CCCTC结合因子通过抵抗凋亡促进奥沙利铂相关胃癌药物耐受细胞形成

doi:10.3969/j.issn.1006-5725.2025.04.005

Abstract

Abstract:

Objective To investigate the role of CCCTC-binding factor （CTCF） in the development of oxaliplatin （OXA）-induced gastric cancer drug-tolerant cells （DTCs） and to preliminarily elucidate its underlying mechanisms. Methods The DTCs model of gastric cancer was established by treating MGC803 cells with OXA. Overexpression and knockdown of CTCF in MGC803 cells were performed to observe their effects on the formation of DTCs in gastric cancer. Additionally， Bcl2-like protein 1 （BCL2L1） was knocked down in CTCF-overexpressing cells， and its impact on DTCs formation was evaluated. Flow cytometry was used to analyze the effects of varying CTCF/BCL2L1 expression levels on the apoptosis of gastric cancer cells under OXA treatment. Immunohistochemistry （IHC） was employed to detect the expression levels of CTCF/BCL2L1 in gastric cancer tissues， and the therapeutic outcomes of neoadjuvant chemotherapy in patients with different CTCF/BCL2L1 expression levels were assessed. Results Gastric cancer DTCs can be obtained following a regimen of continuous treatment of MGC803 cells with a specific concentration of oxaliplatin （OXA， 1.5 μmol/L） for 5 days， followed by an additional 5-day culture period post-treatment cessation. The upregulation of CTCF has been shown to facilitate the formation of DTCs in gastric cancer， whereas its downregulation inhibits this process （P < 0.05）. In MGC803 gastric cancer cells， the expression level of BCL2L1 is positively correlated with that of CTCF. Knockdown of BCL2L1 in MGC803 cells overexpressing CTCF can reverse the pro-DTC formation effect of CTCF （P < 0.05）. Overexpression of CTCF confers resistance to OXA-induced apoptosis in gastric cancer cells， and this anti-apoptotic effect can be reversed by BCL2L1 knockdown in MGC803 cells overexpressing CTCF （P < 0.05）. In the tumor tissues of the majority of gastric cancer patients， the expression levels of BCL2L1 are positively correlated with those of CTCF， and the efficacy of neoadjuvant chemotherapy is notably reduced in patients with high expression of the CTCF/BCL2L1 axis compared to those with low expression （P < 0.05）. Conclusion CTCF promotes the formation of OXA-related gastric cancer DTCs by upregulating BCL2L1 expression and inhibiting apoptosis， making the CTCF/BCL2L1 axis a potential therapeutic target for DTCs in gastric cancer.

Key words: gastric cancer, oxaliplatin, drug tolerant cells, apoptosis, CTCF, BCL2L1

CLC Number:

R735.2

Zonglin LI,Chunlin FENG,Xin LIU,Xingming SHU,Min. SONG. CCCTC⁃binding factors promote the formation of oxaliplatin related gastric cancer drug-tolerant cells by resisting apoptosis[J]. The Journal of Practical Medicine, 2025, 41(4): 490-499.

