LncRNA SLCO4A1-AS1 suppresses lung cancer progression by sequestering the TOX4-NTSR1 signaling axis.

BACKGROUND: Metastasis is a multistep process involving the migration and invasion of cancer cells and is a hallmark of cancer malignancy. Long non-coding RNAs (lncRNAs) play critical roles in the regulation of metastasis. This study aims to elucidate the role of the lncRNA solute carrier organic anion transporter family member 4A1-antisense 1 (SLCO4A1-AS1) in metastasis and its underlying regulatory mechanisms. METHODS: A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify metastasis-associated lncRNAs. Transwell migration and invasion assays, and a tail vein-injection mouse model were used to assess the migration and invasion of cancer cells in vitro and in vivo, respectively. High-throughput screening methods, including MASS Spectrometry and RNA sequencing (RNA-seq), were used to identify the downstream targets of SLCO4A1-AS1. Reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting, RNA pull-down, RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH), and chromatin immunoprecipitation (ChIp) assays were conducted to identify and validate the underlying regulatory mechanisms of SLCO4A1-AS1. RESULTS: SLCO4A1-AS1 reduced cancer cell migration and invasion by disrupting cytoskeleton filaments, and was associated with longer overall survival in patients with lung adenocarcinoma. SLCO4A1-AS1 directly interacted with the DNA-binding protein, TOX High Mobility Group Box Family Member 4 (TOX4), to inhibit TOX4-induced migration and invasion. Furthermore, RNA-seq revealed that neurotensin receptor 1 (NTSR1) is a novel and convergent downstream target of SLCO4A1-AS1 and TOX4. Mechanistically, SLCO4A1-AS1 functions as a decoy of TOX4 by interrupting its interaction with the NTSR1 promoter and preventing NTSR1 transcription. Functionally, NTSR1 promotes cancer cell migration and invasion through cytoskeletal remodeling, and knockdown of NTSR1 significantly inhibits TOX4-induced migration and invasion. CONCLUSION: These findings demonstrated that SLCO4A1-AS1 antagonizes TOX4/NTSR1 signaling, underscoring its pivotal role in lung cancer cell migration and invasion. These findings hold promise for the development of novel therapeutic strategies targeting the SLCO4A1-AS1/TOX4/NTSR1 axis as a potential avenue for effective therapeutic intervention in lung cancer.

SLCO4A1-AS1 regulates laryngeal squamous cell carcinoma cell phenotypes via the Wnt pathway.

AIM: Long non-coding RNAs were widely reported to regulate laryngeal squamous cell carcinoma (LSCC), a prevalent tumor in the head and neck. We aimed to investigate the role of solute carrier organic anion transporter family member 4A1 antisense RNA 1 (SLCO4A1-AS1) in LSCC. MATERIALS & METHODS: CCK-8 and colony formation assays were conducted to examine the viability and proliferation of LSCC cells. The apoptosis of LSCC cells was evaluated using flow cytometry and TUNEL assays. The distribution of SLCO4A1-AS1 in LSCC cells was detected by subcellular fractionation assay. The interaction between molecules was confirmed using luciferase reporter assay. RESULTS: SLCO4A1-AS1 was overexpressed in LSCC tissues and cells. Furthermore, silenced SLCO4A1-AS1 repressed the proliferation and facilitated apoptosis of LSCC cells. Mechanistical investigation revealed that SLCO4A1-AS1 was a competing endogenous RNA (ceRNA) to upregulate SETD7 by binding with miR-7855-p. Additionally, SLCO4A1-AS1 positively regulated the Wnt/ß-catenin signaling pathway by upregulating SETD7. Rescue experiments demonstrated that SLCO4A1-AS1 promoted LSCC proliferation and inhibited LSCC apoptosis by upregulation of SETD7 and activation of the Wnt/ß-catenin pathway. CONCLUSION: SLCO4A1-AS1 promotes proliferation and inhibits apoptosis of LSCC cells by upregulation of SETD7 in a miR-7855-5p dependent way to activate the Wnt/ß-catenin pathway.

