肿瘤相关成纤维细胞上调hsa-miR-18b-5p靶向FBXL3促进前列腺癌的增殖及转移

doi:10.12122/j.issn.1673-4254.2024.07.08

摘要/Abstract

摘要：

目的探讨受肿瘤相关成纤维细胞（CAFs）调控的hsa-miR-18b-5p在前列腺癌（PCa）中的表达水平及作用，并研究对其在PCa发生发展过程中的分子机制。方法利用生物信息学技术分析在PCa中高表达的miRNA，构建肿瘤相关成纤维细胞并与PCa细胞系共培养，验证CAFs对PCa细胞增殖和迁移的影响及对hsa-miR-18b-5p的调控作用；RT-qPCR验证20例患者癌组织及癌旁正常组织、前列腺正常上皮增生细胞及PCa各细胞系中hsa-miR-18b-5p的表达水平；通过脂质体法将阴性对照及hsa-miR-18b-5p抑制物分别转染入PCa细胞C4-2、LNCAP中，分为NC inhibitor组和hsa-miR-18b-5p inhibitor组；采用细胞集落形成、CCK-8实验、划痕愈合、Transwell、IC₅₀实验、流式细胞术分别检测C4-2、LNCAP细胞增殖、迁移、侵袭、耐药能力、凋亡和周期；建立PCa裸鼠移植瘤模型，定期测量移植瘤的质量和体积，Kaplan-Meier生存曲线分析裸鼠生存情况；利用靶基因预测分析网站（Targetscan、Mirtarbase、miRDB、miRDIP）预测has-miR-18b-5p的靶基因，并通过双荧光素酶报告基因分析验证hsa-miR-18b-5p与靶基因的靶向关系，RT-qPCR、Western blotting检测各组细胞靶基因的表达水平。结果生物信息学分析结果显示，在PCa中高表达的miRNA有17个，结合差异表达程度以及相关文献筛选出拟研究的基因：miR-148a、miR-17、miR-18b-5p、miR-770、miR-297-3p。CAFs与PCa细胞系共培养后hsa-miR-18b-5p的表达水平升高（P<0.01），且促进PCa细胞的增殖与迁移（P<0.01），敲除has-miR-18b-5p可抵消CAFs对PCa细胞增殖及迁移的影响，确定has-miR-18b-5p为研究基因。与正常前列腺上皮细胞或肿瘤旁组织相比，PCa细胞或肿瘤组织中hsa-miR-18b-5p的表达升高（P<0.05）；敲除hsa-miR-18b-5p可抑制C4-2、LNCAP细胞的增殖、迁移、侵袭以及耐药（P<0.05）；敲除hsa-miR-18b-5p可抑制裸鼠移植瘤质量和体积的增长，增加裸鼠的生存时间（P<0.05）。靶基因预测分析网站显示，FBXL3是hsa-miR-18b-5p的一个潜在作用靶点，双荧光素酶报告基因证实has-miR-18b-5p与FBXL3基因间存在结合位点，且敲除hsa-miR-18b-5p可增加C4-2、LNCAP细胞中FBXL3的蛋白表达（P<0.05）。结论 CAFs上调前列腺癌细胞hsa-miR-18b-5p的表达水平，后者可能通过靶向调控FBXL3基因的表达促进PCa细胞的增殖和转移。

关键词: hsa-miR-18b-5p, 肿瘤相关成纤维细胞, FBXL3, 前列腺癌, 促癌

Abstract:

Objective To explore the mechanism of tumor-associated fibroblasts (CAFs) for regulating proliferation and migration of prostate cancer (PCa) cells. Methods We conducted a bioinformatics analysis to identify miRNAs with high expression in PCa. The proliferation, migration and hsa-miR-18b-5p expression levels were observed in PCa cells co-cultured with CAFs. We further examined hsa-miR-18b-5p expression level in 20 pairs of PCa and adjacent tissue samples and in different PCa cell lines and normal epithelial cells using RT-qPCR. In PCa cell lines C4-2 and LNCAPNC, the effects of transfection with a hsa-miR-18b-5p inhibitor on cell proliferation, migration, invasion, drug resistance, apoptosis and cell cycle were evaluated, and the effects of has-miR-18b-5p knockdown on C4-2 cell xenograft growth and mouse survival were observed in nude mice. Dual luciferase reporter gene assay was used to validate the targeting relationship between hsa-miR-18b-5p and its target genes, whose expressions were detected in PCa cells using RT-qPCR and Western blotting. Results The expression of hsa-miR-18b-5p was significantly increased in the co-culture of CAFs and PCa cell lines, which exhibited significantly enhanced proliferation and migration abilities. Transfection with has-miR-18b-5p inhibitor strongly attenuated the effect of CAFs for promoting proliferation and migration of PCa cells, and in C4-2 and LNCAP cells cultured alone, inhibition of hsa-miR-18b-5p obviously suppressed cell proliferation, migration, invasion, and drug resistance. In the tumor-bearing mice, hsa-miR-18b-5p knockdown in the transplanted cells significantly inhibited xenograft growth and increased the survival time of the mice. Target gene prediction suggested that FBXL3 was a potential target of hsa-miR-18b-5p, and dual luciferase reporter gene confirmed a binding site between them. In C4-2 and LNCAP cells, hsa-miR-18b-5p knockdown resulted in significantly increased expression levels of FBXL3. Conclusion CAFs promotes proliferation and migration of PCa cells by up-regulating hsa-miR-18b-5p to suppress FBXL3 expression.

