The Downregulation of LSAMP Expression Promotes Lung Cancer Progression and Is Associated with Poor Survival Prognosis

Abstract

Lung cancer has been a leading cause of cancer-related death for decades and therapeutic strategies for non-driver mutation lung cancer are still lacking. A novel approach for this type of lung cancer is an emergent requirement. Here we find that loss of LSAMP (Limbic System Associated Membrane Protein), compared to other IgLON family of proteins NTM (Neurotrimin) and OPCML (OPioid-binding Cell adhesion MoLecule), exhibits the strongest prognostic and therapeutic significance in predicting lung adenocarcinoma (LUAD) progression. Lower expression of LSAMP and NTM, but not OPCML, were found in tumor parts compared with normal parts in six LUAD patients, and this was validated by public datasets, Oncomine® and TCGA. The lower expression of LSAMP, but not NTM, was correlated to shorter overall survival. Two epigenetic regulations, including hypermethylation and miR-143-3p upregulation but not copy number variation, were associated with downregulation of LSAMP in LUAD patients. Pathway network analysis showed that NEGR1 (Neuronal Growth Regulator 1) was involved in the regulatory loop of LSAMP. The biologic functions by LSMAP knockdown in lung cancer cells revealed LSMAP was linked to cancer cell migration via epithelial-mesenchymal transition (EMT) but not proliferation nor stemness of LUAD. Our result showed for the first time that LSAMP acts as a potential tumor suppressor in regulating lung cancer. A further deep investigation into the role of LSAMP in lung cancer tumorigenesis would provide therapeutic hope for such affected patients.

Identification of recurrent 3q13.31 chromosomal rearrangement indicates LSAMP as a tumor suppressor gene in neuroblastoma

“…LSAMP knockdown led to a significant increase in cell proliferation and viability in the LSAMP wild-type cell lines SH-SY5Y and SK-N-BE(2). These results are in concordance with previous publications (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44), suggesting that LSAMP could be a putative tumor suppressor gene also in NB. In addition, re-expression of LSAMP in KELLY cells (with homozygous LSAMP deletion) and overexpression of LSAMP in SK-N-AS cells (with heterozygous LSAMP deletion) inhibited cell proliferation and viability.…”

“…In addition, recurrent alterations in other genes associated with neurodevelopment and NB have recently been described by Lopez et al (17). Notably, LSAMP has previously been described as a tumor suppressor gene in osteosarcoma (33)(34)(35)(36)(37), ovarian cancer (38), renal cell carcinoma (39), prostatic cancer (40,41), epithelioid glioblastoma (42), myeloid leukemia (43) and recently in lung cancer (44). Gene expression analysis among NB cell lines indicated that the average expression levels were lower in LSAMP-rearranged samples, although no statistically significant difference was detected between the groups; however, in the cell line KELLY with a homozygous deletion rearrangement inside LSAMP, no expression levels were detected at exons 1-2 and 2-4.…”

“…In addition, LSAMP is reportedly involved in axon guidance during the limbic system development (30), neurite outgrowth in dorsal root ganglia (31) and psychiatric disorders (24,32). Notably, it has also previously been reported as a tumor suppressor gene in several types of cancer (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44).…”

Identification and validation of a prognostic risk-scoring model based on sphingolipid metabolism-associated cluster in colon adenocarcinoma

“…Furthermore, Chang et al. demonstrated that LSMAP, a tumor suppressor, influences the incidence and progression of lung cancer by regulating the epithelial-mesenchymal transition pathway ( 90 ). C2CD4A is a possible diagnostic marker for colon cancer, and its expression is strongly associated with the tumor stage of colon cancer, which is almost compatible with our results ( 91 ).…”

Identification of plasma proteins associated with oesophageal cancer chemotherapeutic treatment outcomes using SWATH-MS

“…LSAMP (limbic system-associated membrane protein) has been reported to be a candidate tumour suppressor gene in a range of cancer types [44][45][46][47][48]. Interestingly, the downregulation of LSAMP expression in cancer cell lines is associated with poor survival prognosis by promoting lung cancer progression [49]. CALL5 (calmodulin-like protein 5) is also thought to have tumour suppressor activities and is silenced at an early stage of carcinogenesis in squamous cell carcinoma of uterine cervix [50].…”