Figures/Tables 13

Fig. 1

Fig. 2

Tab. 1

Tab. 2

Fig.3

Fig.4

Tab.3

Tab.4

Fig.5

Tab. 5

Fig.6

Fig.7

Tab.6

References 28

1	XIA C， DONG X， LI H， et al. Cancer statistics in China and United States， 2022： Profiles， trends， and determinants［J］. Chin Med J （Engl）， 2022， 135（5）： 584-590. doi:10.1097/cm9.0000000000002108 doi: 10.1097/cm9.0000000000002108
2	LI Z， SHU X， LIU X， et al. Cellular and molecular mechanisms of chemoresistance for gastric cancer［J］. Int J Gen Med， 2024， 17： 3779-3788. doi:10.2147/ijgm.s473749 doi: 10.2147/ijgm.s473749
3	LEE J， MASHIMA T， KAWATA N， et al. Pharmacologic Targeting of Histone H3K27 Acetylation/BRD4-dependent Induction of ALDH1A3 for Early-phase Drug Tolerance of Gastric Cancer［J］. Cancer Res Commun， 2024， 4（5）： 1307-1320. doi:10.1158/2767-9764.crc-23-0639 doi: 10.1158/2767-9764.crc-23-0639
4	KAWAKAMI R， MASHIMA T， KAWATA N， et al. Aldh1a3-mtor axis as a therapeutic target for anticancer drug-tolerant persister cells in gastric cancer［J］. Cancer Sci， 2020， 111（3）： 962-973. doi:10.1111/cas.14316 doi: 10.1111/cas.14316
5	PU Y， LI L， PENG H， et al. Drug-tolerant persister cells in cancer： The cutting edges and future directions［J］. Nat Rev Clin Oncol， 2023， 20（11）： 799-813. doi:10.1038/s41571-023-00815-5 doi: 10.1038/s41571-023-00815-5
6	SONG X， LAN Y， ZHENG X， et al. Targeting drug-tolerant cells： A promising strategy for overcoming acquired drug resistance in cancer cells［J］. MedComm （2020）， 2023， 4（5）： e342. doi:10.1002/mco2.342 doi: 10.1002/mco2.342
7	DEBAUGNY R E， SKOK J A. Ctcf and ctcfl in cancer［J］. Curr Opin Genet Dev， 2020， 61： 44-52. doi:10.1016/j.gde.2020.02.021 doi: 10.1016/j.gde.2020.02.021
8	BOSE S， SAHA S， GOSWAMI H， et al. Involvement of ccctc-binding factor in epigenetic regulation of cancer［J］. Mol Biol Rep， 2023， 50（12）： 10383-10398. doi:10.1007/s11033-023-08879-3 doi: 10.1007/s11033-023-08879-3
9	SUN L， HUANG C， ZHU M， et al. Gastric cancer mesenchymal stem cells regulate pd-l1-ctcf enhancing cancer stem cell-like properties and tumorigenesis［J］. Theranostics， 2020， 10（26）： 11950-11962. doi:10.7150/thno.49717 doi: 10.7150/thno.49717
10	YU L， GAO Y， JI B， et al. CTCF-induced upregulation of LINC01207 promotes gastric cancer progression via miR-1301-3p/PODXL axis［J］. Dig Liver Dis， 2021， 53（4）： 486-495. doi:10.1016/j.dld.2020.12.006 doi: 10.1016/j.dld.2020.12.006
11	中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会（CSCO）胃癌诊疗指南（2024版）［M］. 北京：人民卫生出版社， 2024： 166.
12	CARA S， TANNOCK I F. Retreatment of patients with the same chemotherapy： Implications for clinical mechanisms of drug resistance［J］. Ann Oncol， 2001， 12（1）： 23-27. doi:10.1023/a:1008389706725 doi: 10.1023/a:1008389706725
13	WANG P， KE B， MA G. Drug-tolerant persister cancer cells［J］. J Natl Cancer Cent， 2024， 4（1）： 1-5. doi:10.1016/j.jncc.2023.12.002 doi: 10.1016/j.jncc.2023.12.002
14	ISHIDA K， ITO C， OHMORI Y， et al. Inhibition of pi3k suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil［J］. Sci Rep， 2017， 7（1）： 2262. doi:10.1038/s41598-017-02548-9 doi: 10.1038/s41598-017-02548-9
