LINC00355 promotes gastric carcinogenesis by scaffolding p300 to activate CDC42 transcription and enhancing HNRNPA2B1 to stabilize CDC42 mRNA dependent on m6A.

LINC00355 is involved in the tumorigenesis of several types of cancer. We verified that LINC00355 is upregulated in gastric cancer (GC) and contributes to GC cells' proliferation and metastasis. RNA sequencing (RNA-seq) and rescue assays suggested that LINC00355 controls gastric carcinogenesis by regulating the expression of cell division cycle 42 (CDC42) guanosine triphosphatase (GTPases), thereby activating their downstream pathways. Most previous studies have shown that LINC00355 acts as a ceRNA by sponging miRNAs to modulate downstream gene expression. Our group focus on epigenetic regulatory potential of LINC00355 in gene expression. Mechanistically, LINC00355 binds to p300 histone acetyltransferase, specifying the histone modification pattern on the CDC42 promoter to activate CDC42 transcription, thereby altering GC cell biology. In addition, HNRNPA2B1, which is upregulated by LINC00355, recognizes the N6-methyladenosine (m6A) sites of CDC42 and enhances the stability of CDC42 mRNA transcripts. Therefore, LINC00355 is mechanistically, functionally, and clinically oncogenic in GC cells.

LINC_00355 promotes gastric cancer progression by upregulating PHF19 expression through sponging miR-15a-5p.

BACKGROUND: Long non-coding RNAs exert vital roles in several types of cancer. The objective of this study was to explore the role of LINC_00355 in gastric cancer (GC) progression and its potential mechanism. METHODS: The expression levels of LINC_00355 in GC tissues and cells were detected by quantitative real-time PCR, followed by assessing the effects of LINC_00355 knockdown or overexpression on cell properties. Dual-luciferase reporter assay was utilized to identify the relationship between LINC_00355 and microRNA (miR)-15a-5p and miR-15a-5p and PHD finger protein 19 (PHF19), followed by the rescue experiments. RESULTS: The results showed that LINC_00355 was highly expressed in GC tissues and cells compared with the corresponding control. LINC_00355 knockdown decreased the viability, migration, and invasion and increased the accumulation of GC cells in G1 phase and apoptosis. Meanwhile, LINC_00355 downregulation markedly increased cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase protein levels, whereas decreased cyclin D1, cyclin E, matrix metalloproteinase (MMP) 9, MMP2, and N-cadherin protein levels in GC cells. However, LINC_00355 overexpression had the opposite effects. It was verified that LINC_00355 upregulated the expression of PHF19 through sponging miR-15a-5p. Furthermore, PHF19 overexpression reversed the effect of LINC_00355 knockdown on GC cell properties, including cell viability, migration, invasion, and apoptosis. CONCLUSIONS: Collectively, these results suggest that LINC_00355 promotes GC progression by up-regulating PHF19 through sponging miR-15a-5p. Our findings may provide an important clinical basis for reversing the malignant phenotype of GC.

Exosomal LINC00355 derived from cancer-associated fibroblasts promotes bladder cancer cell proliferation and invasion by regulating miR-15a-5p/HMGA2 axis.

We have previously demonstrated that exosomes derived from cancer-associated fibroblasts (CAFs) promote bladder cancer (BC) cell proliferation and invasion by transferring LINC00355. In this study, the molecular mechanisms underlying the pro-bladder cancer action of exosomal LINC00355 were explored. CAFs were obtained from BC tumor tissues, and normal fibroblasts (NFs) were obtained from adjacent normal tissues. Human BC cell lines (T24 and 5367) were incubated with NF-Exo (exosomes from NFs), CAF-Exo (exosomes from CAFs), CAFsi-Ctrl-Exo (exosomes from si-Ctrl-transfected CAFs), and CAFsi-LINC00355-Exo (exosomes from si-LINC00355-transfected CAFs). BC cell proliferation and invasion were evaluated by MTT and Transwell assays, respectively. The interaction between miR-15a-5p and LINC00355 or HMGA2 was examined by online bioinformatics analysis and luciferase activity assay. Results showed that HMGA2 is a direct target of miR-15a-5p, and LINC00355 functions as a sponge of miR-15a-5p to upregulate HMGA2 expression. The promoting effects of CAF-Exo on HMGA2 expression, cell proliferation, and cell invasion were hindered when LINC00355 expression was inhibited in BC cells. These promoting effects were also hindered when miR-15a-5p was overexpressed or HMGA2 was silenced in BC cells. In conclusion, exosomal LINC00355 derived from CAFs promotes BC cell proliferation and invasion by regulating miR-15a-5p/HMGA2 axis.

