The novel prognostic marker SPOCK2 regulates tumour progression in melanoma.

Secreted protein acidic and cysteine rich/osteonectin, cwcv and kazal-like domain proteoglycan 2 (SPOCK2) is a protein that regulates cell differentiation and growth. Recent studies have reported that SPOCK2 plays important roles in the progression of various human cancers; however, the role of SPOCK2 in melanoma remains unknown. Therefore, this study investigated the roles of SPOCK2 and the related mechanisms in melanoma progression. To evaluate the clinical significance of SPOCK2 expression in patients with melanoma, we analysed the association between SPOCK2 expression and its prognostic value for patients with melanoma using systematic multiomic analysis. Subsequently, to investigate the roles of Spock2 in melanoma progression in vitro and in vivo, we knocked down Spock2 in the B16F10 melanoma cell line. High SPOCK2 levels were positively associated with good prognosis and long survival rate of patients with melanoma. Spock2 knockdown promoted melanoma cell proliferation by inducing the cell cycle and inhibiting apoptosis. Moreover, Spock2 downregulation significantly increased cell migration and invasion by upregulating MMP2 and MT1-MMP. The increased cell proliferation and migration were inhibited by MAPK inhibitor, and ERK phosphorylation was considerably enhanced in Spock2 knockdown cells. Therefore, Spock2 could function as a tumour suppressor gene to regulate melanoma progression by regulating the MAPK/ERK signalling pathway. Additionally, Spock2 knockdown cell injection induced considerable tumour growth and lung metastasis in C57BL6 mice compared to that in the control group. Our findings suggest that SPOCK2 plays crucial roles in malignant progression of melanoma and functions as a novel therapeutic target of melanoma.

Low Muscle and High Fat Percentages Are Associated with Low Natural Killer Cell Activity: A Cross-Sectional Study.

This study aimed to investigate whether body fat and muscle percentages are associated with natural killer cell activity (NKA). This was a cross-sectional study, conducted on 8058 subjects in a medical center in Korea. The association between the muscle and fat percentage tertiles and a low NKA, defined as an interferon-gamma level lower than 500 pg/mL, was assessed. In both men and women, the muscle mass and muscle percentage were significantly low in participants with a low NKA, whereas the fat percentage, white blood cell count, and C-reactive protein (CRP) level were significantly high in those with a low NKA. Compared with the lowest muscle percentage tertile as a reference, the fully adjusted odd ratios (ORs) (95% confidence intervals (CIs)) for a low NKA were significantly lower in T2 (OR: 0.69; 95% CI: 0.55-0.86) and T3 (OR: 0.74; 95% CI: 0.57-0.95) of men, and T3 (OR: 0.76; 95% CI: 0.59-0.99) of women. Compared with the lowest fat percentage tertile as a reference, the fully adjusted OR was significantly higher in T3 of men (OR: 1.31; 95% CI: 1.01-1.69). A high muscle percentage was significantly inversely associated with a low NKA in men and women, whereas a high fat percentage was significantly associated with a low NKA in men.

Relationship between Serum Cortisol, Dehydroepiandrosterone Sulfate (DHEAS) Levels, and Natural Killer Cell Activity: A Cross-Sectional Study.

The adrenal steroid hormones, cortisol and dehydroepiandrosterone sulfate (DHEAS), are associated with the immune system in opposite actions. This study aimed to investigate the relationship between cortisol and DHEAS serum concentrations, their ratio (CDR), and natural killer cell activity (NKA). This cross-sectional study included 2275 subjects without current infection or inflammation in the final analyses. NKA was estimated by measuring the amount of interferon-gamma (IFN-γ) released by activated natural killer cells; low NKA was defined as IFN-γ level < 500 pg/mL. Cortisol, DHEAS levels, and CDRs were categorized by quartiles in men, premenopausal women, and postmenopausal women. Compared with the lowest quartile as reference, the adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for low NKA of the highest cortisol and CDR group were 1.66 (1.09-2.51) and 1.68 (1.11-2.55) in men, 1.58 (1.07-2.33) and 2.33 (1.58-3.46) in premenopausal women, and 2.23 (1.28-3.87) and 1.85 (1.07-3.21) in postmenopausal women. Only in premenopausal women, the highest DHEAS group showed significantly lower risk of low NKA (OR: 0.51, 95% CI: 0.35-0.76). HPA axis activation indicated as high cortisol level, CDR was significantly associated with low NKA, while high DHEAS levels were inversely associated with low NKA in premenopausal women.