15	NAKAMURA A， MASHIMA T， LEE J， et al. Intratumor transforming growth factor-beta signaling with extracellular matrix-related gene regulation marks chemotherapy-resistant gastric cancer［J］. Biochem Biophys Res Commun， 2024， 721： 150108. doi:10.1016/j.bbrc.2024.150108 doi: 10.1016/j.bbrc.2024.150108
16	KIM T H， ABDULLAEV Z K， SMITH A D， et al. Analysis of the vertebrate insulator protein ctcf-binding sites in the human genome［J］. Cell， 2007， 128（6）： 1231-1245. doi:10.1016/j.cell.2006.12.048 doi: 10.1016/j.cell.2006.12.048
17	ZHOU T， CHEN Z， CHEN Y， et al. Chronic stress promotes non-small cell lung cancer （nsclc） progression through circmboat2 upregulation mediated by ctcf［J］. Cancer Gene Ther， 2024， 31（11）：1721-1733. doi:10.1038/s41417-024-00830-3 doi: 10.1038/s41417-024-00830-3
18	KAKANI P， DHAMDHERE S G， PANT D， et al. Hypoxia-induced ctcf promotes emt in breast cancer［J］. Cell Rep， 2024， 43（7）： 114367. doi:10.1016/j.celrep.2024.114367 doi: 10.1016/j.celrep.2024.114367
19	DONG H， LIU Q， CHEN C， et al. LncRNA OGFRP1 promotes angiogenesis and epithelial-mesenchymal transition in colorectal cancer cells through miR-423-5p/CTCF axis［J］. Immunobiology， 2022， 227（2）： 152176. doi:10.1016/j.imbio.2022.152176 doi: 10.1016/j.imbio.2022.152176
20	WU H， XIA L， SUN L， et al. Rpl35a drives ovarian cancer progression by promoting the binding of yy1 to ctcf promoter［J］. J Cell Mol Med， 2024， 28（6）： e18115. doi:10.1111/jcmm.18115 doi: 10.1111/jcmm.18115
21	ZHAN H， XIAO J， WANG P， et al. Exosomal CTCF Confers Cisplatin Resistance in Osteosarcoma by Promoting Autophagy via the IGF2-AS/miR-579-3p/MSH6 Axis［J］. J Oncol， 2022， 2022： 9390611. doi:10.1155/2022/9390611 doi: 10.1155/2022/9390611
22	聂微，严芝强，成兴真，等. 奥沙利铂通过自噬诱导胃癌细胞耐药的机制［J］. 实用医学杂志， 2022， 38（7）： 828-835.
23	LI J， HUANG K， HU G， et al. An alternative ctcf isoform antagonizes canonical ctcf occupancy and changes chromatin architecture to promote apoptosis［J］. Nat Commun， 2019， 10（1）： 1535. doi:10.1038/s41467-019-08949-w doi: 10.1038/s41467-019-08949-w
24	DOCQUIER F， FARRAR D， D'ARCY V， et al. Heightened expression of ctcf in breast cancer cells is associated with resistance to apoptosis［J］. Cancer Res， 2005， 65（12）： 5112-5122. doi:10.1158/0008-5472.can-03-3498 doi: 10.1158/0008-5472.can-03-3498
25	LI M， WANG D， HE J， et al. Bcl-x（l）： A multifunctional anti-apoptotic protein［J］. Pharmacol Res， 2020， 151： 104547. doi:10.1016/j.phrs.2019.104547 doi: 10.1016/j.phrs.2019.104547
26	PARK H， CHO S Y， KIM H， et al. Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer［J］. Proc Natl Acad Sci U S A， 2015， 112（40）： 12492-12497. doi:10.1073/pnas.1507491112 doi: 10.1073/pnas.1507491112
27	王晓通，吴锟，李雷，等. Shrna-siva1慢病毒载体的构建及其对胃癌细胞耐药性的影响［J］. 实用医学杂志， 2020， 36（3）： 282-287.
28	WEI Y， ZHANG L， WANG C， et al. Anti-apoptotic protein bcl-xl as a therapeutic vulnerability in gastric cancer［J］. Animal Model Exp Med， 2023， 6（3）： 245-254. doi:10.1002/ame2.12330 doi: 10.1002/ame2.12330

