血管生成素样蛋白 13（VASN）过表达促进局部进展期直肠癌患者的肺转移和对辅助化疗的耐药性。

Vasorin (VASN) overexpression promotes pulmonary metastasis and resistance to adjuvant chemotherapy in patients with locally advanced rectal cancer.

机构信息

Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Centre, Guangzhou, Guangdong, 510060, P. R. China.

State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China.

出版信息

J Transl Med. 2024 Aug 6;22(1):742. doi: 10.1186/s12967-024-05473-4.

DOI:10.1186/s12967-024-05473-4

PMID:39107788

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11301854/

Abstract

BACKGROUND

LARC patients commonly receive adjuvant therapy, however, hidden micrometastases still limit the improvement of OS. This study aims to investigate the impact of VASN in rectal cancer with pulmonary metastasis and understand the underlying molecular mechanisms to guide adjuvant chemotherapy selection.

METHODS

Sequencing data from rectal cancer patients with pulmonary metastasis from Sun Yat-sen University Cancer Center (SYSUCC) and publicly available data were meticulously analyzed. The functional role of VASN in pulmonary metastasis was validated in vivo and in vitro. Coimmunoprecipitation (co-IP), immunofluorescence, and rescue experiments were conducted to unravel potential molecular mechanisms of VASN. Moreover, VASN expression levels in tumor samples were examined and analyzed for their correlations with pulmonary metastasis status, tumor stage, adjuvant chemotherapy benefit, and survival outcome.

RESULTS

Our study revealed a significant association between high VASN expression and pulmonary metastasis in LARC patients. Experiments in vitro and in vivo demonstrated that VASN could promote the cell proliferation, metastasis, and drug resistance of colorectal cancer. Mechanistically, VASN interacts with the NOTCH1 protein, leading to concurrent activation of the NOTCH and MAPK pathways. Clinically, pulmonary metastasis and advanced tumor stage were observed in 90% of VASN-positive patients and 53.5% of VASN-high patients, respectively, and VASN-high patients had a lower five-year survival rate than VASN-low patients (26.7% vs. 83.7%). Moreover, the Cox analysis and OS analysis indicated that VASN was an independent prognostic factor for OS (HR = 7.4, P value < 0.001) and a predictor of adjuvant therapy efficacy in rectal cancer.

CONCLUSIONS

Our study highlights the role of VASN in decreasing drug sensitivity and activating the NOTCH and MAPK pathways, which leads to tumorigenesis and pulmonary metastasis. Both experimental and clinical data support that rectal cancer patients with VASN overexpression detected in biopsies have a higher risk of pulmonary metastasis and adjuvant chemotherapy resistance.

摘要

背景

长效可逆避孕（LARC）患者通常接受辅助治疗，但隐匿性微转移仍然限制了总生存期（OS）的改善。本研究旨在探讨 VASN 在直肠癌伴肺转移中的作用，并探讨其潜在的分子机制，以指导辅助化疗的选择。

方法

仔细分析了中山大学肿瘤防治中心（SYSUCC）直肠癌伴肺转移患者的测序数据和公开可用的数据。通过体内和体外实验验证了 VASN 在肺转移中的功能作用。进行了共免疫沉淀（co-IP）、免疫荧光和拯救实验，以揭示 VASN 的潜在分子机制。此外，检测了肿瘤样本中 VASN 的表达水平，并分析其与肺转移状态、肿瘤分期、辅助化疗获益和生存结局的相关性。

结果

我们的研究表明，VASN 高表达与 LARC 患者的肺转移显著相关。体外和体内实验表明，VASN 可促进结直肠癌细胞的增殖、转移和耐药性。机制上，VASN 与 NOTCH1 蛋白相互作用，导致 NOTCH 和 MAPK 通路的同时激活。临床上，90%的 VASN 阳性患者和 53.5%的 VASN 高表达患者出现肺转移和晚期肿瘤分期，VASN 高表达患者的五年生存率低于 VASN 低表达患者（26.7%比 83.7%）。此外，Cox 分析和 OS 分析表明，VASN 是 OS 的独立预后因素（HR=7.4，P 值<0.001），也是直肠癌辅助治疗疗效的预测因子。