SLC11A1 promotes kidney renal clear cell carcinoma (KIRC) progression by remodeling the tumor microenvironment.

Kidney renal clear cell carcinoma (KIRC) is a highly immune-infiltrated kidney cancer with the highest mortality rate and the greatest potential for invasion and metastasis. Solute carrier family 11 member1 (SLC11A1) is a phagosomal membrane protein located in monocytes and plays a role in innate immunity, autoimmune diseases, and infection, but its expression and biological role in KIRC is still unknown. In this study, we sought to investigate the potential value of SLC11A1 according to tumor growth and immune response in KIRC. TIMER and UALCAN database was used to analyze the expression feature and prognostic significance of SLC11A1 and its correlation with immune-related biomarkers in KIRC. Proliferation, migration, and invasion were measured using colony formation, EdU, and transwell assays. Role of SLC11A1 on KIRC tumor growth was examined by the xenograft tumor model in vivo. Effects of KIRC cells on macrophage polarization and the proliferation and apoptosis of CD8+ T cells were analyzed using flow cytometry assays. Herein, SLC11A1 was highly expressed in KIRC tissues and cell lines. SLC11A1 downregulation repressed KIRC cell proliferation, migration, invasion, macrophage, and lymphocyte immunity in vitro, as well as hindered tumor growth in vivo. SLC11A1 is significantly correlated with immune cell infiltration and immune-related biomarkers. In KIRC patients, SLC11A1 is highly expressed and positively correlated with the immune-related factors CCL2 and PD-L1. SLC11A1 induced CCL2 and PD-L1 expression, thereby activating the JAK/STAT3 pathway. SLC11A1 deficiency constrained KIRC cell malignant phenotypes and immune response via regulating CCL2 and PD-L1-mediated JAK/STAT3 pathway, providing a promising therapeutic target for KIRC treatment.

Solute carrier family 11 member 1 genetic polymorphisms rs17235409 and rs3731865 associate with susceptibility to extremity post-traumatic osteomyelitis in a Chinese Han population.

Genetic variations in the solute carrier family 11 member 1 (SLC11A1) gene have been implicated in developing inflammatory disorders. However, it is still unclear whether such polymorphisms contribute to the pathogenesis of post-traumatic osteomyelitis (PTOM). Therefore, this study investigated the roles of genetic variations of the SLC11A1 gene (rs17235409 and rs3731865) in PTOM development in a Chinese Han cohort. The SNaPshot method was used for genotyping 704 participants (336 patients and 368 controls) for rs17235409 and rs3731865. Outcomes revealed that rs17235409 increased the risk of PTOM occurrence by dominant (p = .037, odds ratio [OR] = 1.44) and heterozygous models (p = .035, OR = 1.45), implying AG genotype as a risk factor for PTOM development. In addition, patients with AG genotype had relatively higher levels of inflammatory biomarkers than those with AA and GG genotypes, especially for the white blood cell count and C-reactive protein. Despite no statistically significant differences achieved, rs3731865 may reduce the PTOM susceptibility, suggested by the results of dominant (p = .051, OR = 0.67) and heterozygous (p = .068, OR = 0.69) models. In short, rs17235409 confers an elevated chance of developing PTOM, with AG genotype as a risk factor. Whether rs3731865 involves in the pathogenesis of PTOM requires further investigations.

A Multigene-Panel Study Identifies Single Nucleotide Polymorphisms Associated with Prostate Cancer Risk.