SLCO4A1-AS1 triggers the malignant behaviours of melanoma cells via sponging miR-1306-5p to enhance PCGF2.

Melanoma belongs to cutaneous malignancy. Long non-coding RNAs (lncRNAs) have been suggested as crucial effectors in modulating progression of different malignancies, including melanoma. However, novel lncRNA solute carrier organic anion transporter family member 4A1 antisense RNA 1 (SLCO4A1-AS1) was not reported in melanoma. Herein, SLCO4A1-AS1 was detected to be up-regulated in melanoma cell lines compared with human normal melanocytes (HEM-a). Additionally, proliferation, migration and invasion of melanoma cells were weakened but apoptosis was facilitated due to SLCO4A1-AS1 down-regulation. Subsequently, miR-1306-5p was revealed to be sequestered by SLCO4A1-AS1 and down-regulated in melanoma cells. Functional assays further sustained that overexpressed miR-1306-5p had inhibitory influence on proliferation, migration and invasion and promoting influence on apoptosis of melanoma cells. Polycomb group ring finger 2 (PCGF2) was predicted as the downstream of miR-1306-5p, displaying aberrantly high expression in melanoma cell lines. Furthermore, PCGF2 expression was negatively modulated by miR-1306-5p and positively regulated by SLCO4A1-AS1. Finally, rescue assays demonstrated melanoma cell malignant behaviours suppressed by SLCO4A1-AS1 knockdown could be reversed by overexpressed PCGF2. Our study suggested that SLCO4A1-AS1 promoted the melanoma cell malignant behaviours via targeting miR-1306-5p/PCGF2, which might facilitate the discovery of novel biomarkers for melanoma treatment.

SLCO4A1-AS1 promotes colorectal tumourigenesis by regulating Cdk2/c-Myc signalling.

BACKGROUND: SLCO4A1-AS1 was found to be upregulated in several cancer types, including colorectal cancer (CRC). However, the detailed roles of SLCO4A1-AS1 in CRC remain to be elucidated. Therefore, we investigated the functions, mechanism, and clinical significance of SLCO4A1-AS1 in colorectal tumourigenesis. METHODS: We measured the expression of SLCO4A1-AS1 in CRC tissues using qRT-PCR and determined its correlation with patient prognosis. Promoter methylation analyses were used to assess the methylation status of SLCO4A1-AS1. Gain- and loss-of-function assays were used to evaluate the effects of SLCO4A1-AS1 on CRC growth in vitro and in vivo. RNA pull-down, RNA immunoprecipitation, RNA-seq, luciferase reporter and immunohistochemistry assays were performed to identify the molecular mechanism of SLCO4A1-AS1 in CRC. RESULTS: SLCO4A1-AS1 was frequently upregulated in CRC tissues based on multiple CRC cohorts and was associated with poor prognoses. Aberrant overexpression of SLCO4A1-AS1 in CRC is partly attributed to the DNA hypomethylation of its promoter. Ectopic SLCO4A1-AS1 expression promoted CRC cell growth, whereas SLCO4A1-AS1 knockdown repressed CRC proliferation both in vitro and in vivo. Mechanistic investigations revealed that SLCO4A1-AS1 functions as a molecular scaffold to strengthen the interaction between Hsp90 and Cdk2, promoting the protein stability of Cdk2. The SLCO4A1-AS1-induced increase in Cdk2 levels activates the c-Myc signalling pathway by promoting the phosphorylation of c-Myc at Ser62, resulting in increased tumour growth. CONCLUSIONS: Our data demonstrate that SLCO4A1-AS1 acts as an oncogene in CRC by regulating the Hsp90/Cdk2/c-Myc axis, supporting SLCO4A1-AS1 as a potential therapeutic target and prognostic factor for CRC.

Kawasaki disease: lncRNA Slco4a1 regulates the progression of human umbilical vein endothelial cells by targeting the miR-335-5p/POU5F1 axis.

