<italic style="font-style: italic">TC</italic>2<italic style="font-style: italic">N</italic>基因促进黑色素瘤的生长及其机制

娄义霞; 顾晶; 朱磊; 孙胜琪; 刘康乐; 姜晓; 韩飞; 陈建平; 曹佳; 刘晋祎

doi:10.16016/j.2097-0927.202301120

您当前的位置：

首页 >

文章列表页 >

TC2N基因促进黑色素瘤的生长及其机制

基础医学 | 更新时间：2026-01-09

- TC2N基因促进黑色素瘤的生长及其机制
- Mechanism of TC2N gene promoting the growth of melanoma
- 陆军军医大学学报 2023年45卷第10期页码：1020-1029
- 作者机构：
  
  1.400038 重庆，陆军军医大学(第三军医大学)军事预防医学系毒理学研究所
  2.750004 银川，宁夏医科大学公共卫生与管理学院劳动卫生与环境卫生教研室
  3.400016 重庆，重庆医科大学公共卫生学院毒理学教研室
- 作者简介：
  
  [刘晋祎, E-mail: jinyiliutmmu@163.comLIU Jinyi, E-mail: jinyiliutmmu@163.com
- 基金信息：
  
  国家自然科学基金青年科学基金(81902711);国家自然科学基金青年项目(82002446)
- DOI：10.16016/j.2097-0927.202301120
  中图分类号： R394.3;R730.23;R739.5
- 收稿：2023-01-31，
  
  修回：2023-03-21，
  
  纸质出版：2023-05-30
- 稿件说明：
移动端阅览
娄义霞, 顾晶, 朱磊, 等. TC2N基因促进黑色素瘤的生长及其机制[J]. 陆军军医大学学报, 2023,45(10):1020-1029.

Yixia LOU, Jing GU, Lei ZHU, et al. Mechanism of TC2N gene promoting the growth of melanoma[J]. Journal of Army Medical University, 2023, 45(10): 1020-1029.
娄义霞, 顾晶, 朱磊, 等. TC2N基因促进黑色素瘤的生长及其机制[J]. 陆军军医大学学报, 2023,45(10):1020-1029. DOI： 10.16016/j.2097-0927.202301120.

Yixia LOU, Jing GU, Lei ZHU, et al. Mechanism of TC2N gene promoting the growth of melanoma[J]. Journal of Army Medical University, 2023, 45(10): 1020-1029. DOI： 10.16016/j.2097-0927.202301120.

摘要

目的

初步探讨

基因对皮肤黑色素瘤(skin cutaneous melanoma，SKCM)发生的影响及其作用机制。

方法

使用人类蛋白质图谱(The Human Protein Atlas

HPA)和肿瘤基因图谱(The Cancer Genome Atlas

TCGA)数据库分析

在SKCM中的表达及与临床病理特征的关系。利用人黑色素瘤A375构建

基因的过表达细胞模型，采用CCK-8法检测

在细胞增殖中的作用。利用

基因敲除小鼠构建皮肤黑色素移植瘤模型，观察并测量移植瘤的生长，通过免疫组化测定Ki67在移植瘤组织中的表达，分析肿瘤细胞的增殖。此外，进行基因集富集分析(Gene Set Enrichment