Anti-Inflammation and Anti-Melanogenic Effects of Maca Root Extracts Fermented Using Lactobacillus Strains.

Maca is a well-known biennial herb with various physiological properties, such as antioxidant activity and immune response regulation. In this study, the antioxidant, anti-inflammatory, and anti-melanogenic effects of fermented maca root extracts were investigated. The fermentation was carried out using Lactobacillus strains, such as Lactiplantibacillus plantarum subsp. plantarum, Lacticaseibacillus rhamnosus, Lacticaseibacillus casei, and Lactobacillus gasseri. In RAW 264.7 cells, the non-fermented maca root extracts increased the secretion of nitric oxide (NO), an inflammatory mediator, in a dose-dependent manner. In contrast, the fermented extracts showed considerably lower NO secretion than the non-fermented extracts at concentrations of 5% and 10%. This indicates the effective anti-inflammatory effects of fermented maca. The fermented maca root extracts also inhibited tyrosinase activity, melanin synthesis, and melanogenesis by suppressing MITF-related mechanisms. These results show that fermented maca root extracts exhibit higher anti-inflammatory and anti-melanogenesis effects than non-fermented maca root extracts. Thus, maca root extracts fermented using Lactobacillus strains have the potential to be used as an effective cosmeceutical raw material.

Alterations and Co-Occurrence of C-MYC, N-MYC, and L-MYC Expression are Related to Clinical Outcomes in Various Cancers.

Background and Objectives: MYC, also known as an oncogenic reprogramming factor, is a multifunctional transcription factor that maintains induced pluripotent stem cells (iPSCs). Although MYC is frequently upregulated in various cancers and is correlated with a poor prognosis, MYC is downregulated and correlated with a good prognosis in lung adenocarcinoma. MYC and two other MYC family genes, MYCN and MYCL, have similar structures and could contribute to tumorigenic conversion both in vitro and in vivo. Methods and Results: We systematically investigated whether MYC family genes act as prognostic factors in various human cancers. We first evaluated alterations in the expression of MYC family genes in various cancers using the Oncomine and The Cancer Genome Atlas (TCGA) database and their mutation and copy number alterations using the TCGA database with cBioPortal. Then, we investigated the association between the expression of MYC family genes and the prognosis of cancer patients using various prognosis databases. Multivariate analysis also confirmed that co-expression of MYC/MYCL/MYCN was significantly associated with the prognosis of lung, gastric, liver, and breast cancers. Conclusions: Taken together, our results demonstrate that the MYC family can function not only as an oncogene but also as a tumor suppressor gene in various cancers, which could be used to develop a novel approach to cancer treatment.

The Orphan GPR50 Receptor Regulates the Aggressiveness of Breast Cancer Stem-like Cells via Targeting the NF-kB Signaling Pathway.

The expression of GPR50 in CSLC and several breast cancer cell lines was assessed by RT-PCR and online platform (UALCAN, GEPIA, and R2 gene analysis). The role of GPR50 in driving CSLC, sphere formation, cell proliferation, and migration was performed using shGPR50 gene knockdown, and the role of GPR50-regulated signaling pathways was examined by Western blotting and Luciferase Assay. Herein, we confirmed that the expression of G protein-coupled receptor 50 (GPR50) in cancer stem-like cells (CSLC) is higher than that in other cancer cells. We examined that the knockdown of GPR50 in CSLC led to decreased cancer properties, such as sphere formation, cell proliferation, migration, and stemness. GPR50 silencing downregulates NF-kB signaling, which is involved in sphere formation and aggressiveness of CSLC. In addition, we demonstrated that GPR50 also regulates ADAM-17 activity by activating NOTCH signaling pathways through the AKT/SP1 axis in CSLC. Overall, we demonstrated a novel GPR50-mediated regulation of the NF-κB-Notch signaling pathway, which can provide insights into CSLC progression and prognosis, and NF-κB-NOTCH-based CSLC treatment strategies.

Advanced 3D dynamic culture system with transforming growth factor-ß3 enhances production of potent extracellular vesicles with modified protein cargoes via upregulation of TGF-ß signaling.

INTRODUCTION: Mesenchymal stromal cells (MSCs) release extracellular vesicles (MSC-EVs) containing various cargoes. Although MSC-EVs show significant therapeutic effects, the low production of EVs in MSCs hinders MSC-EV-mediated therapeutic development. OBJECTIVES: Here, we developed an advanced three-dimensional (a3D) dynamic culture technique with exogenous transforming growth factor beta-3 (TGF-ß3) treatment (T-a3D) to produce potent MSC-EVs. METHODS: Our system enabled preparation of a highly concentrated EV-containing medium for efficient EV isolation and purification with higher yield and efficacy. RESULTS: MSC spheroids in T-a3D system (T-a3D spheroids) showed high expression of CD9 and TGF-ß3, which was dependent on TGF-ß signaling. Treatment with EVs produced under T-a3D conditions (T-a3D-EVs) led to significantly improved migration of dermal fibroblasts and wound closure in an excisional wound model. The relative total efficacy (relative yield of single-batch EVs (10-11-fold) × relative regeneration effect of EVs (2-3-fold)) of T-a3D-EVs was approximately up to 33-fold higher than that of 2D-EVs. Importantly the quantitative proteomic analyses of the T-a3D spheroids and T-a3D-EVs supported the improved EV production as well as the therapeutic potency of T-a3D-EVs. CONCLUSION: TGF-ß signalling differentially regulated by fluid shear stress produced in our system and exogenous TGF-ß3 addition was confirmed to play an important role in the enhanced production of EVs with modified protein cargoes. We suggest that the T-a3D system leads to the efficient production of MSC-EVs with high potential in therapies and clinical development.

Systematic Multiomic Analysis of PKHD1L1 Gene Expression and Its Role as a Predicting Biomarker for Immune Cell Infiltration in Skin Cutaneous Melanoma and Lung Adenocarcinoma.

The identification of genetic factors that regulate the cancer immune microenvironment is important for understanding the mechanism of tumor progression and establishing an effective treatment strategy. Polycystic kidney and hepatic disease 1-like protein 1 (PKHD1L1) is a large transmembrane protein that is highly expressed in immune cells; however, its association with tumor progression remains unclear. Here, we systematically analyzed the clinical relevance of PKHD1L1 in the tumor microenvironment in multiple cancer types using various bioinformatic tools. We found that the PKHD1L1 mRNA expression levels were significantly lower in skin cutaneous melanoma (SKCM) and lung adenocarcinoma (LUAD) than in normal tissues. The decreased expression of PKHD1L1 was significantly associated with unfavorable overall survival (OS) in SKCM and LUAD. Additionally, PKHD1L1 expression was positively correlated with the levels of infiltrating B cells, cluster of differentiation (CD)-8+ T cells, and natural killer (NK) cells, suggesting that the infiltration of immune cells could be associated with a good prognosis due to increased PKHD1L1 expression. Gene ontology (GO) analysis also revealed the relationship between PKHD1L1-co-altered genes and the activation of lymphocytes, including B and T cells. Collectively, this study shows that PKHD1L1 expression is positively correlated with a good prognosis via the induction of immune infiltration, suggesting that PKHD1L1 has potential prognostic value in SKCM and LUAD.

Bacterial Prevalence in Skin, Urine, Diarrheal Stool, and Respiratory Samples from Dogs.

