DCBLD1 reduces cisplatin sensitivity in oral squamous cell carcinoma <italic style="font-style: italic">via</italic> glycolytic reprogramming and ROS scavenging, and silencing it reverses drug resistance

Luo Jun; Zhang Qingzi; Chen Yongqin; Guo Foqing; Xia Feifei; Chen Xiaoxue; Li Changxue

doi:10.16016/j.2097-0927.202606103

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DCBLD1 reduces cisplatin sensitivity in oral squamous cell carcinoma via glycolytic reprogramming and ROS scavenging, and silencing it reverses drug resistance

Basic Medicine | 更新时间：2026-10-19

- DCBLD1 reduces cisplatin sensitivity in oral squamous cell carcinoma via glycolytic reprogramming and ROS scavenging, and silencing it reverses drug resistance
- Journal of Army Medical University Vol. 48, Issue 19, Pages: 2733-2744(2026)
- 作者机构：
  
  1.石河子大学第一附属医院口腔颌面外科，新疆石河子
  2.石河子大学医学院，新疆石河子
  3.厦门大学附属第一医院耳鼻喉头颈外科，福建厦门
- 作者简介：
  
  Li Changxue， E-mail： lichangxue100@163.com
- 基金信息：
  
  Science and Technology Program of XPCC(2023ZD017)
- DOI：10.16016/j.2097-0927.202606103
  CLC： R739.8;R966;R979.11
- Received：26 June 2026，
  
  Revised：2026-07-31，
  
  Accepted：20 August 2026，
  
  Published：15 October 2026
- 稿件说明：
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骆骏，张晴子，陈永琴，等.DCBLD1经糖代谢重编程及ROS清除降低口腔鳞状细胞癌顺铂敏感性且沉默其可逆转耐药［J］.陆军军医大学学报，2026，48（19）：2733-2744.DOI：10.16016/j.2097-0927.202606103.

Luo J，Zhang Q Z，Chen Y Q，et al.DCBLD1 reduces cisplatin sensitivity in oral squamous cell carcinoma via glycolytic reprogramming and ROS scavenging， and silencing it reverses drug resistance［J］.J Army Med Univ，2026，48（19）：2733-2744.DOI：10.16016/j.2097-0927.202606103.
骆骏，张晴子，陈永琴，等.DCBLD1经糖代谢重编程及ROS清除降低口腔鳞状细胞癌顺铂敏感性且沉默其可逆转耐药［J］.陆军军医大学学报，2026，48（19）：2733-2744.DOI：10.16016/j.2097-0927.202606103. DOI：

Luo J，Zhang Q Z，Chen Y Q，et al.DCBLD1 reduces cisplatin sensitivity in oral squamous cell carcinoma via glycolytic reprogramming and ROS scavenging， and silencing it reverses drug resistance［J］.J Army Med Univ，2026，48（19）：2733-2744.DOI：10.16016/j.2097-0927.202606103. DOI：

摘要

目的

口腔鳞状细胞癌（oral squamous cell carcinoma，OSCC）恶性程度高、预后差，顺铂（cisplatin，CDDP）是其一线化疗基石，但耐药频发导致临床获益受限。本研究旨在筛选并验证OSCC顺铂基础敏感性关键调控基因，阐明其经糖代谢重编程与氧化还原稳态失衡降低顺铂敏感性的分子通路，为提升OSCC化疗敏感性提供潜在分子靶点与实验理论支撑。

方法

自GEO数据库下载GSE30784、GSE31056、GSE102787三套OSCC表达谱数据集，基于R语言开展差异表达基因筛选、加权基因共表达网络分析（weighted gene co-expression network analysis，WGCNA）及韦恩交集分析，进一步利用TCGA-HNSC队列进行生存预后评估，依据统计学显著性与临床相关性对候选基因进行优先级排序，以锁定与OSCC顺铂基础敏感性降低相关的核心候选基因。

