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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.
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：LARC患者通常接受辅助治疗，然而,隐藏的微转移仍然限制了OS的改善。本研究旨在探讨VASN对直肠癌肺转移的影响，了解其潜在的分子机制，以指导辅助化疗的选择。
方法：对中山大学肿瘤防治中心（SYSUCC）直肠癌肺转移患者的测序数据和公开数据进行细致分析。在体内和体外验证了VASN在肺转移中的功能作用。共免疫沉淀（co-IP），免疫荧光，并进行了救援实验，以揭示VASN的潜在分子机制。此外，检查肿瘤样本中的VASN表达水平，并分析其与肺转移状态的相关性。肿瘤分期,辅助化疗获益，和生存结果。
结果：我们的研究揭示了LARC患者VASN高表达与肺转移之间的显著关联。体内外实验证明VASN能促进细胞增殖,转移,结直肠癌的耐药性。机械上,VASN与NOTCH1蛋白相互作用，导致同时激活NOTCH和MAPK通路。临床上,在90％的VASN阳性患者和53.5％的VASN高患者中观察到肺转移和晚期肿瘤分期，分别,高VASN患者的五年生存率低于低VASN患者(26.7%vs.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.
结论：我们的研究强调了VASN在降低药物敏感性和激活NOTCH和MAPK通路中的作用。导致肿瘤发生和肺转移。实验和临床数据均支持活检中检测到VASN过表达的直肠癌患者肺转移和辅助化疗耐药的风险更高。
方法：对中山大学肿瘤防治中心（SYSUCC）直肠癌肺转移患者的测序数据和公开数据进行细致分析。在体内和体外验证了VASN在肺转移中的功能作用。共免疫沉淀（co-IP），免疫荧光，并进行了救援实验，以揭示VASN的潜在分子机制。此外，检查肿瘤样本中的VASN表达水平，并分析其与肺转移状态的相关性。肿瘤分期,辅助化疗获益，和生存结果。
结果：我们的研究揭示了LARC患者VASN高表达与肺转移之间的显著关联。体内外实验证明VASN能促进细胞增殖,转移,结直肠癌的耐药性。机械上,VASN与NOTCH1蛋白相互作用，导致同时激活NOTCH和MAPK通路。临床上,在90％的VASN阳性患者和53.5％的VASN高患者中观察到肺转移和晚期肿瘤分期，分别,高VASN患者的五年生存率低于低VASN患者(26.7%vs.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.
结论：我们的研究强调了VASN在降低药物敏感性和激活NOTCH和MAPK通路中的作用。导致肿瘤发生和肺转移。实验和临床数据均支持活检中检测到VASN过表达的直肠癌患者肺转移和辅助化疗耐药的风险更高。
