抑制Sox4通过P38信号通路增加耐药黑色素瘤细胞对顺铂的敏感性

IF 1.6 4区 医学 Q4 BIOCHEMICAL RESEARCH METHODS
Cheng Qiong, Zuo Fuguo
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引用次数: 0

摘要

背景:SRY-Box转录因子4 (Sox4)已被发现在许多恶性肿瘤中过表达,并与耐药有关。然而,Sox4在顺铂耐药黑色素瘤中的潜在机制尚不清楚。方法:采用免疫组化(IHC)方法检测Sox4在黑色素瘤、色素痣和正常皮肤组织中的表达。体外诱导制备顺铂耐药细胞株SK-MEL-28R和A375R。CCK8试验测定顺铂耐药细胞的IC50值。慢病毒关闭SK-MEL-28R和A375R细胞中的Sox4。然后利用Affymetrix基因芯片阵列检测SK-MEL-28R干扰Sox4信号通路的变化。采用Western blot、qRT-PCR、流式细胞术、caspase 3活性检测等方法验证Sox4影响黑色素瘤顺铂耐药的生物学过程。结果:Sox4在黑色素瘤中的表达明显高于色素痣和正常皮肤组织(pp4)。结论:抑制Sox4可通过P38信号通路提高耐药黑色素瘤细胞对顺铂的敏感性,从而为黑色素瘤的治疗开辟了一条新的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of Sox4 Increases the Sensitivity of Drug-resistant Melanoma Cells to Cisplatin through the P38 Signaling Pathway.

Background: SRY-Box Transcription Factor 4 (Sox4) has been found to be overexpressed in a number of malignancies and is linked to medication resistance. The underlying mechanism of Sox4 in cisplatin-resistant melanomas, however, remains unknown.

Methods: Immunohistochemistry (IHC) was used to examine the expression of Sox4 in melanoma, pigmented nevi, and normal skin tissue. Induction in vitro was used to create the cisplatin- resistant cell lines SK-MEL-28R and A375R. The CCK8 test was used to determine the IC50 values of cisplatin-resistant cells. Lentivirus shut down Sox4 in SK-MEL-28R and A375R cells. The Affymetrix GeneChip array was then utilized to detect changes in signaling pathways in SK-MEL-28R interfering with Sox4. Western blot, qRT-PCR, flow cytometry, and a caspase 3 activity kit were used to confirm the biological process of Sox4 impacting cisplatin resistance in melanoma.

Results: Sox4 expression in melanoma was substantially higher than in pigmented nevus and normal skin tissue (p<0.05, p<0.01).SK-MEL-28R and A375R melanoma cisplatin-resistant strains were created effectively. They were 12.6 and 10.2 times more resistant to cisplatin, respectively than the parental cells. P-gp protein expression was substantially higher in cisplatinresistant strains than in parental strains. Sox4 inhibition lowered the IC50 value of cisplatin in resistant cells. (The IC50 value of SK-MEL-28R+NC was 122.7 mg/L and 24.4 mg/L for SKMEL- 28R+sh-sox4; the IC50 value of A375R+NC was 40.55 mg/L and 5.99 mg/L for A375R+sh-sox4). Meanwhile, Sox4 knockdown causes S phase arrest and enhanced caspase-3 activity in cisplatin-resistant melanoma cells. Sox4 knockdown led to activation of the P38 signaling pathway in resistant cells, according to genome-wide expression analysis, qRT-PCR, and Western blot detection.

Conclusion: Our findings imply that inhibiting Sox4 can improve the sensitivity of drugresistant melanoma cells to cisplatin via the P38 signaling pathway, thus opening up a new route for melanoma treatment.

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来源期刊
CiteScore
3.10
自引率
5.60%
发文量
327
审稿时长
7.5 months
期刊介绍: Combinatorial Chemistry & High Throughput Screening (CCHTS) publishes full length original research articles and reviews/mini-reviews dealing with various topics related to chemical biology (High Throughput Screening, Combinatorial Chemistry, Chemoinformatics, Laboratory Automation and Compound management) in advancing drug discovery research. Original research articles and reviews in the following areas are of special interest to the readers of this journal: Target identification and validation Assay design, development, miniaturization and comparison High throughput/high content/in silico screening and associated technologies Label-free detection technologies and applications Stem cell technologies Biomarkers ADMET/PK/PD methodologies and screening Probe discovery and development, hit to lead optimization Combinatorial chemistry (e.g. small molecules, peptide, nucleic acid or phage display libraries) Chemical library design and chemical diversity Chemo/bio-informatics, data mining Compound management Pharmacognosy Natural Products Research (Chemistry, Biology and Pharmacology of Natural Products) Natural Product Analytical Studies Bipharmaceutical studies of Natural products Drug repurposing Data management and statistical analysis Laboratory automation, robotics, microfluidics, signal detection technologies Current & Future Institutional Research Profile Technology transfer, legal and licensing issues Patents.
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