Background: Kawasaki disease (KD) is an autoimmune disease with systemic vasculitis as the main pathological change, and is most common in children under 5. The role of long non-coding RNAs (lncRNAs) in human diseases has been highlighted. LncRNA Slco4a1 was reported to promote cell growth and act as an oncogenic regulator in cancer. However, the role of lncRNA Slco4a1 in KD remains unclear. This study aimed to investigate the role and mechanism of lncRNA Slco4a1 in KD. Methods: Enzyme linked immunosorbent assay (ELISA), qRT-PCR, Western blot, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining were conducted to explore the function of lncRNA Slco4a1. The interaction between POU5F1 and miR-335-5p was analyzed by the RIP assay and dual luciferase assay. Results: LncRNA Slco4a1 was significantly upregulated in the serum of KD patients compared with healthy controls. LncRNA Slco4a1 was upregulated in human umbilical vein endothelial cells (HUVECs) stimulated with KD serum. LncRNA Slco4a1 overexpression could promote the expression of inflammatory factors and apoptosis in HUVECs. The number of inflammatory cells and the infiltration area of the coronary artery in KD rats were decreased after lncRNA Slco4a1 silencing. Furthermore, lncRNA Slco4a1 is a sponge of miR-335-5p and negatively regulated the expression of miR-335-5p. POU5F1 was the downstream target of miR-335-5p, and miR-335-5p overexpression could upregulate the expression of POU5F1. Additionally, miR-335-5p overexpression could inhibit the expression of inflammatory factors and apoptosis in HUVECs. We further investigated the effect of lncRNA Slco4a1 on the mitogen-activated protein kinase (MAPK) signaling pathway, and the results showed that lncRNA Slco4a1 could promote the activation of the MAPK signaling pathway. Conclusions: Together, these results indicated that lncRNA Slco4a1 could regulate the progression of HUVECs in KD by targeting the miR-335-5p/POU5F1 axis, providing new insights for KD treatment.

SLCO4A1 expression is associated with activated inflammatory pathways in high-grade serous ovarian cancer.

Patients with high-grade serous ovarian cancer (HGSOC) have a very poor overall survival. Current therapeutic approaches do not bring benefit to all patients. Although genetic alterations and molecular mechanisms are well characterized, the molecular pathological conditions are poorly investigated. Solute carrier organic anion transporter family member 4A1 (SLCO4A1) encodes OATP4A1, which is an uptake membrane transporter of metabolic products. Its expression may influence various signaling pathways associated with the molecular pathophysiological conditions of HGSOC and consequently tumor progression. RNA sequencing of 33 patient-derived HGSOC cell lines showed that SLCO4A1 expression was diverse by individual tumors, which was further confirmed by RT-qPCR, Western blotting and immunohistochemistry. Gene Set Enrichment Analysis revealed that higher SLCO4A1 level was associated with inflammation-associated pathways including NOD-like receptor, adipocytokine, TALL1, CD40, NF-κB, and TNF-receptor 2 signaling cascades, while low SLCO4A1 expression was associated with the mitochondrial electron transport chain pathway. The overall gene expression pattern in all cell lines was specific to each patient and remained largely unchanged during tumor progression. In addition, genes encoding ABCC3 along with SLCO4A1-antisense RNA 1, were associated with higher expression of the SLCO4A1, indicating their possible involvement in inflammation-associated pathways that are downstream to the prostaglandin E2/cAMP axis. Taken together, increased SLCO4A1/OATP4A1 expression is associated with the upregulation of specific inflammatory pathways, while the decreased level is associated with mitochondrial dysfunction. These molecular pathophysiological conditions are tumor specific and should be taken into consideration by the development of therapies against HGSOC.

SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis.

