BACKGROUND: The metastasis and aggressive nature of prostate cancer (PCa) has become a major malignancy related threat that concerns men\'s health. The efficacy of immune monotherapy against PCa is questionable due to its lymphocyte-suppressive nature.
METHODS: Endoplasmic reticulum stress- (ERS-) and PCa-prognosis-related genes were obtained from the Molecular Signatures Database and the Cancer Genome Atlas database. The expression, prognosis and immune infiltration values of key genes were explored by \"survival R package\", \"rms\", \"xCELL algorithm\", and univariate-multivariate Cox and LASSO regression analyses. The \"consensus cluster plus R package\" was used for cluster analysis.
RESULTS: As ERS-related genes, ERLIN2 and CDK5RAP3 showed significant expressional, prognostic and clinic-pathologic values. They were defined as the key genes significantly correlated with immune infiltration and response. The nomogram was constructed with T-stage and primary treatment outcome, and the risk-prognostic model was constructed in the following way: Riskscore = (- 0.1918) * ERLIN2 + (0.5254) * CDK5RAP3. Subsequently, prognostic subgroups based on key genes classified the high-risk group as a pro-cancer subgroup that had lower mutation rates of critical genes (SPOP and MUC16), multiple low-expression immune-relevant molecules, and differences in macrophages (M1 and M2) expressions. Finally, ERLIN2 as an anti-oncogene and CDK5RAP3 as a pro-oncogene were further confirmed by cell phenotype assays and immunohistochemistry.
CONCLUSIONS: We identified ERLIN2 and CDK5RAP3 as ERS-related genes with important prognostic and immunologic values, and classified patients between high- and low-risk subgroups, which provided new prognostic markers, immunotherapeutic targets, and basis for prognostic assessments.

BACKGROUND: SPG18 is caused by mutations in the endoplasmic reticulum lipid raft associated 2 (ERLIN2) gene. Autosomal recessive (AR) mutations are usually associated with complicated hereditary spastic paraplegia (HSP), while autosomal dominant (AD) mutations use to cause pure SPG18.
OBJECTIVE: To define the variegate clinical spectrum of the SPG18 and to evaluate a dominant negative effect of erlin2 (encoded by ERLIN2) on oligomerization as causing differences between AR and AD phenotypes.
METHODS: In a four-generation pedigree with an AD pattern, a spastic paraplegia multigene panel test was performed. Oligomerization of erlin2 was analyzed with velocity gradient assay in fibroblasts of the proband and healthy subjects.
RESULTS: Despite the common p.V168M mutation identified in ERLIN2, a phenoconversion to amyotrophic lateral sclerosis (ALS) was observed in the second generation, pure HSP in the third generation, and a complicated form with psychomotor delay and epilepsy in the fourth generation. Erlin2 oligomerization was found to be normal.
CONCLUSIONS: We report the first AD SPG18 family with a complicated phenotype, and we ruled out a dominant negative effect of V168M on erlin2 oligomerization. Therefore, our data do not support the hypothesis of a relationship between the mode of inheritance and the phenotype, but confirm the multifaceted nature of SPG18 on both genetic and clinical point of view. Clinicians should be aware of the importance of conducting an in-depth clinical evaluation to unmask all the possible manifestations associated to an only apparently pure SPG18 phenotype. We confirm the genotype-phenotype correlation between V168M and ALS emphasizing the value of close follow-up.

Mutations in ERLIN2 and MFN2 lead to the development of spastic paraplegia-18 (SPG18) and Charcot-Marie-Tooth type-2A (CMT2A), respectively. These disorders are unified by the fact that both can be termed inherited axonopathies. With whole-exome sequencing (WES), more patients of neurological disorders with clinical overlaps receive a genetic result than ever before. This study describes an Iranian family who harbor mutations in ERLIN2 and MFN2, simultaneously. The proband was a 73-year old man who has experienced weakness and spasticity of lower limbs since late childhood. He was diagnosed with hereditary spastic paraplegia (HSP). His WES identified a novel homozygous variant in ERLIN2 as well as a known heterozygous variant in MFN2. These variants were cosegregated with the phenotypes among the family members. His sister with a similar phenotype just carried the homozygous ERLIN2 variant, whereas, his asymptomatic brother and daughter carried the heterozygous variant of MFN2. Re-evaluation of the MFN2 variant carriers by nerve conduction study revealed that only the proband\'s daughter has peripheral neuropathy. Herein, using WES two distinct disease-causing variants with different modes of inheritance in ERLIN2 and MFN2 were detected in the proband. As expected, individuals with a defined MFN2 variant, p.Arg468His, were asymptomatic or had a mild phenotype. The co-occurrence of such diseases, SPG18 and CMT2A, may result in the milder phenotype to be overlooked or its features considered as a part of the symptoms of other disease. Certainly, providing genetic counseling in such cases can be challenging. These cases reveal the importance of WES.

OBJECTIVE: Hereditary spastic paraplegia (HSP) due to ERLIN2 gene mutations was designated as spastic paraplegia 18 (SPG18). To date, SPG18 families/cases are still rarely reported. All early reported cases shared the autosomal recessive (AR) inheritance pattern. Over the past 3 years, autosomal dominant (AD) or sporadic SPG18 cases had been continuously reported. Here, we reported the clinical and genetic features of the first autosomal dominant SPG18 pedigree in Chinese.
METHODS: We conducted detailed medical history inquiry, neurological examinations of the proband and his family members, and charted the family tree. The proband underwent brain and cervical magnetic resonance imaging (MRI), electromyography (EMG), and whole exome sequencing. Sanger sequencing was performed to verify the genetic variation in the proband and some family members. A literature review of all reported SPG18 families/cases was carried out to summarize the clinical-genetic characteristics of SPG18 under different inheritance patterns.
RESULTS: Four patients were clinically diagnosed as chronic spastic paraplegia in three consecutive generations with the autosomal dominant inheritance model. All the patients presented juvenile-adolescent onset and gradually worsening pure HSP phenotype. Clinical phenotypes were consistent within the family. Whole exome sequencing in the proband identified a previously reported heterozygous c.502G > A (p.V168M) mutation in exon 8 of ERLIN2 gene. This mutation was cosegregated with the phenotype in the family and was classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. To date, eight AR-SPG18 families, five AD-SPG18 families, and three sporadic cases had been reported. Clinical phenotype of AD-SPG18 was juvenile-adolescent onset pure HSP, while the phenotype of AR-SPG18 was mostly complicated HSP with earlier onset and more severe conditions. In rare cases, the initial spastic paraplegia could evolve to rapidly progressive amyotrophic lateral sclerosis (ALS).
CONCLUSIONS: We reported the first autosomal dominant SPG18 pedigree in Chinese Han population, which added more pathogenic evidence for V168M mutation. As more SPG18 cases reported, the essentials of SPG18 need to be updated in clinical practice. Special attentions should be given in gene test for upper motor neuron disorders in case of missing heterozygous mutations in ERLIN2.

暂无摘要。

Endoplasmic reticulum lipid raft-associated protein 2 (ERLIN2) is protein contained in the membrane of the endoplasmic reticulum. In lung adenocarcinoma (LUAD), the molecular function of ERLIN2 and the correlation between ERLIN2 and tumor-infiltrating immune cells have been unclear. The aim of our study was to determine the role of ERLIN2 in LUAD development to provide a better understanding of the molecular pathogenesis of this disease and identify new therapeutic targets for its treatment.
Immunohistochemistry, Western blotting, and real-time quantitative polymerase chain reaction were used to detect protein and mRNA levels of ERLIN2 in LUAD and adjacent normal tissues. Using the A549, H1299 cell line, ERLIN2-short hairpin RNA was applied to silence ERLIN2 to determine its role in LUAD cell proliferation and invasion. Based on mRNA expression of ERLIN2 from the Cancer Genome Atlas (TCGA) database, we identified ERLIN2-related protein-coding genes and analyzed the Kyoto Encyclopedia of Genes and Genomes pathway to explore its potential biological functions and determined the correlation between ERLIN2 and tumor-infiltrating immune cells.
ERLIN2 was abnormally expressed in a variety of tumor tissues and is highly expressed in LUAD. This overexpression was associated with histological grade (P = 0.044), TNM stage (P = 0.01), and lymph node metastasis (P = 0.038). Patient overall survival was poorer with ERLIN2 overexpression. Downregulation of ERLIN2 inhibited LUAD cell proliferation and invasion in vitro. Based on mRNA expression of ERLIN2 from the TCGA database, 13 ERLIN2-related genes and 10 pathways were identified and showed a correlation between ERLIN2 and naive B cells and neutrophils.
ERLIN2 could serve as a potential diagnostic and prognostic biomarker for LUAD and has demonstrated to be correlated with immune infiltrates, which suggests that it may represent a new therapeutic target for LUAD.

Copy number alterations are widespread in cancer genomes and are part of the genomic instability underlying the pathogenesis of neoplastic diseases. Recurrent copy number alterations of specific chromosomal loci may result in gains of oncogenes or losses of tumor suppressor genes and become entrenched in the genomic framework of certain types of cancers. The locus at chromosome 8p11.23 presents recurrent amplifications most commonly in squamous lung carcinomas, breast cancers, squamous esophageal carcinomas, and urothelial carcinomas. Amplification is rare in other cancers. The amplified segment involves several described oncogenes that may promote cancer cell survival and proliferation, as well as less well characterized genes that could also contribute to neoplastic processes. Genes proposed to be \"drivers\" in 8p11.23 amplifications include ZNF703, FGFR1 and PLPP5. Additional genes in the locus that could be functionally important in neoplastic networks include co-chaperone BAG4, lysine methyltransferase NSD3, ASH2L, a member of another methyltransferase complex, MLL and the mRNA processing and translation regulators LSM1 and EIF4EBP1. In this paper, genes located in the amplified segment of 8p11.23 will be examined for their role in cancer and data arguing for their importance for cancers with the amplification will be presented.

BACKGROUND: Astrocytoma is a common tumor type in primary central nervous system and has a high death rate around the world. Aberrant expression of long non-coding RNAs (lncRNAs) has been introduced by emerging studies to result in the development of diverse cancers.
METHODS: RT-qPCR examined the expression of SNHG17, miR-876-5p and ERLIN2, and western blot evaluated ERLIN2 protein level. RNA pull down and luciferase reporter assays illustrated the relationships between SNHG17 and its downstream molecules.
RESULTS: SNHG17 was up-regulated in astrocytoma cells. Moreover, SNHG17 silence could repress the proliferation, migration and invasion of astrocytoma cells. Besides, miR-876-5p was selected out as a downstream molecule of SNHG17 in astrocytoma. ERLIN2 was determined to be targeted by miR-876-5p. ERLIN2 mRNA and protein levels were lessened by miR-876-5p overexpression and SNHG17 silence. Additionally, miR-876-5p overexpression decelerated the biological processes of astrocytoma cells, so did ERLIN2 knockdown. More importantly, the impacts of SNHG17 down-regulation on the malignant behaviors of astrocytoma cells were counteracted by overexpressed ERLIN2 or inhibited miR-876-5p.
CONCLUSIONS: SNHG17 could induce the progression of astrocytoma by sponging miR-876-5p to elevate the expression of ERLIN2. This study indicated that SNHG17 has a high potential to be a therapeutic target for astrocytoma.