The immune system plays a critical role in modulating cancer development and progression. Polymorphisms in key genes involved in immune responses are known to affect susceptibility to cancer. Here, we analyzed 35 genes to evaluate the association between variants of genes involved in immune responses and prostate cancer risk. Thirty-five genes were analyzed in 47 patients with prostate cancer and 43 healthy controls using next-generation sequencing. Allelic and genotype frequencies were calculated in both cohorts, and a generalized linear mixed model was applied to test the relationship between prostate cancer risk and nucleotide substitution. Odds ratios were calculated to describe the association between each single nucleotide polymorphism (SNP) and prostate cancer risk. Significant changes in allelic and genotypic distributions were observed for IL4R, IL12RB1, IL12RB2, IL6, TMPRSS2, and ACE2. Furthermore, a generalized linear mixed model identified statistically significant associations between prostate cancer risk and SNPs in IL12RB2, IL13, IL17A, IL4R, MAPT, and TFNRS1B. Finally, a statistically significant association was observed between IL2RA and TNFRSF1B and Gleason scores, and between SLC11A1, TNFRSF1B and PSA values. We identified SNPs in inflammation and two prostate cancer-associated genes. Our results provide new insights into the immunogenetic landscape of prostate cancer and the impact that SNPs on immune genes may have on affecting the susceptibility to prostate cancer.

Characterization of Global Gene Expression, Regulation of Metal Ions, and Infection Outcomes in Immune-Competent 129S6 Mouse Macrophages.

Nutritional immunity involves cellular and physiological responses to invading pathogens, such as limiting iron, increasing exposure to bactericidal copper, and altering zinc to restrict the growth of pathogens. Here, we examine infection of bone marrow-derived macrophages from 129S6/SvEvTac mice by Salmonella enterica serovar Typhimurium. The 129S6/SvEvTac mice possess a functional Slc11a1 (Nramp-1), a phagosomal transporter of divalent cations that plays an important role in modulating metal availability to the pathogen. We carried out global RNA sequencing upon treatment with live or heat-killed Salmonella at 2 h and 18 h postinfection and observed widespread changes in metal transport, metal-dependent genes, and metal homeostasis genes, suggesting significant remodeling of iron, copper, and zinc availability by host cells. Changes in host cell gene expression suggest infection increases cytosolic zinc while simultaneously limiting zinc within the phagosome. Using a genetically encoded sensor, we demonstrate that cytosolic labile zinc increases 45-fold at 12 h postinfection. Further, manipulation of zinc in the medium alters bacterial clearance and replication, with zinc depletion inhibiting both processes. Comparing the transcriptomic changes to published data on infection of C57BL/6 macrophages revealed notable differences in metal regulation and the global immune response. Our results reveal that 129S6 macrophages represent a distinct model system compared to C57BL/6 macrophages. Further, our results indicate that manipulation of zinc at the host-pathogen interface is more nuanced than that of iron or copper. The 129S6 macrophages leverage intricate means of manipulating zinc availability and distribution to limit the pathogen's access to zinc, while simultaneously ensuring sufficient zinc to support the immune response.

Structural characterization and molecular dynamics simulations of the caprine and bovine solute carrier family 11 A1 (SLC11A1).

Natural Resistance-Associated Macrophage Proteins are a family of transmembrane divalent metal ion transporters, with important implications in life of both bacteria and mammals. Among them, the Solute Carrier family 11 member A1 (SLC11A1) has been implicated with susceptibility to infection by Mycobacterium avium subspecies paratuberculosis (MAP), potentially causing Crohn's disease in humans and paratuberculosis (PTB) in ruminants. Our previous research had focused on sequencing the mRNA of the caprine slc11a1 gene and pinpointed polymorphisms that contribute to caprine SLC11A1's susceptibility to infection by MAP in PTB. Despite its importance, little is known on the structural/dynamic features of mammalian SLC11A1 that may influence its function under normal or pathological conditions at the protein level. In this work we studied the structural architecture of SLC11A1 in Capra hircus and Bos taurus through molecular modeling, molecular dynamics simulations in different, functionally relevant configurations, free energy calculations of protein-metal interactions and sequence conservation analysis. The results of this study propose a three dimensional structure for SLC11A1 with conserved sequence and structural features and provide hints for a potential mechanism through which divalent metal ion transport is conducted. Given the importance of SLC11A1 in susceptibility to PTB, this study provides a framework for further studies on the structure and dynamics of SLC11A1 in other organisms, to gain 3D structural insight into the macromolecular arrangements of SLC11A1 but also suggesting a potential mechanism which divalent metal ion transport is conducted.

Associations between the presence of specific antibodies to the West Nile Virus infection and candidate genes in Romanian horses from the Danube delta.

The West Nile virus (WNV) is a mosquito-borne flavivirus causing meningoencephalitis in humans and animals. Due to their particular susceptibility to WNV infection, horses serve as a sentinel species. In a population of Romanian semi-feral horses living in the Danube delta region, we have analyzed the distribution of candidate polymorphic genetic markers between anti WNV-IgG seropositive and seronegative horses. Thirty-six SNPs located in 28 immunity-related genes and 26 microsatellites located in the MHC and LY49 complex genomic regions were genotyped in 57 seropositive and 32 seronegative horses. The most significant association (pcorr < 0.0002) was found for genotypes composed of markers of the SLC11A1 and TLR4 genes. Markers of five other candidate genes (ADAM17, CXCR3, IL12A, MAVS, TNFA), along with 5 MHC class I and LY49-linked microsatellites were also associated with the WNV antibody status in this model horse population. The OAS1 gene, previously associated with WNV-induced clinical disease, was not associated with the presence of anti-WNV antibodies.

Susceptibility to leishmaniasis is affected by host SLC11A1 gene polymorphisms: a systematic review and meta-analysis.

Leishmaniases are cutaneous, mucocutaneous, and visceral diseases affecting humans and domesticated animals mostly in the tropical and subtropical areas of the planet. Host genetics have been widely investigated for their role in developing various infectious diseases. The SLC11A1 gene has been reported to play a role in neutrophil function and is associated with susceptibility to infectious and inflammatory diseases such as tuberculosis or rheumatoid arthritis. In the present meta-analysis, we investigate the genetic association of SLC11A1 polymorphisms with susceptibility to leishmaniasis. Genotypes and other risk-related data were collected from 13 case-control and family-based studies (after literature search). Conventional random-effects meta-analysis was performed using STATA 13. To pool case-control and family-based data, the weighted Stouffer's method was also applied. Eight polymorphisms were investigated: rs2276631, rs3731865, rs3731864, rs17221959, rs201565523, rs2279015, rs17235409, and rs17235416. We found that rs17235409 (D543N) and rs17235416 (1729 + 55del4) are significantly associated with a risk for cutaneous leishmaniasis (CL), whereas rs17221959, rs2279015, and rs17235409 are associated with visceral leishmaniasis (VL). Our results suggest that polymorphisms in SLC11A1 affect susceptibility to CL and VL. These findings open new pathways in understanding macrophage response to Leishmania infection and the genetic factors predisposing to symptomatic CL or VL that can lead to the usage of predictive biomarkers in populations at risk.

Diminished Susceptibility of African-Americans to Non-tuberculous Mycobacterial Disease.

The incidence of three granulomatous response diseases-sarcoidosis, tuberculosis, and non-tuberculous mycobacterial pulmonary disease-differ markedly in African-Americans versus Caucasians. In reviewing a large compendium of non-cystic-fibrosis bronchiectasis, we noted that complicating infection with non-tuberculous mycobacteria was relatively infrequent among individuals of African-American descent, confirming previous observations of their inherent resistance. Disease-specific variance among African-Americans in the efficacy of their granulomatous response suggests a nexus, a mediating, immunological mechanism. Environmentally conditioned selection of SLC11A1 (Nramp1) alleles may account for this ethnic variance.

Slc11a1 (Nramp-1) gene modulates immune-inflammation genes in macrophages during pristane-induced arthritis in mice.