In this study, we intended to figure out the biological significance of long non-coding RNAs (lncRNAs) solute carrier organic anion transporter family member 4A1 antisense RNA 1 (SLCO4A1-AS1) in pancreatic cancer (PC). Cell counting kit-8, colony formation, wound healing, transwell, and flow cytometry experiments were performed to reveal how SLCO4A1-AS1 influences PC cell proliferation, migration, invasion, and apoptosis. Thereafter, bioinformatics analysis, RNA immunoprecipitation assay, luciferase reporter assay, and RNA pull-down assay were applied for determining the binding sites and binding capacities between SLCO4A1-AS1 and miR-4673 or kinesin family member 21B (KIF21B) and miR-4673. The results depicted that SLCO4A1-AS1 was upregulated in PC, and SLCO4A1-AS1 knockdown suppressed PC cell growth, migration, invasion, and induced cell apoptosis. Furthermore, SLCO4A1-AS1 was verified to modulate the expression of KIF21B by binding with miR-4673. SLCO4A1-AS1 exerted an oncogenic function in PC. The overexpression of SLCO4A1-AS1 aggravated the malignant behaviors of PC via the upregulation of KIF21B by sponging miR-4673. Our findings revealed a novel molecular mechanism mediated by SLCO4A1-AS1, which might play a significant role in modulating the biological processes of PC.

SLCO4A1 is a Prognosis-Associated Biomarker Involved in Neutrophil-Mediated Immunity in Thyroid Cancer.

OBJECTIVE: The study aimed to investigate the value of solute carrier organic anion transporter family member 4A1 (SLCO4A1) in thyroid cancer mainly from three aspects: expression, prognosis, and biological function analyses. METHODS: Based on various bioinformatic approaches, genes co-expressed with vascular endothelial growth factor C (VEGFC) in thyroid cancer were used for further survival and expression analyses to identify the target gene. After evaluation of the SLCO4A1 expression levels in thyroid cancer, Cox regression analysis was utilized to predict the risk factors for survival of thyroid cancer patients. And receiving operating characteristic curve analysis was performed to validate the prognostic value of SLCO4A1. Additionally, WebGestalt was employed for enrichment analysis of SLCO4A1 and its co-expressed genes. Further, the relation between SLCO4A1 and neutrophil was analyzed, followed by exploring the association of SLCO4A1 with immunomodulators. RESULTS: A total of 38 consistent VEGFC co-expressed genes were generated, and SLCO4A1 was selected as the target gene due to its oncogenic characteristics. SLCO4A1 was highly expressed in thyroid cancer at both gene and protein levels, and SLCO4A1 mRNA expression was significantly associated with the cancer stage (all P <0.05). Besides, high SLCO4A1 expression led to unfavorable progression-free survival (PFS) of thyroid cancer patients (P =0.0066). Further, Cox regression analysis indicated that high SLCO4A1 expression was an independent predictor of poor PFS in patients with papillary thyroid cancer, particularly in patients at stage 1 and female patients (all P <0.001). The enrichment analysis results showed that SLCO41A was involved in the neutrophil-mediated immunity pathway. Moreover, SLCO4A1 had a positive relation with neutrophils (all P <0.05). Finally, a significant correlation between SLCO4A1 and immunomodulators was observed (all P <0.001). CONCLUSION: SLCO4A1 was a potential prognostic biomarker for papillary thyroid cancer patients. And SLCO4A1 might affect PFS in thyroid cancer patients by positive regulation of neutrophil-mediated immunity pathway.

LncRNA SLCO4A1-AS1 Accelerates Growth and Metastasis of Gastric Cancer via Regulation of the miR-149/XIAP Axis.

