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SMC1A 着丝粒蛋白基因沉默与贝伐珠单抗联合作用对结直肠癌的影响。

The synergism of SMC1A cohesin gene silencing and bevacizumab against colorectal cancer.

机构信息

Istituto di Tecnologie Biomediche (ITB), Consiglio Nazionale delle Ricerche (CNR), Via Moruzzi, Pisa, 1 56124, Italy.

IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

出版信息

J Exp Clin Cancer Res. 2024 Feb 16;43(1):49. doi: 10.1186/s13046-024-02976-2.

DOI:10.1186/s13046-024-02976-2
PMID:38365745
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10870497/
Abstract

BACKGROUND

SMC1A is a subunit of the cohesin complex that participates in many DNA- and chromosome-related biological processes. Previous studies have established that SMC1A is involved in cancer development and in particular, is overexpressed in chromosomally unstable human colorectal cancer (CRC). This study aimed to investigate whether SMC1A could serve as a therapeutic target for CRC.

METHODS

At first, we studied the effects of either SMC1A overexpression or knockdown in vitro. Next, the outcome of SMC1A knocking down (alone or in combination with bevacizumab, a monoclonal antibody against vascular endothelial growth factor) was analyzed in vivo.

RESULTS

We found that SMC1A knockdown affects cell proliferation and reduces the ability to grow in anchorage-independent manner. Next, we demonstrated that the silencing of SMC1A and the combo treatment were effective in increasing overall survival in a xenograft mouse model. Functional analyses indicated that both treatments lead to atypical mitotic figures and gene expression dysregulation. Differentially expressed genes were implicated in several pathways including gene transcription regulation, cellular proliferation, and other transformation-associated processes.

CONCLUSIONS

These results indicate that SMC1A silencing, in combination with bevacizumab, can represent a promising therapeutic strategy for human CRC.

摘要

背景

SMC1A 是黏连复合物的一个亚基，参与许多与 DNA 和染色体相关的生物学过程。先前的研究已经证实 SMC1A 参与癌症的发展，特别是在染色体不稳定的人类结直肠癌（CRC）中过表达。本研究旨在探讨 SMC1A 是否可以作为 CRC 的治疗靶点。

方法

首先，我们研究了 SMC1A 过表达或敲低在体外的影响。接下来，分析了 SMC1A 敲低（单独或与贝伐单抗联合，一种针对血管内皮生长因子的单克隆抗体）在体内的结果。

结果

我们发现 SMC1A 敲低影响细胞增殖并降低锚定非依赖性生长的能力。接下来，我们证明了 SMC1A 的沉默和联合治疗在异种移植小鼠模型中有效提高了总生存率。功能分析表明，两种治疗方法均导致非典型有丝分裂和基因表达失调。差异表达的基因涉及包括基因转录调控、细胞增殖和其他转化相关过程在内的几个途径。

结论

这些结果表明，SMC1A 沉默联合贝伐单抗可能代表一种有前途的人类 CRC 治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba8/10870497/32d7a42f398e/13046_2024_2976_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba8/10870497/474dbac4b06d/13046_2024_2976_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba8/10870497/d1ea1878b7b5/13046_2024_2976_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba8/10870497/8732d2056179/13046_2024_2976_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba8/10870497/03837f8b0656/13046_2024_2976_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba8/10870497/6932dbd8b120/13046_2024_2976_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba8/10870497/32d7a42f398e/13046_2024_2976_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba8/10870497/474dbac4b06d/13046_2024_2976_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba8/10870497/d1ea1878b7b5/13046_2024_2976_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba8/10870497/8732d2056179/13046_2024_2976_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba8/10870497/03837f8b0656/13046_2024_2976_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba8/10870497/6932dbd8b120/13046_2024_2976_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fba8/10870497/32d7a42f398e/13046_2024_2976_Fig6_HTML.jpg

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