OBJECTIVE AND DESIGN: Pristane-induced arthritis (PIA) in AIRmax mice homozygous for Slc11a1 R and S alleles was used to characterize the influence of Slc11a1 gene polymorphism on immune responses during disease manifestation. Previous reports demonstrated that the presence of the Slc11a1 S allele increased the incidence and severity of PIA in AIRmax SS , suggesting that this gene could interact with inflammatory loci to modulate PIA. We investigated the effects of Slc11a1 alleles on the activation of phagocytes during PIA. TREATMENT: Mice were injected intraperitoneally with two doses of 0.5 mL of mineral oil pristane at 60-day intervals. Arthritis development was accompanied for 180 days. RESULTS: AIRmax SS mice showed differential peritoneal macrophage gene expression profiles during PIA, with higher expression and production of H2O2, NO, IL-1ß, IL-6, TNF-α, and several chemokines. The presence of the Slc11a1 R allele, on the other hand, diminished the intensity of macrophage activation, restricting arthritis development. CONCLUSION: Our data demonstrated the fine-tuning roles of Slc11a1 alleles modulating macrophage activation, and consequent PIA susceptibility, in those mouse lines.

Nramp1 and Other Transporters Involved in Metal Withholding during Infection.

During the course of infection, many natural defenses are set up along the boundaries of the host-pathogen interface. Key among these is the host response to withhold metals to restrict the growth of invading microbes. This simple act of nutritional warfare, starving the invader of an essential element, is an effective means of limiting infection. The physiology of metal withholding is often referred to as "nutritional immunity," and the mechanisms of metal transport that contribute to this host response are the focus of this review.

Positive selection in the SLC11A1 gene in the family Equidae.

Immunity-related genes are a suitable model for studying effects of selection at the genomic level. Some of them are highly conserved due to functional constraints and purifying selection, while others are variable and change quickly to cope with the variation of pathogens. The SLC11A1 gene encodes a transporter protein mediating antimicrobial activity of macrophages. Little is known about the patterns of selection shaping this gene during evolution. Although it is a typical evolutionarily conserved gene, functionally important polymorphisms associated with various diseases were identified in humans and other species. We analyzed the genomic organization, genetic variation, and evolution of the SLC11A1 gene in the family Equidae to identify patterns of selection within this important gene. Nucleotide SLC11A1 sequences were shown to be highly conserved in ten equid species, with more than 97 % sequence identity across the family. Single nucleotide polymorphisms (SNPs) were found in the coding and noncoding regions of the gene. Seven codon sites were identified to be under strong purifying selection. Codons located in three regions, including the glycosylated extracellular loop, were shown to be under diversifying selection. A 3-bp indel resulting in a deletion of the amino acid 321 in the predicted protein was observed in all horses, while it has been maintained in all other equid species. This codon comprised in an N-glycosylation site was found to be under positive selection. Interspecific variation in the presence of predicted N-glycosylation sites was observed.

Insight into the structures of the second and fifth transmembrane domains of Slc11a1 in membrane mimics.

Slc11a1 is an integral membrane protein with 12 putative transmembrane domains and functions as a pH-coupled divalent metal cation transporter. In the present study, the structures of the peptides corresponding to the second and fifth transmembrane domains of Slc11a1 (from 88 to 109 for TMD2 and from 190 to 215 for TMD5) were determined in membrane-mimic environments by CD and NMR techniques. It was demonstrated that TMD2 and TMD5 form an α-helical structure in 30% 2,2,2-trifluoroethanol (TFE) and 40% hexafluoro-2-propanol (HFIP) aqueous solution, respectively. The α-helix of TMD5 displays a less space-occupied face consisting of the residues Ala194, Gly197, Thr201, Ala204 and Gly208. The α-helix is partially unfolded in the N-terminal region when Gly197 is substituted by Val. The unfolding of the helix in the N-terminal part and/or increase in volume at the less space-occupied face of the helix may exert an effect on the arrangement of TMD5 in membrane.

SLC11A1 predicts the overall survival of patients with colorectal cancer.