OBJECTIVE: Recently, long noncoding RNA SLCO4A1 antisense RNA 1 (SLCO4A1-AS1) has been shown to act as an oncogene in several cancer types; however, its role in gastric cancer (GC) and its underlying molecular mechanisms are yet to be elucidated. METHODS: Using the ENCORI database, we identified SLCO4A1-AS1, miR-149-5p (miR-149), and the X-linked inhibitor of apoptosis (XIAP) whose expressions were obviously changed in GC samples, and analyzed the correlation between their expressions in GC samples. Moreover, we explored the expression of SLCO4A1-AS1, miR-149, and XIAP in clinical samples and GC cell lines using RT-qPCR and western blotting assay; the correlation between them was analyzed using RNA immunoprecipitation and dual-luciferase reporter. CCK-8, colony formation, and Transwell assays were conducted to determine the effects of SLCO4A1-AS1, miR-149, and XIAP expression on cell proliferation, migration, and invasion, respectively. A nude mouse xenograft model was used to explore their function in xenograft growth. RESULTS: SLCO4A1-AS1 was significantly upregulated in the GC samples and cell lines, and a high level of SLCO4A1-AS1 was associated with an advanced tumor stage and shortened patient survival. Mechanistically, SLCO4A1-AS1 post-transcriptionally regulated XIAP by functioning as competing endogenous RNA in GC to sponge miR-149. Further functional assays revealed that the overexpression of miR-149 and knockdown of XIAP considerably inhibited GC cell viability and its migratory and invasive characteristics in vitro. SLCO4A1-AS1 knockdown also determined the function of GC cells but was diminished by the miR-149 inhibitor in vitro. Finally, we demonstrated that the deletion of SLCO4A1-AS1 suppressed tumor growth and metastasis in vivo. CONCLUSIONS: Altogether, these findings suggest that SLCO4A1-AS1 functions as a crucial oncogenic lncRNA in GC and it can facilitate GC tumor growth and metastasis by interacting with miR-149 and enhancing XIAP expression. Therefore, SLCO4A1-AS1 is a potential novel therapeutic target in GC treatment.

The lncRNA SLCO4A1-AS1/miR-876-3p/RBBP6 axis regulates cell proliferation and apoptosis in acute lymphocytic leukemia via the JNK signaling pathway.

INTRODUCTION: Acute lymphocytic leukemia (ALL) is a hematologic malignancy caused by the clonal proliferation of immature lymphocytes. Long noncoding RNAs (lncRNAs) have been reported as critical regulators in several cancers, including ALL. LncRNA SLCO4A1 antisense RNA 1 (SLCO4A1-AS1) has been revealed to be implicated in tumorigenesis of several cancers. Our study focused on the role of SLCO4A1-AS1 in ALL. METHODS: RT-qPCR, Western blot analysis, CCK-8, EdU, and Flow cytometry analysis were used to explore the biological function of SLCO4A1-AS1 in ALL cellular processes. Luciferase reporter and RNA pull-down assays were applied to explore the mechanism of SLCO4A1-AS1 in ALL cells. RESULTS: SLCO4A1-AS1 was upregulated in ALL tissues and cell lines. We found that suppression of SLCO4A1-AS1 suppressed ALL cell proliferation and facilitated cell apoptosis. Our result confirmed that SLCO4A1-AS1 acted as a ceRNA by sponging microRNA 876-3p (miR-876-3p) to upregulate retinoblastoma binding protein 6 (RBBP6) expression in ALL cells. Moreover, SLCO4A1-AS1 activated the JNK signaling pathway by upregulating RBBP6. Rescue assays revealed that the activation of the JNK signaling or overexpression of RBBP6 revered the suppressive effect of SLCO4A1-AS1 knockdown on growth of ALL cells. CONCLUSION: SLCO4A1-AS1 promoted cell growth of ALL by the miR-876-3p/RBBP6 axis to activate the JNK signaling pathway.

Long non-coding RNA SLCO4A1-AS1 drives the progression of non-small-cell lung cancer by modulating miR-223-3p/IKKα/NF-κB signaling.

Globally, lung cancer is known as a major cause of cancer-associated death and non-small-cell lung cancer (NSCLC) accounts for majority of all cases. Growing evidence has emerged that long non-coding RNAs (lncRNAs) act as vital regulatory molecules in various malignancies. Nevertheless, the function of SLCO4A1 antisense RNA 1(SLCO4A1-AS1) in NSCLC is vague. This study intended to investigate the biological role and probable regulatory mechanism of SLCO4A1-AS1 in NSCLC. qRT-PCR revealed that SLCO4A1-AS1 level was upregulated in NSCLC. Function assays manifested that silence of SLCO4A1-AS1 attenuated NSCLC cell proliferation, migration and invasion but promoted NSCLC cell apoptosis. Furthermore, we disclosed that SLCO4A1-AS1 activated NF-κB pathway in NSCLC, and that IKKα, an NF-κB pathway-related gene, possessed an enhanced level in NSCLC tissues and cells. Importantly, miR-223-3p bound with SLCO4A1-AS1 and IKKα. Further, SLCO4A1-AS1 competitively bound with miR-223-3p to increase IKKα expression, thereby activating NF-κB signaling pathway. In conclusion, SLCO4A1-AS1 drove NSCLC progression by activating NF-κB signaling pathway via sponging miR-223-3p to enhance IKKα expression. Thus, SLCO4A1-AS1 might be a promising biomarker for NSCLC treatment.