Analysis

GSEA)探索

表达与ERK/MAPK信号通路的相关性，并利用RT-qPCR和Western blot法检测相关基因

CyclinD

1、

c-Myc

、

CDK

2和

CyclinE

1在体内外的mRNA及蛋白表达水平。

结果

与正常皮肤组织比较，SKCM组织中

的表达水平更高，且

基因的高表达与SKCM患者的临床病理分期和淋巴结转移显著相关(

0.05)。体外细胞实验发现，过表达

基因后，A375细胞的增殖能力显著增加(

0.05)。敲除小鼠皮下移植瘤模型结果显示，与TC2N

+/+

小鼠比较，TC2N

-/-

小鼠肿瘤质量和体积明显降低(

0.05)，提示

基因敲除后显著抑制SKCM的生长。GSEA富集分析提示TC2N与MAPK信号通路显著相关(

0.01)，且

基因与ERK/MAPK下游基因表达呈正相关(

0.01)。体内外实验均发现，

表达显著促进ERK与p-ERK表达，且影响ERK相关分子

CyclinD

1、

c-Myc

、

CDK

2和

CyclinE

1的mRNA和蛋白的表达水平(

0.01)。

结论

基因可能通过激活ERK/MAPK信号通路促进皮肤黑色素瘤的生长。

Abstract

Objective

To investigate the effect and mechanism of

in skin cutaneous melanoma (SKCM).

Methods

Using the Human Protein Atlas (HPA) and The Cancer Genome Atlas (TCGA) databases to analyze the expression and correlation of clinicopathologic feature of

in SKCM. Human melanoma A375 cells were used to construct an overexpression cell model of

. CCK-8 assay method was used to detect the effect of

on cell proliferation. Cutaneous melanin xenograft model was constructed in

knockout mice

and the tumor growth was observed and measured. Based on the animal model

the

expression of Ki67 was detected in transplanted tumor by immunohistochemistry to analyze the proliferation of tumor cells. In addition

Gene Set Enrichment Analysis (GSEA) was performed to investigate the correlation between

expression and ERK/MAPK signaling pathway. RT-qPCR and Western blot assay were used to detect mRNA and protein expression levels of related genes(

CyclinD

c-Myc

CDK

2 and

CyclinE

in vitro

and

in vivo

Results

Compared with normal skin tissues

the expression level of

protein in SKCM tissues was higher

which was significantly associated with clinicopathological stages and lymphatic node metastasis in patients with SKCM (

0.05).

In vitro

cell experiments demonstrated that the proliferation ability of A375 cells were significantly increased after

overexpression (

0.05). The results of skin melanin xenograft model of knockout mouse revealed that compared with TC2N

+/+

mice

the tumor weight and tumor volume of TC2N

-/-

mice were significantly decreased (

0.05)

suggesting that

knockout significantly inhibited the growth of SKCM. GSEA enrichment analysis indicated that

was significantly correlated with MAPK signaling pathway (

0.01)

and

was positively correlated with ERK/MAPK downstream gene expression (all

0.01). Experiments

in vivo

and

in vitro

showed

expression significantly promoted the expression of ERK and p-ERK

and exerted effect on the mRNA and protein expression levels of ERK-related molecues

CyclinD

c-Myc

CDK

2 and

CyclinE

0.01).

Conclusion

gene may promote the growth of cutaneous melanoma through activating ERK/MAPK signaling pathway.

关键词

Keywords

references

POTRONY M, BADENAS C, AGUILERA P, et al . Update in genetic susceptibility in melanoma[J ] . Ann Transl Med, 2015, 3(15): 210. DOI: 10.3978/j.issn.2305-5839.2015.08.11.

DING L, GOSH A, LEE D J, et al . Prognostic biomarkers of cutaneous melanoma[J ] . Photodermatol Photoimmunol Photomed, 2022, 38(5): 418-434. DOI: 10.1111/phpp.12770.

SIEGEL R L, MILLER K D, JEMAL A. Cancer statistics, 2020[J]. CA Cancer J Clin, 2020, 70(1): 7-30. DOI: 10.3322/caac.21590.

IGLESIAS-PENA N, P ARADELA S, TEJERA-VAQUERIZO A, et al . Cutaneous melanoma in the elderly: review of a growing problem[J ] . Actas Dermo Sifiliográficas Engl Ed, 2019, 110(6): 434-447. DOI: 10.1016/j.adengl.2019.05.012.