Exosomal LINC00355 derived from cancer-associated fibroblasts promotes bladder cancer cell resistance to cisplatin by regulating miR-34b-5p/ABCB1 axis.

Cisplatin resistance is a major challenge for bladder cancer (BC). Evidence indicates that exosome derived from cancer-associated fibroblasts (CAF-Exo) can promote chemotherapy resistance in various human tumors by delivering bioactive molecules. We have previously demonstrated that CAF-derived exosomal LINC00355 promotes BC cell proliferation and invasion. However, the underlying mechanisms are still unclear. In this study, we aimed to investigate the role and mechanisms of CAF-derived exosomal LINC00355 in BC cell resistance to cisplatin. Exosomes were isolated from normal fibroblasts (NFs) and BC tumor-derived CAFs, namely, NF-Exo and CAF-Exo. CAFs were transfected with si-Ctrl or si-LINC00355 and then different exosomes were isolated, namely, CAFsi-Ctrl-Exo and CAFsi-LINC00355-Exo. The human BC cell lines (T24 and 5367) were incubated with NF-Exo, CAF-Exo, CAFsi-Ctrl-Exo, and CAFsi-LINC00355-Exo in the presence of cisplatin. MTT proliferation assay and flow cytometric analysis showed that CAF-Exo promoted BC cell resistance to cisplatin and upregulated ABCB1 expression in BC cells by transferring LINC00355 to BC cells. Luciferase activity assay confirmed the interaction between miR-34b-5p and LINC00355 or ABCB1. qRT-PCR and western blot analysis further showed that LINC00355 sponged miR-34b-5p to upregulate ABCB1 expression. However, the promoting effects of CAF-Exo on BC cell resistance to cisplatin were abolished by miR-34b-5p overexpression and ABCB1 silencing. In conclusion, exosomal LINC00355 derived from CAFs promotes BC cell resistance to cisplatin by regulating the miR-34b-5p/ABCB1 axis.

Cancer-associated fibroblasts-derived exosomes-mediated transfer of LINC00355 regulates bladder cancer cell proliferation and invasion.

The aim of this study was to investigate the regulatory mechanism of cancer-associated fibroblasts (CAFs) exosome in bladder cancer (BC) cell proliferation and invasion. CAFs and normal fibroblasts (NFs) were isolated from tumor tissues and adjacent normal tissues of BC patients, and examined by immunocytochemistry for the expression of fibroblast activation protein alpha (FAP) and α-smooth muscle actin (α-SMA). Exosomes were extracted from CAFs and NFs and observed under a transmission electron microscope, and expression of the exosome markers CD9 and CD63 was confirmed by western blotting. The distribution and intensity of fluorescence were observed by confocal laser microscopy to analyze exosomes uptake by BC cell lines T24 or 5367. BC cell proliferation and invasion were detected by MTT and Transwell assays, respectively. LINC00355 levels in CAFs, NFs, CAFs exosome, NFs exosome, and BC cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Results showed that CAFs exosome significantly promoted BC cell proliferation and invasion relative to NFs exosome. LINC00355 expression was significantly elevated in CAFs exosome when compared with that in NFs-exosome. Up-regulated LINC00355 expression was observed both in T24 and 5367 cells co-incubated with CAFs exosome. Exosomes derived from LINC00355 siRNA-transfected CAFs observably repressed BC cell proliferation and invasion when compared with control siRNA-CAFs exosome. In conclusion, CAFs exosome-mediated transfer of LINC00355 regulates BC cell proliferation and invasion. Significance of the study. In this study, our data suggest that the exosomes released from CAFs promote BC cell proliferation and invasion. The mechanism of this effect is, at least in part, related to the increased LINC00355. Regulation of LINC00355 expression in exosomes released from CAFs might be a putative therapeutic strategy against the pathogenesis of BC.