DCBLD1

作为一种含盘状蛋白、

CUB

及

LCCL

结构域的跨膜蛋白，经多数据集联合筛选被确定为后续研究的靶分子。采用Western blotting检测

DCBLD1

在多株OSCC细胞及HOK细胞中的蛋白表达；利用小干扰RNA（small interfering RNA，siRNA）转染构建

DCBLD1

敲低的SCC-15细胞株，分别检测细胞的葡萄糖摄取速率及乳酸生成水平，以评估其Warburg效应；CCK-8法测定顺铂半数抑制浓度（half maximal inhibitory concentration，IC₅₀）评估化疗敏感性；检测外源性补充乳酸和丙酮酸对细胞顺铂基础敏感性的影响；检测磷酸戊糖途径限速酶葡萄糖-6-磷酸脱氢酶（glucose-6-phosphate dehydrogenase，G6PD）及下游还原型烟酰胺腺嘌呤二核苷酸磷酸（reduced nicotinamide adenine dinucleotide phosphate，NADPH）、谷胱甘肽（glutathione，GSH）、活性氧（reactive oxygen species，ROS）含量反映细胞氧化还原状态；借助ROS清除剂N-乙酰-L-半胱氨酸（N-acetyl-L-cysteine，NAC）回补实验明确ROS在

DCBLD1

调控顺铂基础敏感性中的中介作用。

结果

生物信息学联合分析筛选出

DCBLD1

、

WDR66

两个降低OSCC顺铂基础敏感性核心基因；生存分析显示

DCBLD1

高表达与患者不良预后显著相关（

=1.3，

=0.048），而

WDR66

无显著预后价值，选定

DCBLD1

作为后续研究对象。

DCBLD1

在OSCC细胞中显著高表达（

0.05）。沉默

DCBLD1

能够显著抑制SCC-15细胞有氧糖酵解，减少葡萄糖消耗与乳酸释放（

0.05），降低顺铂IC₅₀（

0.05），有效提升顺铂基础敏感性；外源性乳酸、丙酮酸干预无法恢复细胞低敏感性表型。敲低

DCBLD1

可下调

G6PD

表达（

0.05）、抑制磷酸戊糖途径活化，减少胞内NADPH与GSH抗氧化物质储备（

0.05），诱导ROS蓄积；NAC清除ROS后可恢复细胞顺铂低敏感性（

0.05），逆转

DCBLD1

沉默带来的化疗增敏效应。

结论

DCBLD1

通过同步激活有氧糖酵解与磷酸戊糖途径引发糖代谢重编程，并经由磷酸戊糖途径提升抗氧化物质、清除活性氧以削弱顺铂杀伤效应，有望成为降低OSCC顺铂基础敏感性的潜在治疗靶点。

Abstract

Objective

Oral squamous cell carcinoma (OSCC) is highly malignant and associated with poor prognosis. Cisplatin serves as the first‑line chemotherapeutic cornerstone for OSCC

however

the frequent occurrence of drug resistance substantially compromises its clinical benefit. This study aims to screen and validate key regulatory genes underlying baseline cisplatin sensitivity in OSCC

and to clarify the molecular pathways through which these genes reduce cisplatin sensitivity

via

glycolytic reprogramming and redox homeostasis imbalance

thereby providing potential molecular targets and experimental theoretical support for enhancing OSCC chemosensitivity.

Methods

Three OSCC expression profiling datasets (GSE30784

GSE31056

and GSE102787) were downloaded from the GEO database. Differentially expressed genes (DEGs) screening

weighted gene co‑expression network analysis (WGCNA)

and Venn intersection analysis were performed using R language. Furthermore

survival prognosis was evaluated using the TCGA‑HNSC cohort

and candidate genes were prioritized according to statistical significance and clinical relevance to identify core candidate genes associated with reduced baseline cisplatin sensitivity in OSCC. The core gene

DCBLD1

a transmembrane protein containing discoidin

CUB and LCCL domains

was identified as the target molecule through joint screening for multiple datasets. Western blotting was used to detect

DCBLD1

expression in multiple OSCC cell lines and HOK cells. Small interfering RNA (siRNA) transfection was employed to construct SCC‑15 cells with

DCBLD1

knockdown. The Warburg effect was assessed by measuring

intracellular glucose uptake and lactate production. Chemosensitivity was evaluated by determining the half‑maximal inhibitory concentration (IC₅₀) of cisplatin

via

CCK‑8 assay. Exogenous supplementation of lactate and pyruvate was performed to examine their effects on baseline cisplatin sensitivity in cells. The effects of exogenous lactate and pyruvate supplementation on baseline cisplatin sensitivity were examined. The expression of glucose-6-phosphate dehydrogenase (G6PD)

the rate-limiting enzyme of the pentose phosphate pathway

and the levels of reduced nicotinamide adenine dinucleotide phosphate (NADPH)

glutathione (GSH) and reactive oxygen species (ROS) were detected to reflect cellular redox status. Rescue experiments with the ROS scavenger N-acetyl-L-cysteine (NAC) were performed to clarify the mediating role of ROS in DCBLD1-regulated basal cisplatin sensitivity.

Results

Integrated bioinformatics analysis identified

DCBLD1

and WD repeat domain 66 (

WDR66

) as 2 core genes that reduce baseline cisplatin sensitivity in OSCC. Survival analysis revealed that high

DCBLD1

expression was significantly associated with poor prognosis (

=1.3

=0.048)

whereas

WDR66

showed no significant prognostic value (

=0.42). Therefore

DCBLD1

was selected for subsequent investigation.

DCBLD1

was significantly highly expressed in OSCC cells (

0.05). Knockdown of

DCBLD1

significantly suppressed aerobic glycolysis in SCC‑15 cells

reduced glucose consumption and lactate production (

0.05)

decreased the IC

of cisplatin

and effectively enhanced baseline cisplatin sensitivity. Exogenous lactate and pyruvate intervention failed to restore the low‑sensitivity phenotype.

DCBLD1

knockdown downregulated

G6PD

express

ion (

0.05)

inhibited activation of the pentose phosphate pathway (PPP)

reduced intracellular NADPH and GSH antioxidant reserves (

0.05)

and induced ROS accumulation. NAC‑mediated ROS clearance restored the low cisplatin sensitivity and reversed the chemosensitization effect induced by

DCBLD1

silencing.

Conclusion

DCBLD1

triggers glycolytic reprogramming by simultaneously activating aerobic glycolysis and the PPP

and attenuates the cisplatin-induced cytotoxicity by enhancing antioxidant capacity and scavenging

via

the PPP.

DCBLD1

thus represents a potential therapeutic target for reducing baseline cisplatin sensitivity in OSCC.

关键词

Keywords

references

郝小慧，陈敏，仵楠，等 . β-arrestin1在口腔鳞状细胞癌中的表达及其对细胞增殖、迁移、侵袭的作用［J］. 陆军军医大学学报， 2025 ， 47 （ 14 ）： 1632 - 1641 . DOI： 10.16016/j.2097-0927.202504071 http://dx.doi.org/10.16016/j.2097-0927.202504071 .

Hao X H ， Chen M ， Wu N ， et al . Expression of β-arrestin1 in oral squamous cell carcinoma and its effects on cell proliferation， migration， and invasion ［J］. J Army Med Univ ， 2025 ， 47 （ 14 ）： 1632 - 1641 . DOI： 10.16016/j.2097-0927.202504071 http://dx.doi.org/10.16016/j.2097-0927.202504071 .

Dunn L A ， Ho A L ， Pfister D G . Head and neck cancer： a review ［J］. JAMA ， 2026 ， 335 （ 6 ）： 531 . DOI： 10.1001/jama.2025.21733 http://dx.doi.org/10.1001/jama.2025.21733 .

Hu H L ， Li B ， Wang J K ， et al . New advances into cisplatin resistance in head and neck squamous carcinoma： Mechanisms and therapeutic aspects ［J］. Biomed Pharmacother ， 2023 ， 163 ： 114778 . DOI： 10.1016/j.biopha. 2023.114778 http://dx.doi.org/10.1016/j.biopha.2023.114778 .

