Dysregulation in lipid metabolism is among the most prominent metabolic alterations in cancer. Stimulated by retinoic acid 6 (STRA6), a vitamin A transporter has shown to be involved in the pathogenesis of cancers. Nevertheless, the function of STRA6 in non-small cell lung cancer (NSCLC) progression remains undefined. We obtained cancer and adjacent tissues from NSCLC patients and conducted functional experiments on STRA6 on NSCLC cell lines and mice. High STRA6 expression is correlated with poor prognosis in patients with NSCLC. Results from in vitro and in vivo animal studies showed that STRA6 knockdown suppressed the proliferation, migration, and invasion of NSCLC cells in vitro and tumor growth in vivo through regulation of lipid synthesis. Mechanistically, STRA6 activated a Janus kinase 2/signal transducer and activator of transcription 3 (JAK2-STAT3) signaling cascade which inducing the expression of STAT3 target gene. By inducing the expression of the target gene of STAT3, sterol regulatory element binding protein 1 (SREBP-1), STRA6 promotes SREBP-1-mediated adipogenesis and provides energy for NSCLC cell growth. Our study uncovers a novel STRA6/STAT3/SREBP-1 regulatory axis that enhances NSCLC metastasis by reprogramming of lipid metabolism. These results demonstrate the potential use of STRA6 as a biomarker for diagnosing NSCLC, which may therefore potentially serve as a therapeutic target for NSCLC.

BACKGROUND: Fat infiltration of skeletal muscle has been recognized as a common feature of many degenerative muscle disorders. Retinol binding protein 4 (RBP4) is an adipokine that has been demonstrated to be correlated with the presence and severity of sarcopenia in the elderly. However, the exact role and the underlying mechanism of RBP4 in muscle atrophy remains unclear.
METHODS: Denervation-induced muscle atrophy model was constructed in wild-type and RBP4 knockout mice. To modify the expression of RBP4, mice were received intramuscular injection of retinol-free RBP4 (apo-RBP4), retinol-bound RBP4 (holo-RBP4) or oral gavage of RBP4 inhibitor A1120. Holo-RBP4-stimulated C2C12 myotubes were treated with siRNAs or specific inhibitors targeting signalling receptor and transporter of retinol 6 (STRA6)/Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) pathway. Fat accumulation, myofibre cross-sectional area, myotube diameter and the expression of muscle atrophy markers and myogenesis markers were analysed.
RESULTS: The expression levels of RBP4 in skeletal muscles were significantly up-regulated more than 2-fold from 7 days and sustained for 28 days after denervation. Immunofluorescence analysis indicated that increased RBP4 was localized in the infiltrated fatty region in denervated skeletal muscles. Knockout of RBP4 alleviated denervation-induced fatty infiltration and muscle atrophy together with decreased expression of atrophy marker Atrogin-1 and MuRF1 as well as increased expression of myogenesis regulators MyoD and MyoG. By contrast, injection of retinol-bound holo-RBP4 aggregated denervation-induced ectopic fat accumulation and muscle atrophy. Consistently, holo-RBP4 stimulation also had a dose-dependent effect on the reduction of C2C12 myotube diameter and myofibre cross-sectional area, as well as on the increase of Atrogin-1and MuRF1 expression and decrease of MyoD and MyoG expression. Mechanistically, holo-RBP4 treatment increased the expression of its membrane receptor STRA6 (>3-fold) and promoted the phosphorylation of downstream JAK2 and STAT3. Inhibition of STRA6/JAK2/STAT3 pathway either by specific siRNAs or inhibitors could decrease the expression of Atrogin-1 and MuRF1 (>50%) and decrease the expression of MyoD and MyoG (>3-fold) in holo-RBP4-treated C2C12 myotube. RBP4 specific pharmacological antagonist A1120 significantly inhibited the activation of STRA6/JAK2/STAT3 pathway, ameliorated ectopic fat infiltration and protected against denervation-induced muscle atrophy (30% increased myofibre cross-sectional area) in mice.
CONCLUSIONS: In conclusion, our data reveal that RBP4 promotes fat infiltration and muscle atrophy through a STRA6-dependent and JAK2/STAT3 pathway-mediated mechanism in denervated skeletal muscle. Our results suggest that lowering RBP4 levels might serve as a promising therapeutic approach for prevention and treatment of muscle atrophy.

