TCF7 transcriptional activation of MACC1 regulates aerobic glycolysis and promotes oxaliplatin resistance in rectal cancer

Yan YAN; Liqing ZHOU; Jianhong XIA; Tingting MA

doi:10.19401/j.cnki.1007-3639.2024.08.001

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TCF7 transcriptional activation of MACC1 regulates aerobic glycolysis and promotes oxaliplatin resistance in rectal cancer

Article | 更新时间：2025-12-31

- TCF7 transcriptional activation of MACC1 regulates aerobic glycolysis and promotes oxaliplatin resistance in rectal cancer
- China Oncology Vol. 34, Issue 8, Pages: 715-725(2024)
- 作者机构：
  
  淮安市第二人民医院，徐州医科大学附属淮安医院放疗科，江苏淮安 223000
- 作者简介：
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2024.08.001
  CLC： R735.3
- Received：27 December 2023，
  
  Revised：2024-04-12，
  
  Published：30 August 2024
- 稿件说明：
移动端阅览
Yan YAN, Liqing ZHOU, Jianhong XIA, et al. TCF7 transcriptional activation of MACC1 regulates aerobic glycolysis and promotes oxaliplatin resistance in rectal cancer[J]. China Oncology, 2024, 34(8): 715-725.
DOI：

Yan YAN, Liqing ZHOU, Jianhong XIA, et al. TCF7 transcriptional activation of MACC1 regulates aerobic glycolysis and promotes oxaliplatin resistance in rectal cancer[J]. China Oncology, 2024, 34(8): 715-725. DOI： 10.19401/j.cnki.1007-3639.2024.08.001.

摘要

背景与目的：

直肠癌是发生在直肠内壁的癌症，结肠癌转移相关基因-1（metastasis-associated in colon cancer 1，MACC1）能促进结肠癌细胞的耐药性。本研究旨在探究MACC1在直肠癌中对奥沙利铂耐药的影响及机制。

方法：

分析MACC1和转录因子7（transcription factor 7，TCF7）在直肠癌组织中的表达及MACC1富集的信号转导通路。采用实时荧光定量聚合酶链反应（real-time fluorescence quantitative polymerase chain reaction，RTFQ-PCR）检测直肠癌细胞及直肠癌奥沙利铂耐药细胞中MACC1和TCF7的表达，采用细胞计数试剂盒（cell counting kit-8，CCK-8）检测细胞活力，采用细胞集落形成实验检测细胞的增殖情况，采用Seahorse Biosciences XF96检测ECAR值、乳酸生成量和葡萄糖消耗量，采用蛋白质印迹法（Western blot）检测糖酵解相关蛋白的表达，采用双

荧光素酶报告基因和ChIP验证MACC1与TCF7之间的调控关系。采用GraphPad Prism 8.0对各组数据进行正态性检验与方差齐性分析，根据结果是否为正态分布进行单因素方差分析、

检验或Wilcoxon秩和检验。采用双侧检验，

0.05为差异有统计学意义。

结果：

MACC1和TCF7在直肠癌中表达上调，敲低MACC1显著抑制了直肠癌耐药细胞活力及不同浓度奥沙利铂处理后的IC

值，也降低了直肠癌奥沙利铂耐药细胞的增殖能力。过表达MACC1能够促进直肠癌细胞增殖和糖酵解能力。进一步研究发现，MACC1上游存在转录因子TCF7，本研究采用癌症基因组图谱计划（The Cancer Genome Atlas Program，TCGA）数据集分析了TCF7在直肠癌组织中的表达量，结果显示，敲低TCF7能够减弱MACC1对直肠癌细胞糖酵解能力及奥沙利铂耐药的促进作用。

结论：

TCF7/MACC1轴促进有氧糖酵解进而促进直肠癌细胞奥沙利铂耐药，提示靶向TCF7/MACC1轴或抑制有氧糖酵解途径可能是抑制直肠癌奥沙利铂耐药性的新的治疗方法。

Abstract

Background and purpose:

Rectal cancer occurs on the inner wall of the rectum

and metastasis-associated in colon cancer 1 (MACC1) can promote drug resistance in colon cancer cells. This study aimed to investigate the effect of MACC1 on oxaliplatin resistance in rectal cancer and its mechanism.

Methods:

Biosignal analysis of MACC1 and TCF7 expressions in rectal cancer tissues and signaling pathways enriched for MACC1 were carried out. The expressions of MACC1 and TCF7 in rectal cancer cells and rectal cancer oxaliplatin-resistant cells were detected by real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR)

cell viability was detected by cell counting kit-8 (CCK-8)

and cell proliferation was detected by cell colony formation assay. ECAR values

lactate production and glucose consumption were detected by Seahorse Biosciences XF96. Western blot was used to detect the expressions of glycolysis-related proteins. Dual luciferase reporter gene and ChIP were used to validate the regulatory relationship between MACC1 and TCF7. Normality test and homogeneity of variance analysis was performed on the data of each group by GraphPad Prism 8.0. If it conformed to normal distribution

one-way ANOVA or

-test would be used for inter group comparison

otherwise the comparison between groups would be conducted using Wilcoxon rank sum test. Using

a two-sided test

0.05 was considered statistically significant.

Results:

MACC1 and TCF7 expressions were upregulated in rectal cancer

and knockdown of MACC1 significantly inhibited the viability of rectal cancer drug-resistant cells and the IC

values of different concentrations of oxaliplatin treatments

as well as reduced the proliferation ability of rectal cancer oxaliplatin-resistant cells. Overexpression of MACC1 was able to promote the proliferation and glycolytic capacity of rectal cancer cells. Further studies revealed that the transcription factor TCF7 existed in the upper reaches of MACC1. Besides

this study analyzed the data from Cancer Genome Atlas Program (TCGA)

and the result showed that knockdown of TCF7 was able to attenuate the promotional effect of overexpression of MACC1 on the glycolytic capacity and oxaliplatin resistance of rectal cancer cells.

Conclusion:

This study demonstrated that the TCF7/MACC1 axis could promote aerobic glycolysis and thus oxaliplatin resistance in rectal cancer cells. The findings suggest that targeting the TCF7/MACC1 axis or inhibiting the aerobic glycolysis pathway may be a novel therapeutic approach to inhibit oxaliplatin resistance in rectal cancer.

关键词

Keywords

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