LINC00355 Mediates CTNNBIP1 Promoter Methylation and Promotes Endoplasmic Reticulum Stress-Induced Podocyte Injury in Diabetic Nephropathy.

Aims: Endoplasmic reticulum stress (ER stress) plays an important role in podocyte injury in diabetic nephropathy. Wnt/ß-catenin signaling modulates ER stress, yet the epigenetic regulation of ß-catenin in ER stress and podocyte injury remains largely unknown. Herein, we tested the hypothesis that LINC00355 recruits EZH1 to the promoter region of CTNNBIP1 and trimethylates H3K4 to regulate ER-stress induced podocyte injury in DN. Results: LINC00355 is upregulated in podocytes and correlates with renal function decline in DN patients. LINC00355 localizes in the nucleus and exerts biological functions by directly binding EZH1, which epigenetically targets CTNNBIP1 through repressive trimethylation of H3K4 and activates Wnt/ß-catenin signaling and ER stress. Further, we provide mechanistic evidences that LINC00355 recruits EZH1 to the promoter region of CTNNBIP1 and regulates ER-stress induced podocyte injury in DN. Innovation and Conclusion: Our data reveal a major role of LINC00355/EZH1/CTNNBIP1 network in triggering podocyte injury, providing new evidences for understanding the role of ER stress in DN. Antioxid. Redox Signal. 39, 225-240.

Current insights into the oncogenic roles of lncRNA LINC00355.

Long noncoding RNAs (lncRNAs) are a class of nonprotein-coding transcripts that are longer than 200 nucleotides. LINC00355 is a lncRNA located on chromosome 13q21.31 and is consistently upregulated in various cancers. It regulates the expression of downstream genes at both transcriptional and posttranscriptional levels, including eight microRNAs (miR-15a-5p, miR-34b-5p, miR-424-5p, miR-1225, miR-217-5p, miR-6777-3p, miR-195, and miR-466) and three protein-coding genes (ITGA2, RAD18, and UBE3C). LINC00355 plays a role in regulating various biological processes such as cell cycle progression, proliferation, apoptosis, epithelial-mesenchymal transition, invasion, and metastasis of cancer cells. It is involved in the regulation of the Wnt/ß-catenin signaling pathway and p53 signaling pathway. Upregulation of LINC00355 has been identified as a high-risk factor in cancer patients and its increased expression is associated with poorer overall survival, recurrence-free survival, and disease-free survival. LINC00355 upregulation has been linked to several unfavorable clinical characteristics, including advanced tumor node metastasis and World Health Organization stages, reduced Karnofsky Performance Scale scores, increased tumor size, greater depth of invasion, and more extensive lymph node metastasis. LINC00355 induces chemotherapy resistance in cancer cells by regulating five downstream genes, namely HMGA2, ABCB1, ITGA2, WNT10B, and CCNE1 genes. In summary, LINC00355 is a potential oncogene with great potential as a diagnostic marker and therapeutic target for cancer.

Exosomal LINC00355 promotes the malignant progression of gastric cancer through histone deacetylase HDAC3-mediated TP53INP1 transcriptional inhibition.

AIMS: Exosomes are a subpopulation of extracellular vesicles (EV) derived from multivesicular body (MVB) that transmit various cellular molecular constituents, including long noncoding RNAs (lncRNAs), to promote intercellular communication. Our aim was to investigate the function and mechanism of exosomal LINC00355 in gastric cancer cells. MAIN METHODS: Exosomal levels of LINC00355 in GC patients and healthy controls were measured by RT-qPCR. The effects of exosomal LINC00355 on GC cell viability, proliferation, migration and invasion were evaluated by CCK8, colony formation, Transwell and wound healing assays. The expression levels of Ki67 in xenograft tumor tissues were confirmed by immunohistochemistry assay, and apoptosis was analyzed by TUNEL apoptosis assay. Western blotting was used to monitor protein expression. RNA immunoprecipitation and RNA pulldown were performed to detect the interaction between LINC00355 and HDAC3. Chromatin immunoprecipitation was used to assess the interaction of HDAC3 with the TP53INP1 promoter. KEY FINDINGS: Exosomal LINC00355 levels were higher in plasma from gastric cancer patients than in plasma from healthy volunteers. