OSBPL10-CNBP axis mediates hypoxia-induced pancreatic cancer development.

Pancreatic ductal adenocarcinoma (PDAC) is one of malignancies with worst outcomes among digestive system tumors. Identification of novel biomarkers is of great significance for treatment researches and prognosis prediction of pancreatic cancer patients. Due to OSBPL10 known involvement in oncogenic activity in other tumors, we elucidated the mechanism underlying its contribution to pancreatic cancer progression. We employed data from the Gene Expression Omnibus database to detect the expression of OSBPL10 in normal and pancreatic cancer tissues. A series of assays were conducted to assess the impact of OSBPL10 on the proliferation and metastatic capacities of pancreatic cancer cells and the influence of OSBPL10 on macrophages were evaluated by Flow cytometry. In addition, Co-immunoprecipitation, mass spectrometry, and western blot assays were utilized to investigate the potential mechanisms of OSBPL10 activity. From our study, OSBPL10 is revealed to be upregulated in pancreatic cancer, with poor prognosis. The overexpression promotes malignant behaviors of pancreatic cancer cells and has an impact on tumor immune microenvironment by stimulating the transformation M1 macrophages into M2 macrophages. Mechanistically, hypoxia induces the expression of OSBPL10 through interaction between hypoxia-inducible factor 1-α and the promoter region of OSBPL10. Additionally, OSBPL10 directly bound to CNBP, mediating CNBP expression and ultimately regulating the proliferation and metastasis capacity of pancreatic cancer cells, as well as influencing macrophage polarization. The research emphasized the oncogenic role of OSBPL10 in pancreatic cancer, uncovering key mechanisms involving hypoxia, HIF-1α, and CNBP. The finding suggests that OSBPL10 is a novel biomarker in pancreatic cancer, making it a potential therapeutic target for intervention in this malignancy.

OSBPL2 compound heterozygous variants cause dyschromatosis, ichthyosis, deafness and atopic disease syndrome.

PURPOSE: In this study, we identified and diagnosed a novel inherited condition called Dyschromatosis, Ichthyosis, Deafness, and Atopic Disease (DIDA) syndrome. We present a series of studies to clarify the pathogenic variants and specific mechanism. METHODS: Exome sequencing and Sanger sequencing was conducted in affected and unaffected family members. A variety of human and cell studies were performed to explore the pathogenic process of keratosis. RESULTS: Our finding indicated that DIDA syndrome was caused by compound heterozygous variants in the oxysterol-binding protein-related protein 2 (OSBPL2) gene. Furthermore, our findings revealed a direct interaction between OSBPL2 and Phosphoinositide phospholipase C-beta-3 (PLCB3), a key player in hyperkeratosis. OSBPL2 effectively inhibits the ubiquitylation of PLCB3, thereby stabilizing PLCB3. Conversely, OSBPL2 variants lead to enhanced ubiquitination and subsequent degradation of PLCB3, leading to epidermal hyperkeratosis, characterized by aberrant proliferation and delayed terminal differentiation of keratinocytes. CONCLUSIONS: Our study not only unveiled the association between OSBPL2 variants and the newly identified DIDA syndrome but also shed light on the underlying mechanism.

ENST00000534735 inhibits proliferation and migration, promotes apoptosis and pyroptosis of endometrial cancer via OSBPL3 through APMK/SIRT1/NF-κB pathway.

Background: The complete understanding of the biological roles of long non-coding RNAs (lncRNAs) in cancer remains elusive. The findings of this study indicate that the newly discovered lncRNA ENST00000534735 exhibited a decreased expression in both endometrial cancer (EC) tissues and cell lines. Methods: The expression of ENST00000534735 in EC tissues was detected using RNA-sequencing analysis. The effects of ENST00000534735 on cell proliferation, migration, apoptosis, and pyroptosis were determined via in vitro and in vivo experiments. The proteins that interact with ENST00000534735 were confirmed by RNA pull-down assay. Furthermore, an investigation was conducted on the impact of ENST00000534735 on the in vivo growth of EC through a tumorigenicity assay in nude mice. Results: We found that ENST00000534735 was significantly down-regulated in EC tissues compared to their adjacent non-cancerous tissues. The ectopic expression of ENST00000534735 drastically inhibited lung cancer cell proliferation and migration ability and facilitated apoptosis and pyroptosis. Knockdown of ENST00000534735 increased OSBPL3 expression, and the tumor-suppressing effects of ENST00000534735 overexpression were reversed by upregulation of OSBPL3 via the APMK/SIRT1/NF-κB pathway. The in vivo tumorigenic assays conducted on nude mice revealed that the excessive expression of ENST00000534735 impeded the growth of EC. Conclusions: All results elucidated the role and molecular mechanism of ENST00000534735 in the malignant development of EC. ENST00000534735, a new antioncogene in EC, may serve as a survival biomarker or therapeutic target for EC.

Loss of ORP3 induces aneuploidy and promotes bladder cancer cell invasion through deregulated microtubule and actin dynamics.

We have recently shown that loss of ORP3 leads to aneuploidy induction and promotes tumor formation. However, the specific mechanisms by which ORP3 contributes to ploidy-control and cancer initiation and progression is still unknown. Here, we report that ORP3 is highly expressed in ureter and bladder epithelium while its expression is downregulated in invasive bladder cancer cell lines and during tumor progression, both in human and in mouse bladder cancer. Moreover, we observed an increase in the incidence of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced invasive bladder carcinoma in the tissue-specific Orp3 knockout mice. Experimental data demonstrate that ORP3 protein interacts with γ-tubulin at the centrosomes and with components of actin cytoskeleton. Altering the expression of ORP3 induces aneuploidy and genomic instability in telomerase-immortalized urothelial cells with a stable karyotype and influences the migration and invasive capacity of bladder cancer cell lines. These findings demonstrate a crucial role of ORP3 in ploidy-control and indicate that ORP3 is a bona fide tumor suppressor protein. Of note, the presented data indicate that ORP3 affects both cell invasion and migration as well as genome stability through interactions with cytoskeletal components, providing a molecular link between aneuploidy and cell invasion and migration, two crucial characteristics of metastatic cells.

Prognostic and biological function value of OSBPL3 in colorectal cancer analyzed by multi-omic data analysis.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies in the world. This study proposes to reveal prognostic biomarkers for the prognosis and treatment of CRC patients. METHODS: Differential analysis of OSBPL3 was performed in pan-cancer, and the correlation between clinical stage and OSBPL3 was analyzed. Multiple omics analysis was used to compare the relationship between survival of patients and copy number variation, single nucleotide variant, and methylation status. Survival differences between high and low OSBPL3 expression groups were analyzed. Differentially expressed genes (DEGs) between high and low OSBPL3 expression groups were obtained, and functional enrichment analysis was implemented. Correlations between immune cells and OSBPL3 was analyzed. Drug sensitivity between the two OSBPL3 expression groups was compared. Moreover, the expression of OSBPL3 was verified by immunohistochemistry and real-time quantitative PCR. RESULTS: OSBPL3 was differentially expressed in 13 tumors and had some correlations with T and N stages. OSBPL3 expression was regulated by methylation and higher OSBPL3 expression was associated with poorer prognosis in CRC. 128 DEGs were obtained and they were mainly involved in signaling receptor activator activity, aspartate and glutamate metabolism. T cell gamma delta and T cell follicular helper were significantly different in the high and low OSBPL3 expression groups. Moreover, OSBPL3 showed negative correlations with multiple drugs. OSBPL3 was significantly upregulated in CRC samples compared to normal samples. CONCLUSIONS: A comprehensive analysis demonstrated that OSBPL3 had potential prognostic value, and guiding significance for CRC chemotherapeutic.

Integrated bioinformatics analysis reveals the function and prognostic value of OSBPL3 in hepatocellular carcinoma.

Background: Liver hepatocellular carcinoma (LIHC), a variety of highly-aggressive malignancy, has been the major cause of cancer-related mortality. Recent studies have shown that oxysterol-binding protein-like 3 (OSBPL3) plays a crucial role in human cancers. Nevertheless, the specific functional roles and potential clinical values of OSBPL3 in LIHC are not completely known. Methods: Multiple web portals and publicly available tools were used in this study. Comprehensive expression files of OSBPL3 in pan-cancers and the relationship between OSBPL3 expression and clinical traits of patients with LIHC were investigated using TCGA database through UALCAN platform. TIMER database was used to investigate the effect of OSBPL3 on the tumor immune infiltration status in LIHC. Moreover, LinkedOmics, STRING databases, and Gene Ontology analysis were utilized to select OSBPL3-related differentially expressed genes (DEGs) and construct a protein-protein interaction (PPI) network. Results: Upregulated OSBPL3 was observed in LIHC tumor tissues compared with that in normal controls, especially in patients with higher grades and more advanced stages. Furthermore, overexpressed OSBPL3 was closely associated with poor clinical outcomes of patients with LIHC. Six hub genes were selected from the PPI network, which were significantly increased in LIHC and closely associated with poor prognosis. Pathway enrichment showed that OSBPL3-related DEGs were primarily enriched in protein binding, mitotic cytokinesis, inorganic anion transport, and I-kappaB kinase/NF-kappaB signaling processes. Conclusions: OSBPL3 exerts critical functions in hepatocarcinogenesis and it could serve as an available biomarker and effective treatment target for LIHC.

The expression, immune infiltration, prognosis, and experimental validation of OSBPL family genes in liver cancer.

BACKGROUND: Liver cancer is the third most deadly malignant tumor in the world with poor prognosis and lacks early diagnostic markers. It is urgent need to explore new biomarkers and prognostic factors. The oxysterol-binding protein-like family proteins (OSBPLs) are essential mediators of lipid transportation and cholesterol balancing which has been reported to participate in cancer progression. So far, the expression, immune infiltration, and prognosis of OSBPLs have not been elucidated in liver cancer. METHODS: The differential expressions of OSBPLs between liver tumor and normal tissues were assessed by analyzing RNA-seq data from TCGA and protein data from CPTAC, respectively. Subsequently, genetic variations, potential functional enrichment analysis, and immune cell infiltration were analyzed. Further, the prognostic effects of OSBPLs were identified via constructing lasso models and performing receiver operating characteristic curve (ROC) analysis. Moreover, 10 local liver cancer specimens were involved to validate the expression of OSBPL3 via immunohistochemistry (IHC) assay. Finally, CCK-8, cell cycle, apoptosis, transwell assays, real time qPCR (RT-qPCR), and western blot assays were conducted to explore the function of OSBPL3 in liver cancer cells. RESULTS: The mRNA of OSBPL2, OSBPL3, and OSBPL8 were highly expressed while OSBPL6 was lowly expressed in liver cancer samples compared with normal samples. As to the protein expression, OSBPL2 and OSBPL3 were significantly elevated and OSBPL5, OSBPL6, OSBPL9, OSBPL10, OSBPL11 were downregulated in tumor samples. A positive correlation was found between copy number variations (CNV) and the expression of OSBPL2, OSBPL8, OSBPL9, OSBPL11, while DNA methylation was negatively associated with the expressions of OSBPLs. Of these, CNV amplification mainly contributed to the overexpression of OSBPL2 and DNA methylation may be responsible for the high expression of OSBPL3. Interestingly, OSBPL3, OSBPL5, SOBPL7, and OSBPL10 were significantly positively correlated with immune infiltration. Notably, OSBPL3 was identified correlated to overall survival (OS) and disease specific survival (DSS) in liver cancer. Functionally, knocking down OSBPL3 reduced liver cancer cell viability, induced a G2/M cell cycle arrest, promoted apoptosis, and restrained cell migration. CONCLUSION: In aggregate, we reported a heretofore undescribed role of OSBPLs in liver cancer by analyzing multi-omics data. Importantly, we identified OSBPL3 was overexpressed in liver tumor compared with normal and its high expression was correlated with poor OS and DSS. Inhibition of OSBPL3 resulted in a pronounced decrease in cell proliferation and migration.

Oxysterol-binding protein-like 3 is a novel target gene of peroxisome proliferator-activated receptor γ in fatty liver disease.

Oxysterol-binding protein-like 3 (OSBPL3) plays a key role in the development of fatty liver disease. Herein, we found that OSBPL3 is highly expressed in the fatty liver of humans and mice. Although high expression of Osbpl3 was observed in the fatty liver of type 2 diabetic ob/ob mice, liver-specific Pparg knockout ameliorated this increase in these mice. Moreover, high hepatic Osbpl3 expression was observed in other mice models of fatty liver disease, such as leptin receptor-mutant db/db and alcohol-fed mice. Analysis of the human liver transcriptome data revealed that hepatic OSBPL3 expression is higher in patients with advanced non-alcoholic fatty liver disease (NAFLD) when compared to those with mild NAFLD. Reporter and electrophoretic mobility shift assays showed that PPARγ positively regulates Osbpl3 transcription by binding to the two functional PPARγ-responsive elements present in the 5' upstream region. Overall, our results indicate that Osbpl3 is a novel PPARγ target in the fatty liver.

The relationships of OSBPL3 expression with KI-67 expression and KRAS mutations in CRC: implications for diagnosis and prognosis.

BACKGROUND: OSBPL3 is overexpressed in a variety of malignancies and is closely associated with tumor growth and metastasis. However, its expression and function in colorectal cancer (CRC) are unclear. We aimed to investigate its prognostic and therapeutic value in this disease by detecting its expression in CRC and its correlation with the clinicopathological characteristics and prognosis of patients. METHODS: A total of 92 CRC samples were included in this study. According to the 2020 WHO diagnostic criteria, the criteria of the American Joint Committee on Cancer (AJCC) 8th edition staging system were used. OSBPL3 and Ki-67 expression in these samples was detected by immunohistochemistry. OSBPL3 mRNA expression was detected by qRT-PCR. KRAS/NRAS mutations were detected by an amplification refractory mutation system (ARMS). Data analysis was performed using the statistical analysis software Prism 8. RESULTS: OSBPL3 was found to be significantly overexpressed in CRC tumor tissues and was associated with worse progression-free survival and overall survival in patients. Additionally, OSBPL3 expression was negatively correlated with the degree of tumor differentiation. KRAS mutations were detected in approximately 32.6% of patients and were significantly associated with high OSBPL3 expression. In addition, OSBPL3 and Ki-67 expression was significantly correlated. CONCLUSIONS: OSBPL3 is highly expressed in CRC samples and predicts a worse prognosis. OSBPL3 may become a new potential therapeutic target for CRC.

ARL4C depletion suppresses the resistance of ovarian cancer to carboplatin by disrupting cholesterol transport and autophagy via notch-RBP-Jκ-H3K4Me3-OSBPL5.

Increasing studies indicate that cholesterol plays an important role in drug resistance. ARL4C is implicated in the export and import of cholesterol, therefore this study aimed to explore the effect of ARL4C on the resistance of ovarian cancer (OVC) to Carboplatin. This study collected OVC tissue samples from patients who are sensitive or resistant to carboplatin, and established Carboplatin-resistant OVC cell lines, OVCAR3(R) and SKOV3(R) using OVCAR3 and SKOV3. High throughput sequencing was conducted to find genes that regulated by ARL4C. Cholesterol esterification was performed to evaluate the transport of cholesterol from Lysosome (LY) to Endoplasmic reticulum (ER). The fluorescence of LC3-GFP-mRFP was used to evaluate the function of autophagy flux. As indicated by PCR, western blot and Immunohistochemistry, ARL4C was increased in the Carboplatin-resistant OVC tissues and cells. Knockdown of ARL4C attenuated the resistance of OVCAR3(R) and SKOV3(R) to Carboplatin. By suppressing Notch signal, ARL4C knockdown inhibited the transcriptional function of RBP-Jκ and RBP-Jκ-induced H3K4Me3, which collectively reduced OSBPL5 expression. OSBPL5 deficiency inhibited the transport of cholesterol from LYs to ER, which led to the accumulation of cholesterol in LYs and the dysfunction of autophagy. In summary, ARL4C knockdown attenuated the resistance of OVC to Carboplatin by disrupting cholesterol transport and autophagy. This study revealed a promising target to attenuate the resistance of OVC to Carboplatin and elucidated the potential mechanism.

IMPACT and OSBPL1A are two isoform-specific imprinted genes in bovines.

The epigenetic process of genomic imprinting results in the monoallelic expression of genes based on their parental origin. Comparative analysis of imprinted genes between species is useful for investigating the biological significance and regulatory mechanisms of genomic imprinting. Mouse Impact is an imprinted gene, but its human ortholog IMPACT escapes genomic imprinting. Hrh4 and Osbpl1a are the two nearest neighbors of the Impact located in distal and proximal regions, respectively. This study aims to assess the allelic expression of bovine IMPACT, OSBPL1A and HRH4 genes and examine the differentially methylated regions (DMRs) associated with these three genes. Based on an expressed single-nucleotide polymorphism (SNP) approach, we found that both the IMPACT and OSBPL1A genes exhibit isoform-specific monoallelic expression in bovine adult tissues. In the seven detected bovine IMPACT transcripts, only one transcript variant (X6) is monoallelically expressed in bovine adult tissues and paternally expressed in the placenta. However, no DMR was found in the promoter region of the IMPACT gene. We obtained five transcript variants (V1-V5) of the bovine OSBPL1A gene of different lengths that start transcription from distinct alternative promoters by RT-PCR. Only the longest variant V1 was found to be expressed monoallelically in bovine adult tissues and a DMR was identified in its promoter region using the bisulfite sequencing method. Thus, the DMR in OSBPL1A V1 promoter region may contribute to its isoform-specific monoallelic expression. The bovine HRH4 gene is expressed biallelically. Hypermethylation was observed in brains without HRH4 expression, while hypomethylation was found in the spleens with HRH4 expression, so and the level of DNA methylation in the promoter seemed to be related to its expression in tissues.

OSBPL2 mutations impair autophagy and lead to hearing loss, potentially remedied by rapamycin.

Intracellular accumulation of mutant proteins causes proteinopathies, which lack targeted therapies. Autosomal dominant hearing loss (DFNA67) is caused by frameshift mutations in OSBPL2. Here, we show that DFNA67 is a toxic proteinopathy. Mutant OSBPL2 accumulated intracellularly and bound to macroautophagy/autophagy proteins. Consequently, its accumulation led to defective endolysosomal homeostasis and impaired autophagy. Transgenic mice expressing mutant OSBPL2 exhibited hearing loss, but osbpl2 knockout mice or transgenic mice expressing wild-type OSBPL2 did not. Rapamycin decreased the accumulation of mutant OSBPL2 and partially rescued hearing loss in mice. Rapamycin also partially improved hearing loss and tinnitus in individuals with DFNA67. Our findings indicate that dysfunctional autophagy is caused by mutant proteins in DFNA67; hence, we recommend rapamycin for DFNA67 treatment.Abbreviations: ABR: auditory brainstem response; ACTB: actin beta; CTSD: cathepsin D; dB: decibel; DFNA67: deafness non-syndromic autosomal dominant 67; DPOAE: distortion product otoacoustic emission; fs: frameshift; GFP: green fluorescent protein; HsQ53R-TG: human p.Q53Rfs*100-transgenic: HEK 293: human embryonic kidney 293; HFD: high-fat diet; KO: knockout; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NSHL: non-syndromic hearing loss; OHC: outer hair cells; OSBPL2: oxysterol binding protein-like 2; SEM: scanning electron microscopy; SGN: spiral ganglion neuron; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TG: transgenic; WES: whole-exome sequencing; YUHL: Yonsei University Hearing Loss; WT: wild-type.

Silencing of circ_OSBPL10 affects the functional behaviors of oral squamous cell carcinoma cells by the miR-299-3p/CDK6 axis.

BACKGROUND: Circular RNAs (circRNAs) are increasingly implicated in the development of oral squamous cell carcinoma (OSCC). Here, we explored the precise role of circRNA oxysterol binding protein like 10 (circ_OSBPL10, circ_0008549) in OSCC pathogenesis. METHODS: Ribonuclease (RNase) R assay was performed to assess the stability of circ_OSBPL10. The levels of circ_OSBPL10, microRNA (miR)-299-3p and cyclin-dependent kinase 6 (CDK6) mRNA were gauged by qRT-PCR. CDK6 protein level was measured by western blot. Cell proliferation was detected by MTT and colony formation assays. Cell cycle distribution and apoptosis were measured by flow cytometry. Cell migration and invasion were evaluated using transwell assay. Dual-luciferase reporter assay was used to identify the relationship between miR-299-3p and circ_OSBPL10 or CDK6. Animal studies were performed to evaluate the role of circ_OSBPL10 in tumor growth in vivo. RESULTS: Circ_OSBPL10 was up-regulated in OSCC tissues and cells. Silencing of circ_OSBPL10 hindered cell proliferation, cell cycle progression, colony formation, migration, invasion, and promoted apoptosis in vitro and diminished tumor growth in vivo. Mechanistically, circ_OSBPL10 directly targeted miR-299-3p, and circ_OSBPL10 silencing affected cell functional properties in vitro by up-regulating miR-299-3p. CDK6 was a direct and functional target of miR-299-3p. The circ_OSBPL10/miR-299-3p axis regulated cell functional properties in vitro via CDK6. Moreover, circ_OSBPL10 acted as a competing endogenous RNA (ceRNA) to regulate CDK6 expression through miR-299-3p. CONCLUSION: Our present findings first demonstrate that circ_OSBPL10 can regulate the functional behaviors of OSCC cells at least partially by miR-299-3p/CDK6 axis, highlighting circ_OSBPL10 as a promising therapeutic target for OSCC.

Coordination of inter-organelle communication and lipid fluxes by OSBP-related proteins.

Oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) constitute one of the largest families of lipid-binding/transfer proteins (LTPs) in eukaryotes. The current view is that many of them mediate inter-organelle lipid transfer over membrane contact sites (MCS). The transfer occurs in several cases in a 'counter-current' fashion: A lipid such as cholesterol or phosphatidylserine (PS) is transferred against its concentration gradient driven by transport of a phosphoinositide in the opposite direction. In this way ORPs are envisioned to maintain the distinct organelle lipid compositions, with impacts on multiple organelle functions. However, the functions of ORPs extend beyond lipid homeostasis to regulation of processes such as cell survival, proliferation and migration. Important expanding areas of mammalian ORP research include their roles in viral and bacterial infections, cancers, and neuronal function. The yeast OSBP homologue (Osh) proteins execute multifaceted functions in sterol and glycerophospholipid homeostasis, post-Golgi vesicle transport, phosphatidylinositol-4-phosphate, sphingolipid and target of rapamycin (TOR) signalling, and cell cycle control. These observations identify ORPs as lipid transporters and coordinators of signals with an unforeseen variety of cellular processes. Understanding their activities not only enlightens the biology of the living cell but also allows their employment as targets of new therapeutic approaches for disease.

Bone mesenchymal stem cell-derived exosomal microRNA-7-5p inhibits progression of acute myeloid leukemia by targeting OSBPL11.

BACKGROUND: Acute myeloid leukemia (AML) is a malignant clonal disease of hematopoietic stem- and progenitor-cell origin. AML features massive proliferation of abnormal blasts and leukemia cells in the bone marrow and the inhibition of normal hematopoiesis at onset. Exosomes containing proteins or nucleic acids are secreted by cells; they participate in intercellular communication and serve as key modulators of hematopoiesis. The purpose of this study was to investigate the effects of exosomes derived from bone marrow mesenchymal stem cells (BMSCs) on the regulation of AML and the underlying mechanisms mediated by microRNA (miRNA). METHODS: Dysregulated miR-7-5p in AML patients was identified using qRT-PCR and its clinical significance was explored. Bioinformatic analysis revealed the target gene OSBPL11 that could be regulated by miR-7-5p. The findings were validated using a dual-luciferase reporter assay and western blotting. The functional genes of the PI3K/AKT/mTOR signaling pathway were identified, and the functional significance of miR-7-5p in AML cells was determined using a functional recovery assay. AML cells were co-cultured with exosomes originating from BMSCs overexpressing miR-7-5p to determine cell-cell regulation by Exo-miR-7-5p, as well as in vitro and in vivo functional validation via gain- and loss-of-function methods. RESULTS: Expression of miR-7-5p was decreased in AML patients and cells. Overexpression of miR-7-5p curbed cellular proliferation and promoted apoptosis. Overexpression of OSBPL11 reversed the tumorigenic properties of miR-7-5p in AML cells in vitro. Exo-miR-7-5p derived from BMSCs induced formation of AML cells prone to apoptosis and a low survival rate, with OSBPL11 expression inhibited through the PI3K/AKT/mTOR signaling pathway. Exo-miR-7-5p derived from BMSCs exhibited tumor homing effects in vitro and in vivo, and inhibited AML development. CONCLUSIONS: Exo-miR-7-5p derived from BMSCs negatively regulates OSBPL11 by suppressing the phosphorylation of the PI3K/AKT/mTOR signaling pathway, thereby inhibiting AML proliferation and promoting apoptosis. The data will inform the development of AML therapies based on BMSC-derived exosomes.

The LMCD1-AS1/miR-526b-3p/OSBPL5 axis promotes cell proliferation, migration and invasion in non-small cell lung cancer.

PURPOSE: To explore the specific role and regulatory mechanism of oxysterol binding protein like 5 (OSBPL5) in non-small cell lung cancer (NSCLC). METHODS AND RESULTS: Quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrated that OSBPL5 expression was notably elevated in NSCLC tissues and cell lines, and Kaplan-Meier analysis manifested that high OSBPL5 expression was closely related to the poor prognosis of NSCLC patients. Besides, according to the results from western blot analysis, cell counting kit-8, EdU and Transwell assays, knockdown of OSBPL5 suppressed NSCLC cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process. Additionally, by performing qRT-PCR analysis, luciferase reporter and RNA pull-down assays, we verified that OSBPL5 was a downstream target of miR-526b-3p and long noncoding RNA (lncRNA) LMCD1-AS1 served as a sponge for miR-526b-3p. Moreover, from rescue assays, we observed that OSBPL5 overexpression offset LMCD1-AS1 knockdown-mediated inhibition in cell proliferation, migration, invasion and EMT in NSCLC. CONCLUSIONS: This paper was the first to probe the molecular regulatory mechanism of OSBPL5 involving the LMCD1-AS1/miR-526b-3p axis in NSCLC and our results revealed that the LMCD1-AS1/miR-526b-3p/OSBPL5 axis facilitates NSCLC cell proliferation, migration, invasion and EMT, which may offer a novel therapeutic direction for NSCLC.

Global Proximity Interactome of the Human Macroautophagy Pathway.

ABBREVIATIONS: BioID: proximity-dependent biotin identification; GO: gene ontology; OSBPL: oxysterol binding protein like; VAPA: VAMP associated protein A; VAPB: VAMP associated protein B and C.

The emerging roles of OSBP-related proteins in cancer: Impacts through phosphoinositide metabolism and protein-protein interactions.

Oxysterol-binding protein -related proteins (ORPs) form a large family of intracellular lipid binding/transfer proteins. A number of ORPs are implicated in inter-organelle lipid transfer over membrane contacts sites, their mode of action involving in several cases the transfer of two lipids in opposite directions, termed countercurrent lipid transfer. A unifying feature appears to be the capacity to bind phosphatidylinositol polyphosphates (PIPs). These lipids are in some cases transported by ORPs from one organelle to another to drive the transfer of another lipid against its concentration gradient, while they in other cases may act as allosteric regulators of ORPs, or an ORP may introduce a PIP to an enzyme for catalysis. Dysregulation of several ORP family members is implicated in cancers, ORP3, -4, -5 and -8 being thus far the most studied examples. The most likely mechanisms underlying their associations with malignant growth are (i) impacts on PIP-mediated signaling events resulting in altered Ca2+ homeostasis, bioenergetics, cell survival, proliferation, and migration, (ii) protein-protein interactions affecting the activity of signaling factors, and (iii) modification of cellular lipid transport in a way that facilitates the proliferation of malignant cells. In this review I discuss the existing functional evidence for the involvement of ORPs in cancerous growth, discuss the findings in the light of the putative mechanisms outlined above and the possibility of employing ORPs as targets of anti-cancer therapy.

Potential Prognostic Biomarkers of OSBPL Family Genes in Patients with Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy with poor survival outcomes. In addition, oxysterol-binding protein-like (OSBPL) family members are reported to be involved in lipid binding and transport and play critical roles in tumorigenesis. However, relationships between PDAC and OSBPL family members have not comprehensively been elucidated. In this study, we used the Oncomine and GEPIA 2 databases to analyze OSBPL transcription expressions in PDAC. The Kaplan-Meier plotter and TIMER 2.0 were used to assess the relationships between overall survival (OS) and immune-infiltration with OSBPL family members. Co-expression data from cBioPortal were downloaded to assess the correlated pathways with OSBPL gene family members using DAVID. The expressions of OSBPL3, OSBPL8, OSBPL10, and OSBPL11 were found to be highly upregulated in PDAC. Low expressions of OSBPL3, OSBPL8, and OSBPL10 indicated longer OS. The functions of OSBPL family members were mainly associated with several potential signaling pathways in cancer cells, including ATP binding, integrin binding, receptor binding, and the renin-angiotensin system (RAS) signaling pathway. The transcription levels of OSBPL gene family members were connected with several immune infiltrates. Collectively, OSBPL family members are influential biomarkers for the early diagnosis of PDAC and have prognostic value, with the promise of precise treatment of PDAC in the future.

Clinical Value and Potential Mechanisms of Oxysterol-Binding Protein Like 3 (OSBPL3) in Human Tumors.

Cancer remains one of the top culprits causing disease-related deaths. A lack of effective multi-cancer therapeutic targets has limited the prolongation of cancer patients' survival. Therefore, it is important to explore novel oncogenic genes or versatile targets and perform a comprehensive analysis to assess their roles in the process of tumorigenesis. OSBPL3 protein is an intracellular lipid receptor of the oxysterol-binding protein superfamily, which participates in some pathological and physiological processes in tumor progression. However, its clinical roles and potential mechanisms in cancers remain unknown. Thus, we aimed to systematic explore the potential oncogenic roles of OSBPL3 across thirty-three tumors using multiple web-based and publicly available tools, including the Cancer Genome Atlas, Gene Expression Omnibus, Genotype-Tissue Expression, cBioPortal, and Human Protein Atlas database. OSBPL3 is highly expressed in major subtypes of cancers, distinctly associated with the prognosis of tumor patients. We observed X676_splice/V676G alteration in the oxysterol domain and frequent mutations of OSBPL3 involve cell survival in skin cutaneous melanoma. We also first presented that the expression of OSBPL3 was associated with tumor mutational burden (TMB) in nine cancer types. Additionally, OSBPL3 shows an enhanced phosphorylation level at S426, S251, and S273 loci within the pleckstrin homology domain in multiple tumors, such as breast cancer or lung adenocarcinoma. And OSBPL3 expression was associated with active immune cells (CD8+ T cells) and cancer-associated fibroblasts in breast cancer, colon adenocarcinoma, and kidney renal clear cell carcinoma and immune checkpoint genes in more than 30 tumors, but weakly associated with immune suppressive cells (myeloid-derived suppressor cells, T regulatory cells). Moreover, protein processing and mRNA metabolic signaling pathways were involved in the functional mechanisms of OSBPL3. Our study first demonstrated that a novel agent OSBPL3 plays an important role in tumorigenesis from the perspective of publicly available databases and clinical tumor samples in various cancers, which comprehensively provide insights into its biological functions and may be helpful for further investigation.