Colorectal cancer (CRC) remains a significant contributor to cancer-related mortality, emphasizing the critical need for identifying biomarkers that can improve clinical management and patient outcomes. In this retrospective study, we analyzed tumor samples from 25 patients with metastatic CRC, categorized based on long-term (> 50 months) or short-term (< 10 months) survival. Employing the PanCancer Immune Profile Panel, encompassing 770 genes, in the discovery dataset, we identified 54 differentially expressed genes (DEGs) within the tumor microenvironment of metastatic CRC. Validation of potential biomarkers was performed using two publicly available RNA-based sequencing datasets (TCGA 1 (n=371) and TCGA 2 (n=566)). Univariate COX regression unveiled that three significant biomarkers were associated with overall survival in CRC within the discovery dataset, which were SLC11A1 (hazard ratio (HR): 4.09, P=0.012), TNFSF11 (HR: 3.67, P=0.02), and MEF2C (HR: 0.34, P=0.037). Kaplan-Meier survival curve analyses confirmed the correlation between SLC11A1 expression and overall survival in CRC across the discovery set (P=0.0071) and the two independent datasets (TCGA 1 (P=0.0016) and TCGA 2 (P=0.025)). Receiver operating characteristic curve analysis demonstrated an area under the curve ranging from 0.64 to 0.76, with sensitivity of 59% to 87% and specificity of 60% to 73% for predicting CRC overall survival. Immunohistochemistry staining further validated the strong expression of SLC11A1 protein in CRC tumor cells, with high expression correlating with short-term survival. These findings suggest that SLC11A1 serves as a predictive biomarker for overall survival in CRC patients.

Exosomal Small RNA Sequencing Profiles in Plasma from Subjects with Latent Mycobacterium tuberculosis Infection.

Despite huge efforts, tuberculosis (TB) is still a major public health threat worldwide, with approximately 23% of the human population harboring a latent TB infection (LTBI). LTBI can reactivate and progress to active and transmissible TB disease, contributing to its spread within the population. The challenges in diagnosing and treating LTBI patients have been major factors contributing to this phenomenon. Exosomes offer a novel avenue for investigating the process of TB infection. In this study, we conducted small RNA sequencing to investigate the small RNA profiles of plasma exosomes derived from individuals with LTBI and healthy controls. Our findings revealed distinct miRNA profiles in the exosomes between the two groups. We identified 12 differentially expressed miRNAs through this analysis, which were further validated via qRT-PCR using the same exosomes. Notably, six miRNAs (hsa-miR-7850-5p, hsa-miR-1306-5p, hsa-miR-363-5p, hsa-miR-374a-5p, hsa-miR-4654, has-miR-6529-5p, and hsa-miR-140-5p) exhibited specifically elevated expression in individuals with LTBI. Gene ontology and KEGG pathway analyses revealed that the targets of these miRNAs were enriched in functions associated with ferroptosis and fatty acid metabolism, underscoring the critical role of these miRNAs in regulating the intracellular survival of Mycobacterium tuberculosis (Mtb). Furthermore, our results indicated that the overexpression of miR-7850-5p downregulated the expression of the SLC11A1 protein in both Mtb-infected and Mtb-uninfected THP1 cells. Additionally, we observed that miR-7850-5p promoted the intracellular survival of Mtb by suppressing the expression of the SLC11A1 protein. Overall, our findings provide valuable insights into the role of miRNAs and repetitive region-derived small RNAs in exosomes during the infectious process of Mtb and contribute to the identification of potential molecular targets for the detection and diagnosis of latent tuberculosis.

Mycobacterium avium Complex Pulmonary Infection in a Patient With an SLC11A1 Mutation: A Rare Case Report and Review of Literature.

Mycobacterial avium complex (MAC) is one of the non-tuberculous mycobacterium (NTM) that is known to cause pulmonary disease (PD). MAC PD is diagnosed by fulfilling all of the following: presence of respiratory symptoms, imaging studies compatible with pulmonary disease, and isolation of the mycobacterium from either sputum or bronchial wash in symptomatic patients (isolation of at least two sputum specimens or at least one bronchial wash specimen). A mutation in the solute carrier family 11, member 1 (SLC11A1) gene has been associated with Mycobacteria infections, including MAC. Herein, we present a case of a young female diagnosed with pulmonary MAC who was found later to have an SLC11A1 genetic mutation.

Molecular Cloning and Functional Characterization of the 5' Regulatory Region of the SLC11A1 Gene from Yaks.

The solute transport protein family 11 A1 (SLC11A1), also recognized as natural resistance-associated macrophage protein 1 (NRAMP1), represents a transmembrane protein encoded by the SLC11A1 gene. A variety of prior investigations have illuminated its involvement in conferring resistance or susceptibility to bacterial agents, positioning it as a promising candidate gene for breeding disease-resistant animals. Yaks (Bos grunniens), renowned inhabitants of the Qinghai-Tibet Plateau in China, stand as robust ruminants distinguished by their adaptability and formidable disease resistance. Notwithstanding these unique traits, there is scant literature on the SLC11A1 gene in the yak population. Our inquiry commences with the cloning of the 5' regulatory region sequence of the Zhongdian yak SLC11A1 gene. We employ bioinformatics tools to identify transcription factor binding sites, delineating pivotal elements like enhancers and cis-acting elements. To ascertain the promoter activity of this region, we amplify four distinct promoter fragments within the 5' regulatory region of the yak SLC11A1 gene. Subsequently, we design a luciferase reporter gene vector containing four site-specific deletion mutations and perform transient transfection experiments. Through these experiments, we measure and compare the activity of disparate gene fragments located within the 5' regulatory region, revealing regions bearing promoter functionality and discerning key regulatory elements. Our findings validate the promoter functionality of the 5' regulatory region, offering preliminary insights into the core and principal regulatory segments of this promoter. Notably, we identified single nucleotide polymorphisms (SNPs) that may be associated with important regulatory elements such as NF-1 and NF-1/L. This study provides a theoretical framework for in-depth research on the function and expression regulation mechanism of the yak SLC11A1 gene.

Sarcoidosis, Mycobacterium paratuberculosis and Noncaseating Granulomas: Who Moved My Cheese.

Clinical and histological similarities between sarcoidosis and tuberculosis have driven repeated investigations looking for a mycobacterial cause of sarcoidosis. Over 50 years ago, "anonymous mycobacteria" were suggested to have a role in the etiology of sarcoidosis. Both tuberculosis and sarcoidosis have a predilection for lung involvement, though each can be found in any area of the body. A key histopathologic feature of both sarcoidosis and tuberculosis is the granuloma-while the tuberculous caseating granuloma has an area of caseous necrosis with a cheesy consistency; the non-caseating granuloma of sarcoidosis does not have this feature. This article reviews and reiterates the complicity of the infectious agent, Mycobacterium avium subsp. paratuberculosis (MAP) as a cause of sarcoidosis. MAP is involved in a parallel story as the putative cause of Crohn's disease, another disease featuring noncaseating granulomas. MAP is a zoonotic agent infecting ruminant animals and is found in dairy products and in environmental contamination of water and air. Despite increasing evidence tying MAP to several human diseases, there is a continued resistance to embracing its pleiotropic roles. "Who Moved My Cheese" is a simple yet powerful book that explores the ways in which individuals react to change. Extending the metaphor, the "non-cheesy" granuloma of sarcoidosis actually contains the difficult-to-detect "cheese", MAP; MAP did not move, it was there all along.

Association of SLC11A1 Polymorphisms With Tuberculosis Susceptibility in the Chinese Han Population.

Tuberculosis (TB) is an important health issue in the world. Although the relation of SLC11A1 polymorphisms with TB risk has been extensively studied, it has not been reported in the northwest Chinese Han population. Therefore, this study aimed to investigate the relationships between five polymorphisms in or near the SLC11A1 gene and susceptibility to TB. The Agena MassARRAY platform was conducted for genotyping from 510 TB patients and 508 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were analyzed through logistic regression adjustment age and gender to assess the relationships between polymorphisms and TB risk. Our results identified that rs7608307 was related to increased TB risk in males (CT vs. CC: OR = 1.69, 95%CI: 1.12-2.56, p = 0.013; CT-TT vs. CC: OR = 1.61, 95%CI: 1.08-2.41, p = 0.020) and age ≤41 group (CT vs. CC: OR = 1.66, 95%CI: 1.04-2.65, p = 0.035), respectively. The SNP rs13062 was associated with the TB risk both in males (p = 0.012) and age >41 group (p = 0.021). In addition, we observed that the CC genotype of rs4674301 was correlated with increased TB risk in females (p = 0.043). Our results demonstrated the relationships between polymorphisms (rs7608307, rs4674301, and rs13062) in or near the SLC11A1 gene and age- and sex-specific TB risk in the northwest Chinese Han population.

