Wang Ling, Sparks-Wallace Ayrianna, Casteel Jared L, Howell Mary E A, Ning Shunbin
Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.
Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.
Front Oncol. 2021 Mar 31;11:632638. doi: 10.3389/fonc.2021.632638. eCollection 2021.
Non-small-cell lung carcinoma (NSCLC) is the major type of lung cancer, which is among the leading causes of cancer-related deaths worldwide. LIMD1 was previously identified as a tumor suppressor in lung cancer, but their detailed interaction in this setting remains unclear. In this study, we have carried out multiple genome-wide bioinformatic analyses for a comprehensive understanding of LIMD1 in NSCLC, using various online algorithm platforms that have been built for mega databases derived from both clinical and cell line samples. Our results indicate that LIMD1 expression level is significantly downregulated at both mRNA and protein levels in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), with a considerable contribution from its promoter methylation rather than its gene mutations. The gene undergoes mutation only at a low rate in NSCLC (0.712%). We have further identified LIMD1-associated molecular signatures in NSCLC, including its natural antisense long non-coding RNA LIMD1-AS1 and a pool of membrane trafficking regulators. We have also identified a subgroup of tumor-infiltrating lymphocytes, especially neutrophils, whose tumor infiltration levels significantly correlate with LIMD1 level in both LUAD and LUSC. However, a significant correlation of LIMD1 with a subset of immune regulatory molecules, such as IL6R and TAP1, was only found in LUAD. Regarding the clinical outcomes, LIMD1 expression level only significantly correlates with the survival of LUAD (p<0.01) but not with that of LUSC (p>0.1) patients. These findings indicate that LIMD1 plays a survival role in LUAD patients at least by acting as an immune regulatory protein. To further understand the mechanisms underlying the tumor-suppressing function of LIMD1 in NSCLC, we show that LIMD1 downregulation remarkably correlates with the deregulation of multiple pathways that play decisive roles in the oncogenesis of NSCLC, especially those mediated by EGFR, KRAS, PIK3CA, Keap1, and p63, in both LUAD and LUSC, and those mediated by p53 and CDKN2A only in LUAD. This study has disclosed that LIMD1 can serve as a survival prognostic marker for LUAD patients and provides mechanistic insights into the interaction of LIMD1 with NSCLC, which provide valuable information for clinical applications.
非小细胞肺癌（NSCLC）是肺癌的主要类型，在全球癌症相关死亡的主要原因中位列其中。LIMD1先前被确定为肺癌中的一种肿瘤抑制因子，但其在这种情况下的详细相互作用仍不清楚。在本研究中，我们使用了为源自临床和细胞系样本的大型数据库构建的各种在线算法平台，进行了多项全基因组生物信息学分析，以全面了解NSCLC中的LIMD1。我们的结果表明，在肺腺癌（LUAD）和肺鳞状细胞癌（LUSC）中，LIMD1的表达水平在mRNA和蛋白质水平均显著下调，其启动子甲基化而非基因突变起了相当大的作用。该基因在NSCLC中的突变率仅为0.712%。我们进一步在NSCLC中鉴定了与LIMD1相关的分子特征，包括其天然反义长链非编码RNA LIMD1-AS1和一组膜转运调节因子。我们还鉴定了一组肿瘤浸润淋巴细胞，尤其是中性粒细胞，其肿瘤浸润水平在LUAD和LUSC中均与LIMD1水平显著相关。然而，仅在LUAD中发现LIMD1与一部分免疫调节分子如IL6R和TAP1存在显著相关性。关于临床结果，LIMD1表达水平仅与LUAD患者的生存率显著相关（p<0.01），而与LUSC患者的生存率无关（p>0.1）。这些发现表明，LIMD1至少通过作为一种免疫调节蛋白在LUAD患者中发挥生存作用。为了进一步了解LIMD1在NSCLC中肿瘤抑制功能的潜在机制，我们表明，LIMD1的下调与在NSCLC肿瘤发生中起决定性作用的多种信号通路失调显著相关，特别是在LUAD和LUSC中由EGFR、KRAS、PIK3CA、Keap1和p63介导的信号通路，以及仅在LUAD中由p53和CDKN2A介导的信号通路。本研究揭示了LIMD1可作为LUAD患者的生存预后标志物，并为LIMD1与NSCLC的相互作用提供了机制性见解，为临床应用提供了有价值的信息。