In this review, we outline our current understanding of the mechanisms involved in the absorption, storage, and transport of dietary vitamin A to the eye, and the trafficking of rhodopsin protein to the photoreceptor outer segments, which encompasses the logistical backbone required for photoreceptor cell function. Two key mechanisms of this process are emphasized in this manuscript: ocular and systemic vitamin A membrane transporters, and rhodopsin transporters. Understanding the complementary mechanisms responsible for the generation and proper transport of the retinylidene protein to the photoreceptor outer segment will eventually shed light on the importance of genes encoded by these proteins, and their relationship on normal visual function and in the pathophysiology of retinal degenerative diseases.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies, highlighting the urgent need to elucidate the underlying oncogenic mechanisms. VIRMA is a classic isoform of methyltransferases that participates in epigenetic transcriptomic modification in eukaryotic mRNAs. However, the exact roles of VIRMA in PDAC remain unclear. Here, we identified that VIRMA is highly expressed in PDAC, and histone modifications of the promoter may partly account for this dysregulation. Moreover, VIRMA is closely related to glycolysis and poor prognosis in PDAC. We further determined that STRA6 is a direct downstream target of VIRMA in PDAC by RNA sequencing (RNA-seq) and m6A sequencing (m6A-seq). VIRMA is involved in gene expression regulation via 3\' UTR targeting of STRA6 mRNA. Furthermore, the m6A reader IGF2BP2 was shown to critically contribute to the stability of STRA6 mRNA. We describe the role of VIRMA in promoting signaling via the STRA6/STAT3 axis, which results in increased levels of HIF-1α, a key activator of glycolysis. In vivo and in vitro experiments reveal that the VIRMA-STRA6-STAT3-HIF-1α axis plays an instrumental role in glycolysis and tumor progression in PDAC. In conclusion, we demonstrate that VIRMA can increase glycolysis in PDAC by upregulating STRA6, a cell surface membrane protein that stimulates the STAT3 pathway, thereby activating HIF-1α and leading to pancreatic cancer malignancy. Overall, our data strongly suggest that the VIRMA-STRA6-STAT3-HIF-1α axis is a viable therapeutic target in PDAC.

The ANLN gene encodes anillin, a protein that binds to actin. Recent research has identified ANLN\'s function in the initiation and advancement of different cancers. However, its impact on gallbladder cancer (GBC) remains unexplored. This study aimed to elucidate its possible molecular mechanisms in GBC. ANLN expression was assessed using quantitative real-time polymerase chain reaction (QRT-PCR), Western blotting (WB), and immunohistochemistry (IHC), revealing elevated levels in GBC tissues. ANLN knockdown resulted in the inhibition of cell proliferation and migration, leading to apoptosis and cell cycle arrest. Conversely, ANLN overexpression had the opposite effects on GBC cells. In vivo experiments confirmed that ANLN knockdown inhibited GBC cell growth. RNA-seq and bioinformatics analysis revealed ANLN\'s function in activating the PI3K/AKT signaling pathway. We further confirmed that ANLN could upregulate STRA6 expression, which activated PI3K/AKT signaling to enhance the growth and movement of GBC cells. These findings demonstrate ANLN\'s involvement in GBC initiation and progression, suggesting its potential as a novel target for GBC.

A major cause for childhood blindness worldwide is attributed to nutritional vitamin A deficiency. Surprisingly, the molecular basis of the ensuing retinal degeneration has not been well defined. Abundant expression of the retinoid transporter STRA6 in the retinal pigment epithelium (RPE) and homeostatic blood levels of retinol-binding protein delay vitamin A deprivation of the mouse eyes. Hence, genetic dissection of STRA6 makes mice susceptible to nutritional manipulation of ocular retinoid status. We performed RNA-seq analyses and complemented the data with tests of visual physiology, ocular morphology, and retinoid biochemistry to compare eyes with different vitamin A status. Mild ocular vitamin A deficiency decreased transcripts of photoreceptor transduction pathway-related genes and increased transcripts of oxidative stress pathways. The response was associated with impaired visual sensitivity and an accumulation of fluorescent debris in the retina. Severe vitamin A deficiency did not only impair visual perception but also decreased transcripts of genes encoding cell adhesion and cellular junction proteins. This response altered cell morphology, resulted in significant changes in transport pathways of small molecules, and compromised the barrier function of the RPE. Together, our analyses characterize the molecular events underlying nutritional blindness in a novel mouse model and indicate that breakdown of the outer blood-retinal barrier contributes to retinal degeneration and photoreceptor cell death in severe vitamin A deficiency.

