口腔疾病防治 ›› 2021, Vol. 29 ›› Issue (5): 296-305.DOI: 10.12016/j.issn.2096-1456.2021.05.002
收稿日期:
2020-09-25
修回日期:
2020-12-04
出版日期:
2021-05-20
发布日期:
2021-03-08
通讯作者:
陶岚,周海文
作者简介:
徐思明,硕士研究生,Email: 基金资助:
XU Siming1(),SONG Yuhan1,SHAO Yanxiong1,TAO Lan2(
),ZHOU Haiwen1(
)
Received:
2020-09-25
Revised:
2020-12-04
Online:
2021-05-20
Published:
2021-03-08
Contact:
Lan TAO,Haiwen ZHOU
Supported by:
摘要:
目的 探讨环状RNA (circRNA)在口腔白斑(oral leukoplakia,OLK)组织及正常口腔黏膜组织(normal oral mucosal, NOM)中表达谱的差异及临床意义。方法 采用高通量测序技术检测6对OLK和NOM组织中差异表达circRNA,利用qRT-PCR验证所筛选的10个circRNA在6对OLK与NOM组织中的表达情况。通过酶耐受实验和sanger测序验证目标circRNA成环情况,对20对OLK与NOM组织中目标circHLA-C进行qRT-PCR验证。分别使用UCSC基因组浏览器对circHLA-C进行可视化分析;利用GO和KEGG富集分析对差异表达circRNA进行功能分析;TargetScan、MiRanda预测目标circRNA下游miRNA、mRNA,并构建竞争性内源RNA(competing endogenous RNA,ceRNA)网络。结果 测序数据显示OLK组织中共有366个显著差异表达的circRNA,包括65个上调和301个下调circRNA。经qRT-PCR验证,筛选的10个circRNA中有7个表达结果同测序一致。且经酶耐受和sanger测序验证,确定上调的circHLA-C是具有反式剪接位点的真正的circRNA。相关性分析显示circHLA-C与OLK的异常增生程度呈正相关。ROC曲线分析提示circHLA-C具有诊断OLK的潜在价值,且具有较高的准确性和特异性。结论 circRNA在OLK组织中异常表达,上调的circHLA-C表达可能与OLK异常增生程度相关,对OLK诊断具有指导价值。
中图分类号:
徐思明,宋雨翰,邵彦雄,陶岚,周海文. 口腔白斑病组织中环状RNA的差异表达谱分析[J]. 口腔疾病防治, 2021, 29(5): 296-305.
XU Siming,SONG Yuhan,SHAO Yanxiong,TAO Lan,ZHOU Haiwen. Differential expression profile of circRNAs in oral leukoplakia[J]. Journal of Prevention and Treatment for Stomatological Diseases, 2021, 29(5): 296-305.
Number | Age (year) | Sex | Location | Dysplasia degree | Smoking history (No/Yes) | Alcohol history (No/Yes) |
---|---|---|---|---|---|---|
1 | 47 | Female | Dorsal of the tongue | Mild | No | No |
2 | 61 | Female | Ventral of the tongue | Mild | No | No |
3 | 41 | Male | Ventral of the tongue | Mild | No | No |
4 | 51 | Female | Ventral of the tongue | Mild-moderate | No | No |
5 | 69 | Male | Ventral of the tongue | Mild-moderate | No | Yes |
6 | 52 | Female | Buccal | Moderate-severe | No | No |
表1 高通量测序口腔白斑组织的临床特点
Table 1 The clinical characteristics of patients with oral leukoplakia for sequencing
Number | Age (year) | Sex | Location | Dysplasia degree | Smoking history (No/Yes) | Alcohol history (No/Yes) |
---|---|---|---|---|---|---|
1 | 47 | Female | Dorsal of the tongue | Mild | No | No |
2 | 61 | Female | Ventral of the tongue | Mild | No | No |
3 | 41 | Male | Ventral of the tongue | Mild | No | No |
4 | 51 | Female | Ventral of the tongue | Mild-moderate | No | No |
5 | 69 | Male | Ventral of the tongue | Mild-moderate | No | Yes |
6 | 52 | Female | Buccal | Moderate-severe | No | No |
Circular RNA | Primer type | Primer sequence (5’-3’) |
---|---|---|
CircHLA-C (chr6:31238920-31324013-) | Forward | CGGCAAGGATTACATCGC |
Reverse | CCTTCCCGTTCTCCAGGT | |
CircPLIN4 (chr19:4511523-4511918-) | Forward | TGTGTGCAGTGGGGTGAC |
Reverse | CCCTTTGGCGACATTCAC | |
CircMTX2 (chr2:177161588-177202305+) | Forward | TGACGCACTGGTATTTGGC |
Reverse | GCATTTTCAGGCCAAGGTT | |
CircRNF13 (chr3:149613260-149639014+) | Forward | TGGGCATCTGTCTCATCTTG |
Reverse | GTCGTTGGATCCCATGCT | |