The erlin1/2 complex is a ∼2-MDa endoplasmic reticulum membrane-located ensemble of the ∼40-kDa type II membrane proteins erlin1 and erlin2. The best defined function of this complex is to mediate the ubiquitination of activated inositol 1,4,5-trisphosphate receptors (IP3Rs) and their subsequent degradation. However, it remains unclear how mutations of the erlin1/2 complex affect its cellular function and cause cellular dysfunction and diseases such as hereditary spastic paraplegia. Here, we used gene editing to ablate erlin1 or erlin2 expression to better define their individual roles in the cell and examined the functional effects of a spastic paraplegia-linked mutation to erlin2 (threonine to isoleucine at position 65; T65I). Our results revealed that erlin2 is the dominant player in mediating the interaction between the erlin1/2 complex and IP3Rs and that the T65I mutation dramatically inhibits this interaction and the ability of the erlin1/2 complex to promote IP3R ubiquitination and degradation. Remarkably, we also discovered that the erlin1/2 complex specifically binds to phosphatidylinositol 3-phosphate, that erlin2 binds this phospholipid much more strongly than does erlin1, that the binding is inhibited by T65I mutation of erlin2, and that multiple determinants within the erlin2 polypeptide comprise the phosphatidylinositol 3-phosphate-binding site. Overall, these results indicate that erlin2 is the primary mediator of the cellular roles of the erlin1/2 complex and that disease-linked mutations of erlin2 can affect both IP3R processing and lipid binding.

OBJECTIVE: Endoplasmic reticulum lipid raft-associated 2 (ERLIN2) is reported to be overexpressed in human breast cancer cells and plays an important role in cell proliferation. MicroRNAs (miRNAs) act as post-transcriptional regulators of gene expression and are involved in the development of multiple malignancies, including breast cancer. However, the molecular mechanism of the aberrant ERLIN2 expression in human breast cancer remains poorly understood.
METHODS: MiR-410 expression level was analyzed using Real-time PCR, and ERLIN2 expression was analyzed using Western blot, Real-time PCR and immunohistochemical staining. The effect of miR-410 on ERLIN2 3\'UTR intensity was performed using a luciferase assay. Cell proliferation was analyzed using CCK-8 and colony formation assay, together with an Annexin V-PE/7-AAD kit for cell apoptosis assay. Cell migration and invasion was detected using a Transwell migration and invasion assay. Methylation specific PCR was used to examine whether miR-410 promoter was demethylated.
RESULTS: In this study, we validated that ERLIN2 was a direct target of miR-410 and miR-410 suppressed ERLIN2 expression at the post-transcriptional level. Importantly, the regulation of ERLIN2 by miR-410 was estrogen receptor (ER) dependent. Functional studies demonstrated that miR-410 inhibited breast cancer cell proliferation, migration and invasion, but promoted cell apoptosis. However, inhibition of miR-410 resulted in opposite effects. A xenograft nude mouse model further confirmed that miR-410 suppressed breast tumor growth. In addition, miR-410 modulated the expression levels of epithelial-mesenchymal transition (EMT)-related genes. ERLIN2 knockdown suppressed cell proliferation, migration and invasion, as well as EMT. ERLIN2 overexpression can restore the cell proliferation, migration and invasion that were inhibited by miR-410. Furthermore, our data demonstrated that miR-410 inhibition suppressed the expression of endoplasmic reticulum-stress (ERS)-related genes, while ERLIN2 knockdown abrogated the effects of miR-410 inhibitor. Finally, we showed that miR-410 was downregulated in human ER-positive breast cancer tissues, inversely correlated with ERLIN2. We further demonstrated the downregulation of miR-410 in breast cancer might be due to the hypermethylation of its promoter.
CONCLUSIONS: Our study indicates that miR-410 suppresses cell growth, migration and invasion by directly downregulating ERLIN2 in ER positive breast cancer, acting as a tumor suppressor. Our study also suggests that miR-410 may serve as a potential therapeutic target for patients with ER positive breast cancer.