SLCO4A1-AS1 promotes cell growth and induces resistance in lung adenocarcinoma by modulating miR-4701-5p/NFE2L1 axis to activate WNT pathway.

Long noncoding RNAs (lncRNAs) possessed essential functions in the biological behaviors of various human cancers. SLCO4A1 antisense RNA 1 (SLCO4A1-AS1) is a lncRNA that has been reported as a oncogenic regulator in colorectal cancer and bladder cancer. However, whether it exerted functions in the gene expression and cellular processes in lung adenocarcinoma (LUAD) remains still obscure. In the present research, we unveiled the high level of SLCO4A1-AS1 in LUAD tissues and cells. Moreover, functional assays indicated that SLCO4A-AS1 facilitated LUAD cell proliferation, motility, and cisplatin-resistance. Besides, mechanism investigation revealed that miR-4701-5p could interact with SLCO4A1-AS1 and directly target to NFE2L1. The expression correlation between miR-4701-5p and SLCO4A1-AS1 or NFE2L1 was found to be negative. Moreover, NFE2L1 was expressed at a same tendency with SLCO4A1-AS1 in LUAD tissues and cells. In addition, it was confirmed that NFE2L1 was involved in SLCO4A1-AS1-mediated activation of WNT pathway. According to rescue assays, NFE2L1 could involve in SLCO4A1-AS1-mediated LUAD cell growth. Conclusively, our study demonstrated that SLCO4A1-AS1 facilitated cell growth and enhanced the resistance of LUAD cells to chemotherapy via activating WNT pathway through miR-4701-5p/NFE2L1 axis.

lncRNA SLCO4A1-AS1 promotes growth and invasion of bladder cancer through sponging miR-335-5p to upregulate OCT4.

BACKGROUND: Bladder cancer (BC) is among the most frequently occurring cancer types in the urinary system. In recent years, the importance of lncRNAs in BC has been acknowledged. SLCO4A1-AS1 is an oncogene in colorectal cancer. However, the role of SLCO4A1-AS1 in BC remains unknown. MATERIALS AND METHODS: The expression levels of SLCO4A1-AS1 in BC tissues were analyzed by qRT-PCR. The effects of SLCO4A1-AS1 knockdown on proliferation were determined by CCK8 assay. Transwell assay was used to evaluate the role of SLCO4A1-AS1 on migration and invasion. Furthermore, xenograft assay was utilized to test the effect of SLCO4A1-AS1 on BC growth in vivo. RESULTS: SLCO4A1-AS1 expression was more upregulated in BC tissues than in adjacent normal tissues. Moreover, SLCO4A1-AS1 level was positively correlated with the advanced stage and metastasis in BC. The upregulation of SLCO4A1-AS1 indicates poor prognosis in BC patients. The knockdown of SLCO4A1-AS1 downregulated the proliferation, migration, and invasion of EJ and T24 cells in vitro. In addition, the loss of SLCO4A1-AS1 prevented BC growth in vivo. Mechanistic investigation showed that SLCO4A1-AS1 was the sponge for miR-335-5p, and miR-335-5p modulated OCT4 expression. CONCLUSION: High SLCO4A1-AS1 expression level was associated with the progression of BC, and SLCO4A1-AS1 promoted the malignant phenotypes of BC cells through the miR-335-5p/OCT4 axis.

LncRNA SLCO4A1-AS1 promotes colorectal cancer cell proliferation by enhancing autophagy via miR-508-3p/PARD3 axis.