DeBerardinis R J ， Lum J J ， Hatzivassiliou G ， et al . The biology of cancer： metabolic reprogramming fuels cell growth and proliferation ［J］. Cell Metab ， 2008 ， 7 （ 1 ）： 11 - 20 . DOI： 10.1016/j.cmet.2007.10.002 http://dx.doi.org/10.1016/j.cmet.2007.10.002 .

Giacomini I ， Ragazzi E ， Pasut G ， et al . The pentose phosphate pathway and its involvement in cisplatin resistance ［J］. Int J Mol Sci ， 2020 ， 21 （ 3 ）： 937 . DOI： 10.3390/ijms21030937 http://dx.doi.org/10.3390/ijms21030937 .

Wang Y H ， Patti G J . The Warburg effect： a signature of mitochondrial overload ［J］. Trends Cell Biol ， 2023 ， 33 （ 12 ）： 1014 - 1020 . DOI： 10.1016/j.tcb.2023.03.013 http://dx.doi.org/10.1016/j.tcb.2023.03.013 .

Patra K C ， Hay N . The pentose phosphate pathway and cancer ［J］. Trends Biochem Sci ， 2014 ， 39 （ 8 ）： 347 - 354 . DOI： 10.1016/j.tibs.2014.06.005 http://dx.doi.org/10.1016/j.tibs.2014.06.005 .

Hayes J D ， Dinkova-Kostova A T ， Tew K D . Oxidative stress in cancer ［J］. Cancer Cell ， 2020 ， 38 （ 2 ）： 167 - 197 . DOI： 10.1016/j.ccell.2020.06.001 http://dx.doi.org/10.1016/j.ccell.2020.06.001 .

Tan Y Y ， Li J J ， Zhao G Y ， et al . Metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation in platinum-resistant cancer cells ［J］. Nat Commun ， 2022 ， 13 （ 1 ）： 4554 . DOI： 10.1038/s41467-022-32101-w http://dx.doi.org/10.1038/s41467-022-32101-w .

Schmoker A M ， Ebert A M ， Ballif B A . The DCBLD receptor family： emerging signaling roles in development， homeostasis and disease ［J］. Biochem J ， 2019 ， 476 （ 6 ）： 931 - 950 . DOI： 10.1042/BCJ20190022 http://dx.doi.org/10.1042/BCJ20190022 .

Fu L L ， Yan M ， Ma M X ， et al . DCBLD1 overexpression is associated with a poor prognosis in head and neck squamous cell carcinoma ［J］. Front Immunol ， 2022 ， 13 ： 939344 . DOI： 10.3389/fimmu.2022.939344 http://dx.doi.org/10.3389/fimmu.2022.939344 .

Cardin G B ， Bernard M ， Rodier F ， et al . DCBLD1 is associated with the integrin signaling pathway and has prog nostic value in non-small cell lung and invasive breast carcinoma ［J］. Sci Rep ， 2021 ， 11 （ 1 ）： 12753 . DOI： 10.1038/s41598-021-92090-6 http://dx.doi.org/10.1038/s41598-021-92090-6 .

Xu D F ， Wang Y ， Liu X M ， et al . Development and clinical validation of a novel 9-gene prognostic model based on multi-omics in pancreatic adenocarcinoma ［J］. Pharmacol Res ， 2021 ， 164 ： 105370 . DOI： 10.1016/j.phrs.2020.105370 http://dx.doi.org/10.1016/j.phrs.2020.105370 .

Okada R ， Goto Y ， Yamada Y ， et al . Regulation of oncogenic targets by the tumor-suppressive miR-139 duplex （miR-139-5p and miR-139-3p） in renal cell carcinoma ［J］. Biomedicines ， 2020 ， 8 （ 12 ）： 599 . DOI： 10.3390/biomedicines8120599 http://dx.doi.org/10.3390/biomedicines8120599 .

Sakornsakolpat P ， Morrow J D ， Castaldi P J ， et al . Integrative genomics identifies new genes associated with severe COPD and emphysema ［J］. Respir Res ， 2018 ， 19 （ 1 ）： 46 . DOI： 10.1186/s12931-018-0744-9 http://dx.doi.org/10.1186/s12931-018-0744-9 .