组别	OD₄₅₀
组别	1 d	2 d	3 d	4 d	5 d
Vector组	0.025 ± 0.002	0.207 ± 0.024	0.602 ± 0.034	1.284 ± 0.076	2.053 ± 0.142
CTCF?OE组	0.024 ± 0.003	0.213 ± 0.009	0.562 ± 0.103	1.358 ± 0.067	2.141 ± 0.088
t值	0.507	-0.380	0.633	-1.254	-0.909
P值	0.639	0.723	0.561	0.278	0.415
组别	OD₄₅₀
组别	1 d	2 d	3 d	4 d	5 d
shCTRL组	0.024 ± 0.003	0.315 ± 0.038	0.652 ± 0.039	1.255 ± 0.048	2.000 ± 0.092
shCTCF组	0.024 ± 0.003	0.326 ± 0.028	0.703 ± 0.042	1.285 ± 0.121	2.080 ± 0.050
t值	-0.131	-0.444	-1.576	-0.399	-1.318
P值	0.902	0.680	0.190	0.710	0.258

组别	DTCs数量
Vector组	162 ± 25
CTCF?OE组	268 ± 47
t值	-4.261
P值	0.005
组别	DTCs数量
shCTRL组	170 ± 13
shCTCF组	93 ± 21
t值	6.642
P值	0.001

组别	OD₄₅₀
组别	1 d	2 d	3 d	4 d	5 d
Vector?siNC组	0.023 ± 0.002	0.316 ± 0.032	0.692 ± 0.023	1.288 ± 0.033	2.135 ± 0.163
Vector?siBCL2L1组	0.021 ± 0.002	0.308 ± 0.030	0.725 ± 0.366	1.235 ± 0.055	2.066 ± 0.061
CTCF?OE?siNC组	0.023 ± 0.002	0.332 ± 0.017	0.751 ± 0.052	1.368 ± 0.079	2.203 ± 0.074
CTCF?OE?siBCL2L1组	0.024 ± 0.002	0.332 ± 0.023	0.710 ± 0.017	1.371 ± 0.107	2.061 ± 0.064
F值	0.993	0.621	1.546	2.394	1.365
P值	0.444	0.621	0.276	0.144	0.321

组别	DTCs数量
Vector?siNC组	166 ± 29
Vector?siBCL2L1组	76 ± 8
CTCF?OE?siNC组	276 ± 16
CTCF?OE?siBCL2L1组	88 ± 5
t值（a/b/c）	6.600/-7.365/24.896
P值（a/b/c）	< 0.001/< 0.001/< 0.001

组别	DTCs凋亡率
Vector?siNC组	12.6 ± 0.21
Vector?siBCL2L1组	21.67 ± 0.51
CTCF?OE?siNC组	8.17 ± 0.42
CTCF?OE?siBCL2L1组	18.97 ± 0.99
t值（a/b/c）	-28.254/16.621/-17.469
P值（a/b/c）	< 0.001/< 0.001/< 0.001

CCCTC⁃binding factors promote the formation of oxaliplatin related gastric cancer drug-tolerant cells by resisting apoptosis

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 13

References 28

Related Articles 15

Recommended Articles

Metrics

Comments

组别	疗效良好	疗效不良
CTCF/BCL2L1高表达组（n = 23）	8（34.8）	15（65.2）
CTCF/BCL2L1低表达组（n = 18）	12（66.7）	6（33.3）
χ ² 值	4.108
P值	0.043

