f 937.739 <0.001* 29.07 ± 1.87* t - 4.137 3.965 4.296 3.138 3.653 6.571 - - 6.411 P - 0.014* 0.017* 0.013* 0.035* 0.022* 0.003* - - 0.003* *P < 0.05；横向比较：与DDP 0 μg/mL相比，aP < 0.05；与DDP 2.0 μg/mL相比，bP < 0.05；与DDP 4.0 μg/mL相比，cP < 0.05；与DDP 8.0 μg/mL相比，dP < 0.05；与DDP 16.0 μg/mL相比，eP < 0.05；与DDP 32.0 μg/mL相比，fP < 0.05。
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表 12 各组干细胞标志物Oct-4、SOX2和NANOG的表达水平（n = 3，$ \bar x \pm s $）
Table 12. Expression levels of stem cell markers Oct-4，SOX2 and NANOG in each group （n = 3，$ \bar x \pm s $）
组别 Oct-4 SOX2 NANOG miR-210-3p inhibitor+si-NC组 0.41 ± 0.04 0.38 ± 0.04 0.30 ± 0.03 miR-210-3p inhibitor+si-FBXO31组 0.77 ± 0.08 0.62 ± 0.05 0.81 ± 0.07 t 6.971 6.492 11.599 P 0.002* 0.003* <0.001* *P < 0.05。
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表 13 各组裸鼠移植瘤重量和体积的比较（n = 5，$ \bar x \pm s $）
Table 13. Comparison of transplanted tumor weight and volume in each group of nude mice （n = 5，$ \bar x \pm s $）
组别 肿瘤重量/（mg） 肿瘤体积/（mm3） 7 d 14 d 21 d 28 d 对照组 523.49 ± 55.76 90.47 ± 8.19 162.16 ± 13.44▽ 375.94 ± 37.84▽ 505.48 ± 46.31▽ 空载组 530.72 ± 49.04 92.67 ± 7.94 167.20 ± 15.38▽ 380.25 ± 35.72▽ 512.04 ± 51.70▽ miR-210-3p干扰组 312.06 ± 27.85△＃ 53.19 ± 6.48△＃ 97.93 ± 7.17△＃▽ 173.43 ± 19.10△＃▽ 300.69. ± 28.46△＃▽ F 73.586 85.797 95.492 136.372 77.145 P <0.001* <0.001* <0.001* <0.001* <0.001* *P < 0.05；与对照组相比，△P < 0.05；与空载组相比，＃P < 0.05；与前日期相比，▽P < 0.05。
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