Key words: hsa-miR-18b-5p, tumor-associated fibroblasts, FBXL3, prostate cancer, promoting cancer

骆金光, 陶怀祥, 闻志远, 陈龙, 胡昊, 关翰. 肿瘤相关成纤维细胞上调hsa-miR-18b-5p靶向FBXL3促进前列腺癌的增殖及转移[J]. 南方医科大学学报, 2024, 44(7): 1284-1296.

Jinguang LUO, Huaixiang TAO, Zhiyuan WEN, Long CHEN, Hao HU, Han GUAN. Tumor-associated fibroblasts promotes proliferation and migration of prostate cancer cells by suppressing FBXL3 via upregulating hsa-miR-18b-5p[J]. Journal of Southern Medical University, 2024, 44(7): 1284-1296.

图/表 13

表1 RT-qPCR 引物序列

Tab.1 Primer sequences for RT-qPCR

Gene	Primer sequence 5'-3'
hsa-miR-18b-5p	F: AGGCGCATTAAGGTGCATCTAGT
hsa-miR-18b-5p	R: ATCCAGTGCAGGGTCCGAGG
has-miR-148a	F: TCTGAGACACTCCGACTCTG
has-miR-148a	R: AGTTCTGTAGTGCACTGACTTCT
has-miR-17	F: AAGTGCTTACAGTGCAGGTAGT
has-miR-17	R: GTCACCATAATGCTACAAGTGC
has-miR-770	F: CCTCCAGTACCACGTGTCAG
has-miR-770	R: CCCCAGCACCACATCAGG
has-miR-297-3p	F: AGTGCTTACAGTGCAGGTAGT
has-miR-297-3p	R: TCACCATAATGCTACAAGTGCC
U6	F: GCTTCGGCAGCACATATACTAAAAT
U6	R: CGCTTCACGAATTTGCGTGTCAT
FBXL3	F: ATGCTTCACAAGTTTGCCGC
FBXL3	R: CACGGCCAAGCACATCTTTG
GAPDH	F: TCATGACCACAGTCCATGCC
GAPDH	R: TTCTAGACGGCAGGTCAGGT

图1 PCa中差异表达的miRNA热图和火山图

Fig.1 Volcano plot and heat map of the differential miRNAs in prostate cancer. A: Differential miRNA heat map in prostate cancer. B: Volcano plot of differential miRNA in prostate cancer.

图2 CAFs与NFs的鉴定以及分别和PCa C4-2细胞共培养

Fig.2 Identification of CAFs and NFs and co-cultured prostate cancer C4-2 cells. A: Morphology of CAFs and NFs were observed under light microscope. B, C: Expression of vimentin and α-SMA in CAFs and NFs detected by Western blotting. D: RT-qPCR for detecting vimentin and α-SMA mRNAs in co-cultures of C4-2 cells with CAFs or NFs. *P<0.05, **P<0.01.

图3 CAFs对PCa细胞增殖及迁移的影响

Fig.3 Effect of CAFs on proliferation and migration of PCa cells. A, B: Colony formation assays of C4-2 cells co-cultured with CAFs. C, D: Transwell migration assay of C4-2 cells co-cultured with CAFs. **P<0.01.

图4 敲除has-miR-18b-5p可抵消CAFs对PCa细胞增殖及迁移的影响

Fig.4 Knocking down has-miR-18b-5p attenuates the effect of CAFs on proliferation and migration of PCa cells. A, B: Colony formation assays of CAFs co-cultured with C4-2 cells transfected with NC inhibitor and hsa-miR-18b-5p inhibitor. C, D: Transwell migration assays of CAFs co-cultured with C4-2 cells transfected with NC inhibitor and hsa-miR-18b-5p inhibitor. **P<0.01.