The emergence of bacterial infections in companion animals is a growing concern as humans can also be infected through the transmission of pathogenic bacteria. Because there have been few studies conducted on companion animals, the extent and significance of prevalence in veterinary practices remain unknown. This is the first nationwide surveillance report aimed at elucidating the prevalence pattern and associated infections of isolated bacteria from dogs in Korea. Bacterial isolates were collected from seven different laboratories participating in the Korean Veterinary Antimicrobial Resistance Monitoring System from 2018 to 2019. The samples were obtained from the diarrheal stool, skin/ear, urine, and respiratory samples of veterinary hospital-visited dogs. Isolation and identification of bacterial species was carried out using a bacterial culture approach and then confirmed with matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF) and polymerase chain reaction (PCR). Out of 3135 isolates in dogs, 1085, 1761, 171, and 118 were extracted from diarrheal stool, skin/ear, urine, and respiratory samples, respectively. The overall prevalence of bacteria was higher among two age groups (1-5 and 6-10 years) with a 66.5 percent prevalence. This study showed that Escherichia coli was the most prevalent species among isolated bacterial species of diarrheal and urine origin, whereas Staphylococcus pseudintermedius was the most prevalent among skin and respiratory sample isolates. The data on the prevalence of bacteria for each dog specimen could provide basic information to estimate the extent of bacterial infection and antimicrobial resistance development and to guide veterinarians in therapeutic decisions in clinical practices throughout Korea.

Modulation of Osteogenic Differentiation of Adipose-Derived Stromal Cells by Co-Treatment with 3, 4'-Dihydroxyflavone, U0126, and N-Acetyl Cysteine.

Background and Objectives: Flavonoids form the largest group of plant phenols and have various biological and pharmacological activities. In this study, we investigated the effect of a flavonoid, 3, 4'-dihydroxyflavone (3, 4'-DHF) on osteogenic differentiation of equine adipose-derived stromal cells (eADSCs). Methods and Results: Treatment of 3, 4'-DHF led to increased osteogenic differentiation of eADSCs by increasing phosphorylation of ERK and modulating Reactive Oxygen Species (ROS) generation. Although PD98059, an ERK inhibitor, suppressed osteogenic differentiation, another ERK inhibitor, U0126, apparently increased osteogenic differentiation of the 3, 4'-DHF-treated eADSCs, which may indicate that the effect of U0126 on bone morphogenetic protein signaling is involved in the regulation of 3, 4'-DHF in osteogenic differentiation of eADSCs. We revealed that 3, 4'-DHF could induce osteogenic differentiation of eADSCs by suppressing ROS generation and co-treatment of 3, 4'-DHF, U0126, and/or N-acetyl cysteine (NAC) resulted in the additive enhancement of osteogenic differentiation of eADSCs. Conclusions: Our results showed that co-treatment of 3, 4'-DHF, U0126, and/or NAC cumulatively regulated osteogenesis in eADSCs, suggesting that 3, 4'-DHF, a flavonoid, can provide a novel approach to the treatment of osteoporosis and can provide potential therapeutic applications in therapeutics and regenerative medicine for human and companion animals.

Association of Elevated Expression Levels of COL4A1 in Stromal Cells with an Immunosuppressive Tumor Microenvironment in Low-Grade Glioma, Pancreatic Adenocarcinoma, Skin Cutaneous Melanoma, and Stomach Adenocarcinoma.

Aberrant expression of collagen type IV alpha chain 1 (COL4A1) can influence tumor cell behavior. To examine the association of COL4A1 expression in the tumor microenvironment (TME) with tumor progression, we performed bioinformatics analyses of The Cancer Genome Atlas RNA sequencing and RNA microarray datasets available in public databases and identified upregulated COL4A1 expression in most examined tumor types compared to their normal counterparts. The elevated expression of COL4A1 was correlated with low survival rates of patients with low-grade glioma, pancreatic adenocarcinoma, skin cutaneous melanoma, and stomach adenocarcinoma, thus suggesting its potential use as a biomarker for the poor prognosis of these tumors. However, COL4A1 was mostly expressed in adjacent stromal cells, such as cancer-associated fibroblasts (CAFs) and endothelial cells. Additionally, COL4A1 expression was highly correlated with the signatures of CAFs and endothelial cells in all four tumor types. The expression of marker genes for the infiltration of pro-tumoral immune cells, such as Treg, M2, and TAM, and those of immunosuppressive cytokines exhibited very strong positive correlations with COL4A1 expression. Collectively, our data suggest that COL4A1 overexpression in stromal cells may be a potential regulator of tumor-supporting TME composition associated with poor prognosis.