Aberrant expressions of various long non-coding RNAs (lncRNAs) have been involved in the progression and pathogenesis of various carcinomas. However, the expression and biological function of SLCO4A1-AS1 in colorectal cancer (CRC) remain poorly understood. Gain- and loss-of-function assays were applied to determine the roles of SLCO4A1-AS1 in autophagy and CRC progression. qRT-PCR and in situ hybridization (ISH) results showed that SLCO4A1-AS1 was positively associated with PARD3 expression in CRC tissues. In vitro and in vivo studies revealed that SLCO4A1-AS1 knockdown repressed cytoprotective autophagy as assayed by transmission electron microscopy (TEM), and inhibited cell proliferation by directly targeting partition-defective 3 (PARD3). Mechanistically, SLCO4A1-AS1 acted as a sponge of miR-508-3p, leading to upregulation of PARD3 and promotion of CRC cell proliferation. The current study demonstrates that the SLCO4A1-AS1/miR-508-3p/PARD3/autophagy pathway play a critical role in CRC cell proliferation, and might provide novel targets for developing therapeutic strategies for CRC.

LncRNA SLCO4A1-AS1 predicts poor prognosis and promotes proliferation and metastasis via the EGFR/MAPK pathway in colorectal cancer.

It is universally acknowledged that long non-coding RNAs (lncRNAs) involved in tumorigenesis in human cancers. However, the function and mechanism of many lncRNAs in colorectal cancer (CRC) remain unclear. By analyzing the two sets of CRC-related gene microarrays data, downloaded from the Gene Expression Omnibus (GEO) database and the lncRNA expression in a set of RNA sequencing data, we found that lncRNA SLCO4A1-AS1 was significantly upregulated in CRC tissues. We then collected CRC tissue samples and verified that SLCO4A1-AS1 is highly expressed in CRC tissues. Furthermore, SLCO4A1-AS1 was also upregulated in the CRC cell line. In situ hybridization results showed that high expression of SLCO4A1-AS1 was associated with poor prognosis in patients with CRC. Next, we found that SLCO4A1-AS1 promoted CRC cell proliferation, migration, and invasion. Results of western blotting assays show that its mechanism may relate to the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) pathway. Therefore, SLCO4A1-AS1 may be a potential biomarker for CRC prognosis and a new target for colorectal cancer therapy.

LncRNA SLCO4A1-AS1 facilitates growth and metastasis of colorectal cancer through ß-catenin-dependent Wnt pathway.

BACKGROUND: Emerging evidence has shown long noncoding RNAs (lncRNAs) exert important roles in colorectal cancer (CRC) tumorigenesis. However, most lncRNAs involved in this process remain undefined and the underlying molecular mechanisms mediated by lncRNAs are largely unknown. METHODS: An unbiased screening was used to identify novel lncRNAs involved in CRC according to an online-available data dataset. In situ hybridization (ISH) and qRT-PCR was used to detect lncRNA expression patterns. CCK8, colony formation, fluorescence activated cell sorter (FACS), transwell, xenograft nude mouse model and western blot assays were used to analyze the functions of SLCO4A1-AS1. RNA-pulldown, western blot, RNA fluorescence in situ hybridization (RNA-FISH) and electrophoretic mobility shift assay (EMSA) assays were utilized to explore the molecular mechanism of SLCO4A1-AS1. RESULTS: LncRNA SLCO4A1-AS1 was significantly upregulated in CRC tissues and its overexpression was closely related with poor prognosis and tumor metastasis. By knocking down SLCO4A1-AS1, we found that SLCO4A1-AS1 promoted the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of CRC cells in vitro, as well as inhibited cell apoptosis. Moreover, SLCO4A1-AS1 dramatically delayed tumor propagation in vivo. Mechanistically, SLCO4A1-AS1 activates Wnt/ß-catenin signaling. SLCO4A1-AS1 enhanced the stability of ß-catenin by impairing the interaction of ß-catenin with GSKß and inhibiting its phosphorylation. Finally, restoration of ß-catenin protein level rescued the proliferation, migration and invasion in SLCO4A1-AS1-depleted CRC cells. CONCLUSION: SLCO4A1-AS1 serves as an oncogenic role in CRC through activating Wnt/ß-catenin signaling pathway. And SLCO4A1-AS1 might be a useful biomarker for CRC diagnosis and prognosis.