图5 hsa-miR-18b-5p在PCa各细胞系以及临床肿瘤组织中的表达水平

Fig.5 Expression of hsa-miR-18b-5p in prostate cancer cell lines and clinical tumor tissues. A: Expression of hsa-miR-18b-5p in clinical tumor tissues. B: Expression of hsa-miR-18b-5p in prostate cancer cell lines. *P<0.05, **P<0.01 vs BPH-1 group.

图6 hsa-miR-18b-5p对PCa细胞增殖的影响

Fig.6 Effect of Has-miR-18b-5p on proliferation of prostate cancer cells. A: CCK-8 assay of C4-2 and LNCAP cells transfected with NC inhibitor and hsa-miR-18b-5p inhibitor. B, C: Colony formation assay of C4-2 and LNCAP cells transfected with NC inhibitor and hsa-miR-18b-5p inhibitor. *P<0.05, **P<0.01.

图7 hsa-miR-18b-5p对PCa细胞迁移、侵袭的影响

Fig.7 Effect of hsa-miR-18b-5p on migration and invasion of prostate cancer cells. A,B: Wound-healing assay of C4-2 and LNCAP cells transfected with NC inhibitor and hsa-miR-18b-5p inhibitor. C, E: Transwell migration assay of C4-2 and LNCAP cells transfected with NC inhibitor and hsa-miR-18b-5p inhibitor. D, F: Transwell invasion assay of in C4-2 and LNCAP cells transfected with NC inhibitor and hsa-miR-18b-5p inhibitor. *P<0.05, **P<0.01.

图8 hsa-miR-18b-5p对PCa细胞恩杂鲁胺耐药的影响

Fig.8 Effect of hsa-miR-18b-5p on enzalutamide resistance of prostate cancer cells.

图9 hsa-miR-18b-5p对PCa细胞凋亡和周期的影响

Fig.9 Effect of hsa-miR-18b-5p on apoptosis and cell cycle of prostate cancer cells. A,B: Apoptosis assays of C4-2 and LNCAP cells transfected with NC inhibitor and hsa-miR-18b-5p inhibitor. C-F: Cell cycle assays of C4-2 and LNCAP cells transfected with NC inhibitor and hsa-miR-18b-5p inhibitor. *P<0.05, **P<0.01.

图10 hsa-miR-18b-5p对裸鼠体内瘤负荷的影响

Fig.10 Effect of hsa-miR-18b-5p on tumor load in nude mice. A,B: Tumor weight in mice. C: Tumor volume in mice. D: Kaplan-Meier survival curve analysis of survival of the mice. *P<0.05, **P<0.01.

图11 hsa-miR-18b-5p与FBXL3在PCa中的靶向关系

Fig.11 Targeting relationship between hsa-miR-18b-5p and FBXL3 in prostate cancer. A: Wayne diagram of hsa-miR-18b-5p target gene. B: Binding sites of hsa-miR-18b-5p and FBXL3. C: Results of dual luciferase reporter assay. D: RT-qPCR of FBXL3 in C4-2 and LNCAP cells transfected with NC inhibitor and hsa-miR-18b-5p inhibitor. E,F: Western blotting of FBXL3 in C4-2 and LNCAP cells transfected with NC inhibitor and hsa-miR-18b-5p inhibitor. *P<0.05, **P<0.01.

图12 过表达FBXL3可逆转hsa-miR-18b-5p在前列腺癌细胞系中的作用

Fig.12 Overexpression of FBXL3 reverses the effects of hsa-miR-18b-5p knockdown in prostate cancer cell line. A: CCK8 assay of the two co-transfected PCa cell lines. B: Transwell assay of the two co-transfected PCa cell lines. C: Wound healing assay of the two co-transfected PCa cell lines. *P<0.05.