Prevalence of Bacterial Species in Skin, Urine, Diarrheal Stool, and Respiratory Samples in Cats.

Bacterial infections are a significant cause of illness and death in different animals. However, these bacterial infections could be a source of human disease or illness if these pathogenic bacteria are present in companion animals. This study aimed to investigate the prevalence of pathogenic bacteria associated with different site infections in cats in the Republic of Korea. For this purpose, samples were collected from the skin/ear, urine, respiratory, and diarrheal stool origins of cats obtained between 2018 and 2019 from seven different laboratories and centers participating in the Korean Veterinary Antimicrobial Resistance Monitoring System. These samples were subjected to analysis for the identification and isolation of associated bacterial species using a bacterial culture approach. A total of 609 isolates were identified in four different cat samples. Among them, 267, 184, 57, and 101 were extracted from diarrheal stool, skin, urine, and respiratory samples, respectively. The findings of this study showed that Escherichia coli was the most prevalent species among isolated bacterial species of diarrheal stool and urine origin. Staphylococcus felis and Pasteurella multocida were most prevalent in the skin and respiratory tract, respectively. However, there was no significant difference in bacterial distribution among the different age groups in all samples. This is the first nationwide surveillance report that associates bacterial prevalence with their site of origin and helps in the prevention of bacterial infections in cats. Moreover, the pattern of bacterial prevalence could provide sufficient guidance for the selection of empirical antimicrobial therapy against infections in cats.

Prognostic role of EGR1 in breast cancer: a systematic review.

EGR1 (early growth response 1) is dysregulated in many cancers and exhibits both tumor suppressor and promoter activities, making it an appealing target for cancer therapy. Here, we used a systematic multi-omics analysis to review the expression of EGR1 and its role in regulating clinical outcomes in breast cancer (BC). EGR1 expression, its promoter methylation, and protein expression pattern were assessed using various publicly available tools. COSMIC-based somatic mutations and cBioPortal-based copy number alterations were analyzed, and the prognostic roles of EGR1 in BC were determined using Prognoscan and Kaplan-Meier Plotter. We also used bc-GenEx- Miner to investigate the EGR1 co-expression profile. EGR1 was more often downregulated in BC tissues than in normal breast tissue, and its knockdown was positively correlated with poor survival. Low EGR1 expression levels were also associated with increased risk of ER+, PR+, and HER2- BCs. High positive correlations were observed among EGR1, DUSP1, FOS, FOSB, CYR61, and JUN mRNA expression in BC tissue. This systematic review suggested that EGR1 expression may serve as a prognostic marker for BC patients and that clinicopathological parameters influence its prognostic utility. In addition to EGR1, DUSP1, FOS, FOSB, CYR61, and JUN can jointly be considered prognostic indicators for BC. [BMB Reports 2021; 54(10): 497-504].

High Therapeutic and Esthetic Properties of Extracellular Vesicles Produced from the Stem Cells and Their Spheroids Cultured from Ocular Surgery-Derived Waste Orbicularis Oculi Muscle Tissues.

Extracellular vesicles (EVs) are paracrine factors that mediate stem cell therapeutics. We aimed at evaluating the possible therapeutic and esthetic applications of EVs prepared from the waste human facial tissue-derived orbicularis oculi muscle stem cells (OOM-SCs). OOM-SCs were isolated from the ocular tissues (from elders and youngsters) after upper eyelid blepharoplasty or epiblepharon surgeries. EVs were prepared from the OOM-SCs (OOM-SC-EVs) and their three-dimensional spheroids. OOM-SCs showed a spindle-like morphology with trilineage differentiation capacity, positive expression of CD105, CD 90, and CD73, and negative expression of CD45 and CD34, and their stem cell properties were compared with other adult mesenchymal stem cells. OOM-SC-EVs showed a high inhibitory effect on melanin synthesis in B16F10 cells by blocking tyrosinase activity. OOM-SC-EVs treatment led to a significant attenuation of senescence-associated changes, a decrease in reactive oxygen species generation, and an upregulation of antioxidant genes. We demonstrated the regeneration activity of OOM-SC-EVs in in vitro wound healing of normal human dermal fibroblasts and upregulation of anti-wrinkle-related genes and confirmed the therapeutic potential of OOM-SC-EVs in the healing of the in vivo wound model. Our study provides promising therapeutic and esthetic applications of OOM-SC-EVs, which can be obtained from the ocular surgery-derived waste human facial tissues.