TRIPP M K, WATSON M, BALK S J, et al . State of the science on prevention and screening to reduce melanoma incidence and mortality: the time is now[J ] . CA Cancer J Clin, 2016, 66(6): 460-480. DOI: 10.3322/caac.21352.

HUANG B, HAN W, SHENG Z F, et al . Identification of immune-related biomarkers associated with tumorigenesis and prognosis in cutaneous melanoma patients[J ] . Cancer Cell Int, 2020, 20: 195. DOI: 10.1186/s12935-020-01271-2.

VYSOTSKAIA V, KASENIIT K E, BUCHEIT L, et al . Clinical utility of hereditary cancer panel testing: impact of PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D results on patient management and adherence to provider recommendations[J ] . Cancer, 2020, 126(3): 549-558. DOI: 10.1002/cncr.32572.

XIONG Z C, WU J M, SUN Y, et al . Variants in multiple genes are associated with esophageal cancer risk in a Chinese Han population: a case-control study[J ] . J Gene Med, 2020, 22(12): e3266. DOI: 10.1002/jgm.3266.

LI H Y, FANG H, CHANG L, et al . TC2N: a novel vital oncogene or tumor suppressor gene incancers[J ] . Front Immunol, 2021, 12: 764749. DOI: 10.3389/fimmu.2021.764749.

KABEKKODU S P, BHAT S, RADHAKRISHNAN R, et al . DNA promoter methylation-dependent transcription of the double C2-like domain β ( DOC2B ) gene regulates tumor growth in human cervical cancer[J ] . J Biol Chem, 2014, 289(15): 10637-10649. DOI: 10.1074/jbc.M113.491506..

王硕, 朴大勋, 任硕. CPNE1在肿瘤中的研究进展[J]. 现代消化及介入诊疗, 2022, 27(4): 516-519. DOI: 10.3969/j.issn.1672-2159.2022.04.025.

WANG S, PIAO D X, REN S. Research progress of CPNE1 in tumor[J]. Mod Dig Interv, 2022, 27(4): 516-519. DOI: 10.3969/j.issn.1672-2159.2022.04.025.

HAO X L, HAN F, ZHANG N, et al . TC2N, a novel oncogene, accelerates tumor progression by suppressing p53 signaling pathway in lung cancer[J ] . Cell Death Differ, 2019, 26(7): 1235-1250. DOI: 10.1038/s41418-018-0202-8.

HAO X L, GAO L Y, DENG X J, et al . Identification of TC2N as a novel promising suppressor of PI3K-AKT signaling in breast cancer[J ] . Cell Death Dis, 2019, 10(6): 424. DOI: 10.1038/s41419 -019-1663-5.

DOU Y F, XU H K, WU X Q, et al . Tac2-N promotes glioma proliferation and indicates poor clinical outcomes[J ] . Tohoku J Exp Med, 2021, 255(3): 247-256. DOI: 10.1620/tjem.255.247.

FUKUDA M, MIKOSHIBA K. Tac2-N, an atypical C-type tandem C2 protein localized in the nucleus[J]. FEBS Lett, 2001, 503(2/3): 217-218. DOI: 10.1016/s0014-5793(01)02738-7.

BLOMME A, COSTANZA B, DE TULLIO P, et al . Myoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer[J ] . Oncogene, 2017, 36(15): 2116-2130. DOI: 10.1038/onc.2016.369.

PROKOP J W, HARTOG N L, CHESLA D, et al . High-density blood transcriptomics reveals precision immune signatures of SARS-CoV-2 infection in hospitalized individuals[J ] . Front Immunol, 2021, 12: 694243. DOI: 10.3389/fimmu.2021.694243.

刘博, 黄露, 李德峰, 等. 潜在癌基因TC2N在胶质瘤中的表达、临床意义及下游信号通路的综合分析[J]. 中国煤炭工业医学杂志, 2022, 25(4): 341-346. DOI: 10.11723/mtgyyx1007-9564202204002.

