Algorithm-Based Meta-Analysis Reveals the Mechanistic Interaction of the Tumor Suppressor LIMD1 With Non-Small-Cell Lung Carcinoma

Abstract

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 Limd1 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.

New Look of EBV LMP1 Signaling Landscape

“…Interestingly, we have collected preliminary data suggesting that LIMD1, which is induced by LMP1 [76], is also involved in autophagosome formation in response to ROS in EBV latency. In agreement with this, our recent study shows that LIMD1 is associated with a panel of proteins involved in membrane trafficking at the transcriptional level in non-small-cell lung carcinoma [78].…”

“…LIMD1 depletion impairs LMP1 signaling and functions, potentiates ionomycin-induced DNA damage and apoptosis, and inhibits p62-mediated selective autophagy that we have later demonstrated to be induced by oxidative stress in oncoviral latency [76,77]. Thus, LIMD1, known as a tumor suppressor in several tumors such as lung, gastric, and breast cancers [78][79][80], oppositely acts as a tumor promoter in viral hematomalignancies.…”

Smad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma

“…6I, J and Supplementary Data 3 ). Of note, we identified several neutrophil N2 developmental factors (such as Afdn 30 , Cdon 31 , Elf4enif1 32 , and Limd1 33 ) as Smad3 target genes under LLC-CM stimulation conditions (Fig. 6K ).…”

HLA-DRB1 is associated with cefaclor-induced immediate hypersensitivity

“…Further research on the expression and function of this protein in DHRs should be conducted, however, LIMD1 is known as a member of the Zyxin family proteins and functions as a tumor suppressor. 24 , 25 …”