Multi-Omics Analysis of SOX4, SOX11, and SOX12 Expression and the Associated Pathways in Human Cancers.

The Sry-related HMG BOX (SOX) gene family encodes transcription factors containing highly conserved high-mobility group domains that bind to the minor groove in DNA. Although some SOX genes are known to be associated with tumorigenesis and cancer progression, their expression and prognostic value have not been systematically studied. We performed multi-omic analysis to investigate the expression of SOX genes in human cancers. Expression and phylogenetic tree analyses of the SOX gene family revealed that the expression of three closely related SOX members, SOX4, SOX11, and SOX12, was increased in multiple cancers. Expression, mutation, and alteration of the three SOX members were evaluated using the Oncomine and cBioPortal databases, and the correlation between these genes and clinical outcomes in various cancers was examined using the Kaplan-Meier, PrognoScan, and R2 database analyses. The genes commonly correlated with the three SOX members were categorized in key pathways related to the cell cycle, mitosis, immune system, and cancer progression in liver cancer and sarcoma. Additionally, functional protein partners with three SOX proteins and their probable signaling pathways were explored using the STRING database. This study suggests the prognostic value of the expression of three SOX genes and their associated pathways in various human cancers.

The Migration of Human Follicular Dendritic Cell-Like Cell Is Facilitated by Matrix Metalloproteinase 3 Expression That Is Mediated through TNFα-ERK1/2-AP1 Signaling.

Follicular dendritic cells are important stromal components of the germinal center (GC) and have pivotal roles in maintaining the GC microenvironment for high-affinity antibody production. Tumor necrosis factor-α (TNFα) is essential for the development and functions of follicular dendritic cells. Despite the importance of follicular dendritic cells in humoral immunity, their molecular control mechanisms have yet to be fully elucidated due to the lack of an adequate investigation system. Here, we have used a unique human primary follicular dendritic cell-like cell (FDCLC) to demonstrate that the migration of these cells is enhanced by TNFα-mediated metalloproteinase 3 (MMP3) expression. MMP3 was found to be highly expressed in normal human GCs and markedly upregulated in human primary FDCLCs by TNFα. TNFα induced ERK1/2 phosphorylation and the transcription of MMP3 through AP1. TNFα treatment increased FDCLC migration, and a knockdown of MMP3 significantly reduced the TNFα-induced migration of FDCLCs. Overall, we have newly identified a control mechanism for the expression of MMP3 in FDCLCs that modulates their migration and may indicate an important role in GC biology. Since GCs are observed in the lesions of autoimmune diseases and lymphomas, targeting the MMP3/TNFα-mediated migration of stromal cells in the B cell follicle may have great potential as a future therapeutic modality against aberrant GC-associated disorders.

Multiomic Analysis of Cereblon Expression and Its Prognostic Value in Kidney Renal Clear Cell Carcinoma, Lung Adenocarcinoma, and Skin Cutaneous Melanoma.

Cereblon (CRBN) is a component of the E3 ubiquitin ligase complex that plays crucial roles in various cellular processes. However, no systematic studies on the expression and functions of CRBN in solid tumors have been conducted to date. Here, we analyzed CRBN expression and its clinical value using several bioinformatic databases. CRBN mRNA expression was downregulated in various cancer types compared to normal cells. Survival analysis demonstrated that overall survival was significantly positively correlated with CRBN expression in some cancer types including lung adenocarcinoma (LUAD), kidney renal clear cell carcinoma (KIRC), and skin cutaneous melanoma (SKCM). CRBN expression was downregulated regardless of clinicopathological characteristics in LUAD and KIRC. Analysis of genes that are commonly correlated with CRBN expression among KIRC, LUAD, and SKCM samples elucidated the potential CRBN-associated mechanisms of cancer progression. Overall, this study revealed the prognostic value of CRBN and its potential associated mechanisms, which may facilitate the development of anti-cancer therapeutic agents.