Cheng Y L ， Li S M ， Gao L ， et al . The molecular basis and therapeutic aspects of cisplatin resistance in oral squamous cell carcinoma ［J］. Front Oncol ， 2021 ， 11 ： 761379 . DOI： 10.3389/fonc.2021.761379 http://dx.doi.org/10.3389/fonc.2021.761379 .

Tang C Y ， Livingston M J ， Safirstein R ， et al . Cisplatin nephrotoxicity： new insights and therapeutic implications ［J］. Nat Rev Nephrol ， 2023 ， 19 （ 1 ）： 53 - 72 . DOI： 10.1038/s41581-022-00631-7 http://dx.doi.org/10.1038/s41581-022-00631-7 .

Langfelder P ， Horvath S . WGCNA： an R package for weighted correlation network analysis ［J］. BMC Bioinformatics ， 2008 ， 9 ： 559 . DOI： 10.1186/1471-2105-9-559 http://dx.doi.org/10.1186/1471-2105-9-559 .

Liu S ， Zhang X D ， Wang W Z ， et al . Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer ［J］. Mol Cancer ， 2024 ， 23 （ 1 ）： 261 . DOI： 10.1186/s12943-024-02165-x http://dx.doi.org/10.1186/s12943-024-02165-x .

赵亚，付靖，张钧硕，等 . 糖酵解诱导肿瘤靶向药物耐药的相关分子及机制研究进展［J］. 山东医药， 2023 ， 63 （ 8 ）： 112 - 115 .

Zhao Y ， Fu J ， Zhang J S ， et al . Research progress on related molecules and mechanisms of glycolysis-induced tumor-targeted drug resistance ［J］. Shandong Med J ， 2023 ， 63 （ 8 ）： 112 - 115 .

Sosa V ， Moliné T ， Somoza R ， et al . Oxidative stress and cancer： an overview ［J］. Ageing Res Rev ， 2013 ， 12 （ 1 ）： 376 - 390 . DOI： 10.1016/j.arr.2012.10.004 http://dx.doi.org/10.1016/j.arr.2012.10.004 .

Meskers C J W ， Franczak M ， Smolenski R T ， et al . Are we still on the right path（way）？： the altered expression of the pentose phosphate pathway in solid tumors and the potential of its inhibition in combination therapy ［J］. Expert Opin Drug Metab Toxicol ， 2022 ， 18 （ 1 ）： 61 - 83 . DOI： 10.1080/17425255.2022.2049234 http://dx.doi.org/10.1080/17425255.2022.2049234 .

Tang B L . Neuroprotection by glucose-6-phosphate dehydrogenase and the pentose phosphate pathway ［J］. J Cell Biochem ， 2019 ， 120 （ 9 ）： 14285 - 14295 . DOI： 10.1002/jcb.29004 http://dx.doi.org/10.1002/jcb.29004 .

Lin Q S ， Li S ， Jin H J ， et al . Mitophagy alleviates cisplatin-induced renal tubular epithelial cell ferroptosis through ROS/HO-1/GPX4 axis ［J］. Int J Biol Sci ， 2023 ， 19 （ 4 ）： 1192 - 1210 . DOI： 10.7150/ijbs.80775 http://dx.doi.org/10.7150/ijbs.80775 .

He M Y ， Li T ， Wang A ， et al . MARCH8/NSUN6/ROS-mediated DNA damage positive feedback loop regulates cisplatin resistance in osteosarcoma ［J］. Cell Death Differ ， 2025 ， 32 （ 12 ）： 2412 - 2426 . DOI： 10.1038/s41418-025-01544-1 http://dx.doi.org/10.1038/s41418-025-01544-1 .

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⁰

DCBLD1 reduces cisplatin sensitivity in oral squamous cell carcinoma via glycolytic reprogramming and ROS scavenging, and silencing it reverses drug resistance

DOI：10.16016/j.2097-0927.202606103

摘要

Abstract

关键词

Keywords

references