SLC11A1 associated with tumor microenvironment is a potential biomarker of prognosis and immunotherapy efficacy for colorectal cancer.

Colorectal cancer (CRC) is one of the most lethal cancers of the digestive system. The tumor microenvironment (TME) plays a central role in the initiation and development of CRC. However, little is known about the modulation mechanism of the TME in CRC. In our study, we attempted to identify a biomarker related to the TME modulation that could serve as a potential prognostic biomarker for CRC. We identified differentially expressed genes between the ImmuneScore high/low and StromalScore high/low groups. Using univariate COX regression analysis and hub gene analysis (cytoHubba), SLC11A1 was identified as the only candidate gene for subsequent analysis. CIBERSORT, EPIC, MCPcounter, and immunogenic cell death were performed to evaluate the effect of SLC11A1 on the TME. We also collected samples and performed Real-time quantitative PCR to verify the expression levels of SLC11A1 in CRC and adjacent normal tissues. The IMvigor210 cohort, TIDE score, and immunophenoscore (IPS) were used to analyze the association between SLC11A1 and immunotherapy efficacy. SLC11A1 was highly expressed in CRC tissues compared with its expression in normal colorectal tissues and was associated with poor prognosis and advanced clinicopathological stages. Gene set enrichment analysis showed that TGF-ß pathways, JAK-STAT pathways, and angiogenesis were significantly enriched in the high-SLC11A1 group. Single-cell analysis validated the correlation between SLC11A1 and the TME. Using CIBERSORT, EPIC, and MCPcounter algorithms, we found that there was more macrophage and fibroblast infiltration in the SLC11A1 high-expression group. Meanwhile, high-SLC11A1 patients had lower IPS scores, higher TIDE scores, and fewer immunotherapy benefits than those of low-SLC11A1 patients. In conclusion, SLC11A1 plays a crucial role in the TME and could serve as a potential biomarker for poor prognosis and immunotherapy efficacy in CRC.

Association of genetic variants in autophagy-lysosome pathway genes with susceptibility and survival to prostate cancer.

BACKGROUND: Previous studies have indicated the connections between autophagy-lysosome pathway genes dysfunction and prostate cancer, but few studies have investigated whether single nucleotide polymorphisms (SNPs) in autophagy-lysosome pathway genes are implicated in prostate cancer risk and survival. MATERIALS AND METHODS: Logistic regression analysis and stepwise Cox regression analysis were conducted in 4,662 cases and 3,114 controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. The false positive rate probability (FPRP) method was applied to correct for multiple comparisons. Gene-based analysis was calculated by versatile gene-based association study approach. RESULTS: We found that SLC11A1 rs7573065 significantly increased the risk of prostate cancer [adjusted odds ratio (OR) = 1.24, 95% confidence interval (CI) = 1.06-1.46, P = 7.02 × 10-3, FPRP = 0.082]. Furthermore, rs7573065 was confirmed as the independent predicator of overall survival (OS) for prostate cancer patients [Hazard ratio (HR) = 1.30, 95% CI = 1.01-1.66, P = 0.041]. The significant association between SLC11A1 and prostate cancer risk was calculated by gene-based analysis (P = 0.030). We also observed that the mRNA of SLC11A1 in prostate tumor tissues was significantly over-expressed than that in normal tissues. CONCLUSION: This study suggested that rs7573065 in SLC11A1 was associated with an increased risk and poor OS of prostate cancer. Our findings may provide evidence for genetic variants in autophagy-lysosome pathway as the risk and prognostic biomarkers for prostate cancer.