LIU B, HUANG L, LI D F, et al . Identification of TC2N as a promising o ncogene in glioma:an integrated analysis of expression, clinical implication and downstream signaling pathway of TC2N[J ] . Chin J Coal Ind Med, 2022, 25(4): 341-346. DOI: 10.11723/mtgyyx1007-9564202204002.

QURESHI M A, KHAN S, TAUHEED M S, et al . Pan-cancer multiomics analysis of TC 2 N gene suggests its important role(s) in tumourigenesis of many cancers[J ] . Asian Pac J Cancer Prev, 2020, 21(11): 3199-3209. DOI: 10.31557/APJCP.2020.21.11.3199..

SUN H Z, OU B C, ZHAO S L, et al . USP11 promotes growth and metastasis of colorectal cancer via PPP1CA-mediated activation of ERK/MAPK signaling pathway[J ] . EBio Medicine, 2019, 48: 236-247. DOI: 10.1016/j.ebiom.2019.08.061..

DANG F B, NIE L, WEI W Y. Ubiquitin signaling in cell cycle control and tumorigenesis[J]. Cell Death Differ, 2021, 28(2): 427-438. DOI: 10.1038/s41418-020-00648-0.

FAN W D, CHEN T, LIU P J. NIMA related kinase 2 promotes gastric cancer cell proliferation via ERK/MAPK signaling[J ] . World J Gastroenterol, 2019, 25(23): 2898-2910. DOI: 10.3748/wjg.v25.i23.2898.

梁颖, 程钢, 黄邓高. 亚砷酸诱导肺腺癌A549细胞凋亡及对MAPK/ERK信号通路的影响[J]. 中国肿瘤外科杂志, 2020, 12(1): 13-17. DOI: 10.3969/j.issn.1674-4136.2020.01.004.

LIANG Y, CHENG G, HUANG D G. Arsenous acid in the induction of apoptosis of lung adenocarcinoma A549 cells and its effects on MAPK/ERK signaling pathway[J]. Chin J Surg Oncol, 2020, 12(1): 13-17. DOI: 10.3969/j.issn.1674-4136.2020.01.004.

HUANG L P, CHEN S, FAN H J, et al . BZW2 promotes the malignant progression of colorectal cancer via activating the ERK/MAPK pathway[J ] . J Cell Physiol, 2020, 235(5): 4834-4842. DOI: 10.1002/jcp.29361..

NIU M Y, ZHANG B, LI L, et al . Targeting HSP90 inhibits proliferation and induces apoptosis through AKT1/ERK pathway in lung cancer[J ] . Front Pharmacol, 2022, 12: 724192. DOI: 10.3389/fphar.2021.724192.

XU C, ZHENG J H. siRNA against TSG101 reduces proliferation and induces G0/G1 arrest in renal cell carcinoma—involvement of c-myc, cyclin E1, and CDK2[J]. Cell Mol Biol Lett, 2019, 24: 7. DOI: 10.1186/s11658-018-0124-y.

CAO H J, WANG Z Q, WANG Y, et al . PPP1R14D promotes the proliferation, migration and invasion of lung adenocarcinoma via the PKCα/BRAF/MEK/ERK signaling pathway[J ] . Int J Oncol, 2022, 6 1(6): 153. DOI: 10.3892/ijo.2022.5443..

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

超低浓度二甲基亚砜促进皮肤成纤维细胞增殖作用及机制研究

谷胱甘肽过氧化物酶7通过PI3K-AKT通路调控肝癌细胞增殖和衰老

静息期精原前体细胞Rb1基因敲除致精原干细胞特化异常机制初探

生物钟基因PER1调控口腔鳞癌细胞中BAX、BCL2和PCNA表达的昼夜节律

TC2N基因促进黑色素瘤的生长及其机制

Mechanism of TC2N gene promoting the growth of melanoma

DOI：10.16016/j.2097-0927.202301120

摘要

Abstract

关键词

Keywords

references