Zhuang Hongkai, Chen Bo, Tang Chenwei, Chen Xinming, Tan Wenliang, Yang Lei, Xie Zhiqin, Ma Xiaowu, Wang Qingbin, Zhang Chuanzhao, Shang Changzhen, Chen Yajin
Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Front Oncol. 2022 May 12;12:871771. doi: 10.3389/fonc.2022.871771. eCollection 2022.
Smith-like (LSM) family members play critical roles in multiple oncologic processes in several types of malignancies. The study on LSM family members of HCC might provide new insights into the tumorigenesis and therapeutic strategies of HCC.
The clinical significance and oncologic biological functions of LSM family members were assessed through multiple bioinformatics methods and studies. The potential correlation between LSM family members and tumor immunity was also investigated using single sample gene set enrichment analysis (ssGSEA) and the ESTIMATE algorithm.
LSM family member overexpression in HCC was significantly correlated with poor clinical outcomes such as higher TNM stage, advanced histologic grade, and worse prognosis. A risk score system based on LSM5, LSM10, LSM12, and LSM14B showed a reliable predictive ability for OS of HCC patients. Functional enrichment analysis demonstrated that LSM family members overexpressed were all involved in cell cycle related biological processes. Besides, LSM12, LSM14A, and LSM14B were found to be significantly associated with PI3K-Akt-mTOR and T cell receptor signaling pathways. Tumors with LSM12, LSM14A, and LSM14B overexpression exhibited lower infiltration of activated CD8 T cells with declined cytolytic activity and immune score, but increased infiltration of Th2 cells and Th2/Th1. LSM12, LSM14A, and LSM14B overexpression is also associated with higher tumor-related immune checkpoints (e.g., PD-L1, B7-H3, and PVR) expression and increased therapeutic insensitivity to immune checkpoint blockade (ICB). Moreover, the knockdown of LSM12, LSM14A, and LSM14B significantly inhibited the proliferation and invasion of HCC cells.
This study systematically investigated the expression pattern and biological values of LSM family members in HCC and identified LSM family members as novel therapeutic targets in HCC.
类史密斯（LSM）家族成员在多种类型恶性肿瘤的多个肿瘤发生过程中发挥关键作用。对肝癌LSM家族成员的研究可能为肝癌的肿瘤发生和治疗策略提供新的见解。
通过多种生物信息学方法和研究评估LSM家族成员的临床意义和肿瘤生物学功能。还使用单样本基因集富集分析（ssGSEA）和ESTIMATE算法研究LSM家族成员与肿瘤免疫之间的潜在相关性。
肝癌中LSM家族成员的过表达与较差的临床结局显著相关，如更高的TNM分期、更高级别的组织学分级和更差的预后。基于LSM5、LSM10、LSM12和LSM14B的风险评分系统对肝癌患者的总生存期显示出可靠的预测能力。功能富集分析表明，过表达的LSM家族成员均参与细胞周期相关的生物学过程。此外，发现LSM12、LSM14A和LSM14B与PI3K-Akt-mTOR和T细胞受体信号通路显著相关。LSM12、LSM14A和LSM14B过表达的肿瘤表现出活化CD8 T细胞浸润减少，细胞溶解活性和免疫评分下降，但Th2细胞和Th2/Th1浸润增加。LSM12、LSM14A和LSM14B过表达还与更高的肿瘤相关免疫检查点（如PD-L1、B7-H3和PVR）表达以及对免疫检查点阻断（ICB）的治疗不敏感性增加有关。此外，敲低LSM12、LSM14A和LSM14B可显著抑制肝癌细胞的增殖和侵袭。
本研究系统地研究了LSM家族成员在肝癌中的表达模式和生物学价值，并将LSM家族成员确定为肝癌的新型治疗靶点。