Expression of ATP/GTP Binding Protein 1 Has Prognostic Value for the Clinical Outcomes in Non-Small Cell Lung Carcinoma.

ATP/GTP binding protein 1 (AGTPBP1) encodes a crucial protein, cytosolic carboxypeptidase 1 (CCP1), which plays a role in modulating the polyglutamylation of tubulin and has been studied in degenerative diseases. However, the role of AGTPBP1 in malignancy has not been completely studied yet. In this study, we examined the role of AGTPBP1 in cancer progression, its association with patient survival, and related mechanisms in lung cancer, using the A549 cell line and lung cancer gene expression datasets. AGTPBP1 knockdown increased the proliferation, migration, sphere formation, and drug resistance of A549 cells. Lung cancer datasets revealed significantly lower mRNA and protein expression levels of AGTPBP1 in lung cancer tissues, as compared to those in normal tissues. Importantly, AGTPBP1 expression positively correlated with patient survival. Analysis of co-expressed genes revealed that AGTPBP1 expression positively correlated with immune infiltration in lung cancer. Our results conclusively suggested that AGTPBP1 expression was correlated with cancer progression and immune infiltration in lung cancer.

Sestrin2 Expression Has Regulatory Properties and Prognostic Value in Lung Cancer.

Lung cancer remains the most dangerous type of cancer despite recent progress in therapeutic modalities. Development of prognostic markers and therapeutic targets is necessary to enhance lung cancer patient survival. Sestrin family genes (Sestrin1, Sestrin2, and Sestrin3) are involved in protecting cells from stress. In particular, Sestrin2, which mainly protects cells from oxidative stress and acts as a leucine sensor protein in mammalian target of rapamycin (mTOR) signaling, is thought to affect various cancers in different ways. To investigate the role of Sestrin2 expression in lung cancer cells, we knocked down Sestrin2 in A549, a non-small cell lung cancer cell line; this resulted in reduced cell proliferation, migration, sphere formation, and drug resistance, suggesting that Sestrin2 is closely related to lung cancer progression. We analyzed Sestrin2 expression in human tissue using various bioinformatic databases and confirmed higher expression of Sestrin2 in lung cancer cells than in normal lung cells using Oncomine and the Human Protein Atlas. Moreover, analyses using Prognoscan and KMplotter showed that Sestrin2 expression is negatively correlated with the survival of lung cancer patients in multiple datasets. Co-expressed gene analysis revealed Sestrin2-regulated genes and possible associated pathways. Overall, these data suggest that Sestrin2 expression has prognostic value and that it is a possible therapeutic target in lung cancer.

GPR50 Promotes Hepatocellular Carcinoma Progression via the Notch Signaling Pathway through Direct Interaction with ADAM17.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and it is thus critical to identify novel molecular biomarkers of HCC prognosis and elucidate the molecular mechanisms underlying HCC progression. Here, we show that G-protein-coupled receptor 50 (GPR50) in HCC is overexpressed and that GPR50 knockdown may downregulate cancer cell progression through attenuation of the Notch signaling pathway. GPR50 knockdown was found to reduce HCC progression by inactivating Notch signaling in a ligand-independent manner through a disintegrin and metalloproteinase metallopeptidase domain 17 (ADAM17), a proteolytic enzyme that cleaves the Notch receptor, which was corroborated by GPR50 overexpression in hepatocytes. GPR50 silencing also downregulated transcription and translation of ADAM17 through the AKT/specificity protein-1 (SP1) signaling axis. Notably, GPR50 was found to directly interact with ADAM17. Overall, we demonstrate a novel GPR50-mediated regulation of the ADAM17-Notch signaling pathway, which can provide insights into HCC progression and prognosis and development of Notch-based HCC treatment strategies.