参考文献 48

1	Sehn JK. Prostate cancer pathology: recent updates and controversies[J]. Mo Med, 2018, 115(2): 151-5.
2	Kimura T, Egawa S. Epidemiology of prostate cancer in Asian countries[J]. Int J Urol, 2018, 25(6): 524-31.
3	Zelic R, Garmo H, Zugna D, et al. Predicting prostate cancer death with different pretreatment risk stratification tools: a head-to-head comparison in a nationwide cohort study[J]. Eur Urol, 2020, 77(2): 180-8.
4	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-49.
5	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020[J]. CA Cancer J Clin, 2020, 70(1): 7-30.
6	Taylor LG, Canfield SE, Du XL. Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer[J]. Cancer, 2009, 115(11): 2388-99.
7	Zarour L, Alumkal J. Emerging therapies in castrate-resistant prostate cancer[J]. Curr Urol Rep, 2010, 11(3): 152-8.
8	Boulos S, Mazhar D. The evolving role of chemotherapy in prostate cancer[J]. Future Oncol, 2017, 13(12): 1091-5.
9	Sebesta EM, Anderson CB. The surgical management of prostate cancer[J]. Semin Oncol, 2017, 44(5): 347-57.
10	Shevach J, Chaudhuri P, Morgans AK. Adjuvant therapy in high-risk prostate cancer[J]. Clin Adv Hematol Oncol, 2019, 17(1): 45-53.
11	Chistiakov DA, Myasoedova VA, Grechko AV, et al. New biomarkers for diagnosis and prognosis of localized prostate cancer[J]. Semin Cancer Biol, 2018, 52(Pt 1): 9-16.
12	Michlewski G, Cáceres JF. Post-transcriptional control of miRNA biogenesis[J]. RNA, 2019, 25(1): 1-16.
13	Liu T, Zhang Q, Zhang JK, et al. EVmiRNA: a database of miRNA profiling in extracellular vesicles[J]. Nucleic Acids Res, 2019, 47(D1): D89-93.
14	Ali Syeda Z, Langden SSS, Munkhzul C, et al. Regulatory mechanism of microRNA expression in cancer[J]. Int J Mol Sci, 2020, 21(5): 1723-9.
15	Friedman RC, Farh KKH, Burge CB, et al. Most mammalian mRNAs are conserved targets of microRNAs[J]. Genome Res, 2009, 19(1): 92-105.
16	Cocks A, Del Vecchio F, Martinez-Rodriguez V, et al. Pro-tumoral functions of tumor-associated macrophage EV-miRNA[J]. Semin Cancer Biol, 2022, 86(Pt 1): 58-63.
17	Del Valle-Morales D, Le P, Saviana M, et al. The epitranscriptome in miRNAs: crosstalk, detection, and function in cancer[J]. Genes, 2022, 13(7): 1289-95.
18	Smolarz B, Durczyński A, Romanowicz H, et al. miRNAs in cancer (review of literature)[J]. Int J Mol Sci, 2022, 23(5): 2805-13.
19	Iqbal MA, Arora S, Prakasam G, et al. MicroRNA in lung cancer: role, mechanisms, pathways and therapeutic relevance[J]. Mol Aspects Med, 2019, 70: 3-20.
20	Kt RD, Karthick D, Saravanaraj KS, et al. The roles of microRNA in pancreatic cancer progression[J]. Cancer Invest, 2022, 40(8): 700-9.
21	Ismail A, Abulsoud AI, Fathi D, et al. The role of miRNAs in ovarian cancer pathogenesis and therapeutic resistance-A focus on signaling pathways interplay[J]. Pathol Res Pract, 2022, 240: 154222.
22	Hwang GR, Yuen JG, Ju JF. Roles of microRNAs in gastrointestinal cancer stem cell resistance and therapeutic development[J]. Int J Mol Sci, 2021, 22(4): 1624-36.
23	Doghish AS, Ismail A, El-Mahdy HA, et al. A review of the biological role of miRNAs in prostate cancer suppression and progression[J]. Int J Biol Macromol, 2022, 197: 141-56.
24	Mao XQ, Xu J, Wang W, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives[J]. Mol Cancer, 2021, 20(1): 131-8.
25	Tsoumakidou M. The advent of immune stimulating CAFs in cancer[J]. Nat Rev Cancer, 2023, 23(4): 258-69.
26	Wang YF, Liang HY, Zheng J. Exosomal microRNAs mediating crosstalk between cancer cells and cancer-associated fibroblasts in the tumor microenvironment[J]. Pathol Res Pract, 2022, 239: 154159.