The distribution of dietary vitamin A/all-trans retinol/ROL throughout the body is critical for maintaining retinoid function in peripheral tissues and for retinoid delivery to the eye in the support of visual function. In the circulation, all-trans-retinol bound to the RBP4 protein is transported and sequestered into target tissues for long-term storage. Two membrane receptors that facilitate all-trans retinol uptake from RBP4 have been proposed. While it is well established that the membrane receptor, STRA6, binds to circulatory RBP4 for ROL transport into the eye, the second vitamin A receptor, RBPR2, which is expressed in non-ocular tissues, is less characterized. Based on the structural homology between these two RBP4 receptors, published literature, and from our recent work in Rbpr2 -/- deficient mice, we hypothesized that RBPR2 might also have high-binding affinity for RBP4 and this mechanism facilitates ROL transport. Herein, we aimed to elucidate the membrane topology and putative RBP4 binding residues on RBPR2 to understand its physiological function for retinoid homeostasis. Using in silico analysis and site-directed mutagenesis, we identified a potential RBP4 binding domain on RBPR2. We employed an in vitro cell-based system and confirmed that mutations of these residues on RBPR2 affected its binding to exogenous RBP4 and subsequently vitamin A uptake. Using Surface Plasmon Resonance assays, we analyzed both the binding affinities and kinetic parameters of wild-type RBPR2 and individual mutants affecting the RBPR2-RBP4 binding domain with its physiological ligand RBP4. These studies not only revealed a putative RBP4 binding domain on RBPR2 but also provided new structural, biochemical, and critical information on its proposed role in RBP4 binding for ROL transport and retinoid homeostasis.

BRAF mutation is one of the most common genetic alterations contributing to the initiation and progression of papillary thyroid carcinoma (PTC). However, the prognostic value of BRAF mutation for PTC is limited. Novel markers are needed to identify BRAF-mutant patients with poor prognosis.
Transcriptional expression data were downloaded from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Pathway enrichment was performed by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and gene set enrichment analysis (GSEA). Protein-protein interaction networks were predicted by the GeneMANIA. The correlation between STRA6 expression and immune infiltration was analyzed by tumor immune estimation resource (TIMER) and tumor-immune system interaction database (TISIDB). Immunohistochemistry was used to detect the STRA6 protein expression level of PTC. Infiltration of regulatory T cells (Tregs) and CD8+ T cells in tumor samples were analyzed by fluorescent multiplex immunohistochemistry.
In BRAF-mutant PTC, STRA6 was extremely upregulated and predicted unfavorable survival, which was an independent risk factor for increased mortality risk. Bioinformatic analyses indicated that STRA6 might activate the MAPK pathway synergistically with BRAFV600E. The expression of STRA6 was associated with immune infiltrates and T cell exhaustion. Fluorescent multiplex immunohistochemistry showed that STRA6 increased Tregs abundance and decreased CD8+ T cells infiltration in PTC. Moreover, STRA6 promoted epithelial-mesenchymal transition via increased cancer-associated fibroblasts infiltration.
Our study demonstrates STRA6 may serve as a prognostic marker for BRAF-mutated PTC, which may drive thyroid carcinogenesis via activation of oncogenic pathway and regulation of tumor immunosuppressive microenvironment.

Signaling receptor and transporter of retinol STRA6 (STRA6) plays a primary role in transporting retinol. Several studies have reported that STRA6 is involved in several pathways related to tumorigenesis and progression. However, the exact functions and mechanisms of STRA6 in colorectal cancer (CRC) remain unclear. In our work, STRA6 was highly up-regulated in CRC and promoted the proliferation of CRC cells. Additionally, we discovered that STRA6 suppresses apoptosis partly by controlling BCL2 expression, which in turn causes CRC to become resistant to LOHP treatment. Our study demonstrates that STRA6 is a potential prognostic factor and oncogene in CRC by promoting CRC growth and chemoresistance.

Metastasis has emerged to be an important cause for poor prognosis of thyroid carcinoma (TC) and its molecular mechanisms are not fully understood. STRA6 is a multifunctional membrane protein widely expressed in embryonic and adult tissues. The function and mechanism of STRA6 in TC remain elusive.
We aimed to explore the role of STRA6 in TC progression and provide a therapeutic target for TC.
The expression and clinicopathological relevance of STRA6 were explored in TC. Stable STRA6-knockdown TC cells were established and used to determine the biological function of STRA6 in vitro and in vivo. RNA sequencing and co-immunoprecipitation were performed to unveil the molecular mechanism of STRA6 in TC progression. The potential of STRA6 as a therapeutic target was evaluated by lipid nanoparticles (LNPs) containing siRNA.
STRA6 was upregulated in TC and correlated with aggressive clinicopathological features, including extrathyroidal extension and lymph node metastasis, which contributed to the poor prognosis of TC. STRA6 facilitated TC progression by enhancing proliferation and metastasis in vitro and in vivo. Mechanistically, STRA6 could interact with integrin-linked kinase (ILK) and subsequently activate the protein kinase B/mechanistic target of rapamycin (AKT/mTOR) signaling pathway. We further unveiled that STRA6 reprogrammed lipid metabolism through SREBP1, which was crucial for the metastasis of TC. Moreover, STRA6 siRNA delivered by LNPs significantly inhibited cell growth in xenograft tumor models.
Our study demonstrates the critical roles of STRA6 contributing to TC progression via the ILK/AKT/mTOR axis, which may provide a novel prognostic marker as well as a promising therapeutic target for aggressive TC.