Background

Colorectal cancer (CRC) is a leading cause of cancer mortality globally. Lymph node metastasis and immunosuppression are main factors of poor prognosis in CRC patients. Lysyl oxidase like 1 (LOXL1), part of the lysyl oxidase (LOX) family, plays a yet unclear role in CRC. This study aimed to identify effective biomarkers predictive of prognosis and efficacy of immunotherapy in CRC patients, and to elucidate the prognostic value, clinical relevance, functional and molecular features, and immunotherapy predictive role of LOXL1 in CRC and pan-cancer.

Methods

Weighted gene co-expression network analysis (WGCNA) was employed to explore gene modules related to tumor metastasis and CD8 + T cell infiltration. LOXL1 emerged as a hub gene through differential gene expression and survival analysis. The molecular signatures, functional roles, and immunological characteristics affected by LOXL1 were analyzed in multiple CRC cohorts, cell lines and clinical specimens. Additionally, LOXL1's potential as an immunotherapy response indicator was assessed, along with its role in pan-cancer.

Results

Turquoise module in WGCNA analysis was identified as the hub module associated with lymph node metastasis and CD8 + T cell infiltration. Aberrant elevated LOXL1 expression was observed in CRC and correlated with poorer differentiation status and prognosis. Molecular and immunological characterization found that LOXL1 might mediate epithelial-mesenchymal transition (EMT) process and immunosuppressive phenotypes of CRC. Functional study found that LOXL1 enhanced tumor cell proliferation, migration and invasion. Moreover, high LOXL1 levels corresponded to reduced CD8 + T cell infiltration and predicted poor clinical outcomes of immunotherapy. Similar trends were also observed at the pan-cancer level.

Conclusions

Our findings underscore the critical role of LOXL1 in modulating both malignancy and immunosuppression in CRC. This positions LOXL1 as a promising biomarker for predicting prognosis and the response to immunotherapy in CRC patients.

Graphical Abstract

背景

结直肠癌（CRC）是全球癌症死亡的主要原因。淋巴结转移和免疫抑制是结直肠癌患者预后不良的主要因素。赖氨酰氧化酶样 1 (LOXL1) 是赖氨酰氧化酶 (LOX) 家族的一部分，在 CRC 中发挥的作用尚不清楚。本研究旨在鉴定预测 CRC 患者预后和免疫治疗疗效的有效生物标志物，并阐明 LOXL1 在 CRC 和泛癌中的预后价值、临床相关性、功能和分子特征以及免疫治疗预测作用。

方法

采用加权基因共表达网络分析（WGCNA）来探索与肿瘤转移和CD8 + T细胞浸润相关的基因模块。通过差异基因表达和生存分析，LOXL1 成为中心基因。在多个 CRC 队列、细胞系和临床标本中分析了 LOXL1 影响的分子特征、功能作用和免疫学特征。此外，还评估了 LOXL1 作为免疫治疗反应指标的潜力及其在泛癌中的作用。

结果

WGCNA分析中的绿松石模块被确定为与淋巴结转移和CD8+T细胞浸润相关的枢纽模块。在 CRC 中观察到异常升高的 LOXL1 表达，并与较差的分化状态和预后相关。分子和免疫学表征发现 LOXL1 可能介导 CRC 的上皮间质转化 (EMT) 过程和免疫抑制表型。功能研究发现LOXL1增强肿瘤细胞增殖、迁移和侵袭。此外，高 LOXL1 水平对应于 CD8 + T 细胞浸润减少，并预测免疫治疗的不良临床结果。在泛癌水平上也观察到类似的趋势。

结论

我们的研究结果强调了 LOXL1 在调节 CRC 恶性肿瘤和免疫抑制中的关键作用。这使得 LOXL1 成为预测 CRC 患者预后和免疫治疗反应的有前途的生物标志物。

图形概要