CircSENP2 (chr3:185293003-185344181+) | Forward | CCTCAACAGCTGAATGGGA |
Reverse | CCCACATCTCCCCCTTCT | |
CircPLEKHM2 (chr1:16044388-16047883+) | Forward | ACTCCGTCACCTCCACCA |
Reverse | CCGCAGGTAGCTCTCCAA | |
CircEMB (chr5:49694941-49707217-) | Forward | TGCTCAGCAGGAGCTTCA |
Reverse | CTGCATTCAAATCCCCAGA | |
CircERICH1 (chr8:618598-624047-) | Forward | AAAACGCTGCTGCTCCTG |
Reverse | TCTTTGGCTGGTCATGAGG | |
CircALDH3A2 (chr17:19554860-19575269+) | Forward | TCAAAGGTGGATTGGGGA |
Reverse | CATCCAGCATGGTGAGCA | |
CircZNF720 (chr16:31733947-31734674+) | Forward | CGCTGTCTCTAAGCCGGA |
Reverse | GGTGTTCCCACTCCTCCC |
表2 qRT-PCR引物信息
Table 2 The primers used for qRT-PCR experiments
Circular RNA | Primer type | Primer sequence (5’-3’) |
---|---|---|
CircHLA-C (chr6:31238920-31324013-) | Forward | CGGCAAGGATTACATCGC |
Reverse | CCTTCCCGTTCTCCAGGT | |
CircPLIN4 (chr19:4511523-4511918-) | Forward | TGTGTGCAGTGGGGTGAC |
Reverse | CCCTTTGGCGACATTCAC | |
CircMTX2 (chr2:177161588-177202305+) | Forward | TGACGCACTGGTATTTGGC |
Reverse | GCATTTTCAGGCCAAGGTT | |
CircRNF13 (chr3:149613260-149639014+) | Forward | TGGGCATCTGTCTCATCTTG |
Reverse | GTCGTTGGATCCCATGCT | |
CircSENP2 (chr3:185293003-185344181+) | Forward | CCTCAACAGCTGAATGGGA |
Reverse | CCCACATCTCCCCCTTCT | |
CircPLEKHM2 (chr1:16044388-16047883+) | Forward | ACTCCGTCACCTCCACCA |
Reverse | CCGCAGGTAGCTCTCCAA | |
CircEMB (chr5:49694941-49707217-) | Forward | TGCTCAGCAGGAGCTTCA |
Reverse | CTGCATTCAAATCCCCAGA | |
CircERICH1 (chr8:618598-624047-) | Forward | AAAACGCTGCTGCTCCTG |
Reverse | TCTTTGGCTGGTCATGAGG | |
CircALDH3A2 (chr17:19554860-19575269+) | Forward | TCAAAGGTGGATTGGGGA |
Reverse | CATCCAGCATGGTGAGCA | |
CircZNF720 (chr16:31733947-31734674+) | Forward | CGCTGTCTCTAAGCCGGA |
Reverse | GGTGTTCCCACTCCTCCC |
图1 OLK与NOM组织中circRNA的表达谱
Figure 1 Expression profiles of circRNAs in OLK versus NOM tissues a: hierarchical clustering analysis showed circRNA expression profles that were different between OLK tissues and NOM tissues; red represents upregulated circRNAs, and green represents downregulated circRNAs; b: scatter plot of differences in circRNA expression between OLK and NOM tissues; red represents upregulated circRNAs with FC ≥ 2.0 in OLK tissues; green represents downregulated circRNAs with FC ≥ 2.0; c: volcano plot of signifcantly dysregulated circRNAs in OLK tissues; red represents eligible circRNAs (FC ≥ 2.0; P < 0.05). OLK: oral leukoplakia; NOM: normal oral mucosal
图2 显著表达差异circRNA分布特点
Figure 2 Distribution of the characteristics of significantly dysregulated circRNAs a: significantly differentially expressed circRNAs were divided into 4 types according to the host gene structure(exon, intron, antisense, and sense overlapping circRNA); b: filtered circRNAs were classified by whether they were newly discovered; c: classification according to the circRNA length; d: chromosome distribution of upregulated and downregulated signifcantly differentially expressed circRNAs