[1]	Huixia YANG,Ning DING,Runqiu MA,Guizhong LI,Yinju HAO,Shengchao MA,Yideng JIANG,Zhigang. BAI. Role and mechanism of circular RNA mmu_circ_0000818 in dexamethasone⁃induced apoptosis of MC3T3⁃E1 cells [J]. The Journal of Practical Medicine, 2025, 41(4): 478-489.
[2]	Yufen LU,Xiaoming ZHENG,Shaojuan WEI,Liqin CHEN,Tongtong XU,Xiangwei. LÜ. Effects of miR⁃483⁃3p on hypoxia/reoxygenation⁃induced apoptosis and pyroptosis in cardiomyocytes [J]. The Journal of Practical Medicine, 2025, 41(3): 339-346.
[3]	Danping WANG,Yufeng CAI,Dehua HU,Liang. ZHANG. The role of LncRNA RMST in gastric cancer： Expression levels， diagnostic value， and prognostic implicationssion [J]. The Journal of Practical Medicine, 2025, 41(3): 409-413.
[4]	Shan LUO,Ying FENG,Dandan FAN,Wenxin ZHENG,Xingrong GUO,Xuzhi. RUAN. ANGPTL8 knockout reduces lipopolysaccharide⁃induced hepatic lipid deposition [J]. The Journal of Practical Medicine, 2024, 40(9): 1197-1203.
[5]	Wei HE,Liping LIU,Jingwei ZHUO,Xiaodong ZHANG,Tong YANG,Jubin. FENG. CCR5 blockade reduces tumor growth by inducing apoptosis and impairing immunosuppression of tumor microenvironment [J]. The Journal of Practical Medicine, 2024, 40(9): 1204-1210.
[6]	Xiaomei CHEN,Anqi WANG,Jizhen YANG,Miao YU. Prognosis and immune correlation analysis of m1A/m5C/m6A/m7G regulated genes in gastric cancer [J]. The Journal of Practical Medicine, 2024, 40(9): 1230-1237.
[7]	Wenxin LI,Minjun LU,Li LIN,Yueqin LIU,Xiaolan. ZHU. circRAF1 regulates the proliferation and apoptosis of human ovarian granulosa cells [J]. The Journal of Practical Medicine, 2024, 40(7): 910-917.
[8]	Zhen YANG,Shaoru JIANG,Xiaoyan CHEN,Xiaolin CHEN,Weimin DENG,Xinyu. GUO. Effect of Jinghou Zengzhi Granules on ovarian GDF9 secretion and granulosa cells apoptosis in controlled ovarian hyperstimulation rats [J]. The Journal of Practical Medicine, 2024, 40(7): 918-923.
[9]	Jianliang YAN,Zeyu XIE,Rongrong JING,Ming. CUI. Research on establishing gastric cancer lymph node metastasis prediction model based on machine learning and routine laboratory indicators [J]. The Journal of Practical Medicine, 2024, 40(6): 844-849.
[10]	Shu CHEN,Jinglei ZHANG,Kang RONG,Nan ZHANG,Weiyi SUN. Research progress of exosomes in distant metastasis and drug resistance of gastric cancer [J]. The Journal of Practical Medicine, 2024, 40(6): 870-876.
[11]	Li XU,Shanshan HU,Haiming. ZHAO. LncRNA GNAS⁃AS1 participates in the proliferation and migration of gastric cancer cells by regulating the miR⁃449a/Notch1 axis [J]. The Journal of Practical Medicine, 2024, 40(4): 483-489.
[12]	Runwei MA,Chunjie MU,Wenting GUI,Yao DENG,Minzhang ZHAO,Min LIU,Yi SONG. LncRNA SENCR targeted miR⁃206 regulates proliferation and apoptosis of human vascular smooth muscle cells of aortic dissection tissues [J]. The Journal of Practical Medicine, 2024, 40(3): 302-308.
[13]	Lihong DING,Shijia GENG,Yujie WANG. Effects of wedelobata on apoptosis and secretion of inflammatory cytokines in the alveolar epithelium infected by Streptococcus pneumonia [J]. The Journal of Practical Medicine, 2024, 40(3): 316-320.
[14]	Jian ZHAO,Songjie LIU,Guanchao ZHANG,Yuhou SHEN,Fengchen LI,Bing XU. Expression of CENPF and miR⁃1⁃3p in the serum of patients with advanced gastric cancer and their correlation with prognosis [J]. The Journal of Practical Medicine, 2024, 40(3): 365-370.
[15]	Chunfang KONG,Anna LI,Bo KE,Weirong DING,Tingting LIU,Huan FU,Tingting ZHANG,Chenghao JIN,Mei. WU. The inhibitory effect and molecular mechanism of 6-gingerol on human multiple myeloma cells [J]. The Journal of Practical Medicine, 2024, 40(23): 3291-3297.