27	Bullock MD, Pickard KM, Nielsen BS, et al. Pleiotropic actions of miR-21 highlight the critical role of deregulated stromal microRNAs during colorectal cancer progression[J]. Cell Death Dis, 2013, 4(6): e684-92.
28	Gandellini P, Giannoni E, Casamichele A, et al. MiR-205 hinders the malignant interplay between prostate cancer cells and associated fibroblasts[J]. Antioxid Redox Signal, 2014, 20(7): 1045-59.
29	Yan ZQ, Sheng ZM, Zheng YH, et al. Cancer-associated fibroblast-derived exosomal miR-18b promotes breast cancer invasion and metastasis by regulating TCEAL7[J]. Cell Death Dis, 2021, 12(12): 1120-32.
30	Xue F, Xu YH, Shen CC, et al. Non-coding RNA LOXL1-AS1 exhibits oncogenic activity in ovarian cancer via regulation of miR-18b-5p/VMA21 axis[J]. Biomedecine Pharmacother, 2020, 125: 109568.
31	Wang YY, Yan L, Yang S, et al. Long noncoding RNA AC073284.4 suppresses epithelial-mesenchymal transition by sponging miR-18b-5p in paclitaxel-resistant breast cancer cells[J]. J Cell Physiol, 2019, 234(12): 23202-15.
32	Komura K, Sweeney CJ, Inamoto T, et al. Current treatment strategies for advanced prostate cancer[J]. Int J Urol, 2018, 25(3): 220-31.
33	Swarbrick S, Wragg N, Ghosh S, et al. Systematic review of miRNA as biomarkers in Alzheimer's disease[J]. Mol Neurobiol, 2019, 56(9): 6156-67.
34	Pottoo FH, Iqubal A, Iqubal MK, et al. miRNAs in the regulation of cancer immune response: effect of miRNAs on cancer immunotherapy[J]. Cancers, 2021, 13(23): 6145-56.
35	Khan AQ, Ahmed EI, Elareer NR, et al. Role of miRNA-regulated cancer stem cells in the pathogenesis of human malignancies[J]. Cells, 2019, 8(8): 840-8.
36	Hussen BM, Hidayat HJ, Salihi A, et al. MicroRNA: a signature for cancer progression[J]. Biomedecine Pharmacother, 2021, 138: 111528.
37	Liang Y, Lu Q, Li W, et al. Reactivation of tumour suppressor in breast cancer by enhancer switching through NamiRNA network[J]. Nucleic Acids Res, 2021, 49(15): 8556-72.
38	Hu HH, Cheng RJ, Wang YB, et al. Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47[J]. J Clin Invest, 2023, 133(2): e153470.
39	Liu LN, Zhang Y, Hu X, et al. MiR-138-5p inhibits prostate cancer cell proliferation and chemoresistance by targeting APOBEC3B[J]. Transl Oncol, 2023, 35: 101723-36.
40	Li WJ, Liu XZ, Dougherty EM, et al. MicroRNA-34a, prostate cancer stem cells, and therapeutic development[J]. Cancers, 2022, 14(18): 4538-50.
41	Angel CZ, Stafford MYC, McNally CJ, et al. MiR-21 is induced by hypoxia and down-regulates RHOB in prostate cancer[J]. Cancers, 2023, 15(4): 1291-309.
42	Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation[J]. Cell, 2011, 144(5): 646-74.
43	Cirri P, Chiarugi P. Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression[J]. Cancer Metastasis Rev, 2012, 31(1/2): 195-208.
44	Aprelikova O, Yu X, Palla J, et al. The role of miR-31 and its target gene SATB2 in cancer-associated fibroblasts[J]. Cell Cycle, 2010, 9(21): 4387-98.
45	Bronisz A, Godlewski J, Wallace JA, et al. Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320[J]. Nat Cell Biol, 2011, 14(2): 159-67.
46	Yao Q, Cao SY, Li C, et al. Micro-RNA-21 regulates TGF-β-induced myofibroblast differentiation by targeting PDCD4 in tumor-stroma interaction[J]. Int J Cancer, 2011, 128(8): 1783-92.
47	Wang DZ, Han X, Li C, et al. FBXL3 is regulated by miRNA-4735-3p and suppresses cell proliferation and migration in non-small cell lung cancer[J]. Pathol Res Pract, 2019, 215(2): 358-65.
48	Huber AL, Papp SJ, Chan AB, et al. CRY2 and FBXL3 cooperatively degrade c-MYC[J]. Mol Cell, 2016, 64(4): 774-89.

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[14]	欧艺虹，姜耀东，李琦，庄永江，党强，谭万龙. 肥大细胞通过上调p21促进前列腺癌神经内分泌分化及增加对多西他赛化疗的抵抗性[J]. 南方医科大学学报, 2018, 38(06): 723-.
[15]	殷昭阳，齐思勇，成祥，郭靓，陈泓宇，施明. 经股动脉注射途径建立前列腺癌和乳腺癌骨转移模型[J]. 南方医科大学学报, 2017, 37(07): 914-.