CircRNA ID | FC | P | Chromosome | Strand | Gene name | Sequence length(bp) |
---|---|---|---|---|---|---|
CircHLA-C(chr6:31238920-31324013-) | 7.719 | < 0.001 | chr6 | - | HLA-C | 85 094 |
CircPLIN4(chr19:4511523-4511918-) | 5.992 | 0.001 | chr19 | - | PLIN4 | 396 |
CircMTX2(chr2:177161588-177202305+) | 5.980 | 0.003 | chr2 | + | MTX2 | 40 718 |
CircRNF13(chr3:149613260-149639014+) | 5.735 | 0.002 | chr3 | + | RNF13 | 379 |
CircSENP2(chr3:185293003-185344181+) | -8.583 | < 0.001 | chr3 | + | SENP2 | 51 179 |
CircPLEKHM2(chr1:16044388-16047883+) | -6.122 | < 0.001 | chr1 | + | PLEKHM2 | 435 |
CircERICH1(chr8:618598-624047-) | -5.917 | < 0.001 | chr8 | - | ERICH1 | 954 |
CircEMB(chr5:49694941-49707217-) | -5.722 | < 0.001 | chr5 | - | EMB | 12 277 |
CircALDH3A2(chr17:19554860-19575269+) | -5.532 | 0.006 | chr17 | + | ALDH3A2 | 1 290 |
CircZNF720(chr16:31733947-31734674+) | -5.258 | 0.001 | chr16 | + | ZNF720 | 223 |
表3 OLK组织10个显著表达差异circRNA
Table 3 Ten circRNAs differentially expressed in OLK
CircRNA ID | FC | P | Chromosome | Strand | Gene name | Sequence length(bp) |
---|---|---|---|---|---|---|
CircHLA-C(chr6:31238920-31324013-) | 7.719 | < 0.001 | chr6 | - | HLA-C | 85 094 |
CircPLIN4(chr19:4511523-4511918-) | 5.992 | 0.001 | chr19 | - | PLIN4 | 396 |
CircMTX2(chr2:177161588-177202305+) | 5.980 | 0.003 | chr2 | + | MTX2 | 40 718 |
CircRNF13(chr3:149613260-149639014+) | 5.735 | 0.002 | chr3 | + | RNF13 | 379 |
CircSENP2(chr3:185293003-185344181+) | -8.583 | < 0.001 | chr3 | + | SENP2 | 51 179 |
CircPLEKHM2(chr1:16044388-16047883+) | -6.122 | < 0.001 | chr1 | + | PLEKHM2 | 435 |
CircERICH1(chr8:618598-624047-) | -5.917 | < 0.001 | chr8 | - | ERICH1 | 954 |
CircEMB(chr5:49694941-49707217-) | -5.722 | < 0.001 | chr5 | - | EMB | 12 277 |
CircALDH3A2(chr17:19554860-19575269+) | -5.532 | 0.006 | chr17 | + | ALDH3A2 | 1 290 |
CircZNF720(chr16:31733947-31734674+) | -5.258 | 0.001 | chr16 | + | ZNF720 | 223 |
图3 OLK组织10个显著差异表达circRNA
Figure 3 Ten circRNAs differentially expressed in OLK a: ten selected circRNAs were subjected to qRT-PCR validation in 6 NOM and 6 OLK tissues; b: comparison of the results of high-throughput sequencing and qRT-PCR. c: RNase R analysis showed that circHLA-C, circPLIN4 and circRNF13 resisted digestion by RNase R; *:P < 0.05. OLK: oral leukoplakia; FC: fold change; HLA-C: human leukocyte antigen-C; PLIN4: perilipin-4; MTX2: metaxin 2; RNF13: ring finger protein 13; SENP2: sentrin/SUMO-specific proteases; PLEKHM2: pleckstrin homology and RUN domain containing M2; ERICH1: glutamate rich 1; EMB: embigin; ALDH3A2: aldehyde dehydrogenase 3 family member A2; ZNF720: zinc finger protein 720
图5 KEGG分析OLK中差异表达circRNA
Figure 5 KEGG analysis of the differential expression of circRNA in OLK a: top 10 in the KEGG analysis of upregulated circRNAs; b: top 10 in the KEGG analysis of downregulated circRNAs. The terms in the red frame indicate important pathways in OLK; OLK:oral leukoplakia
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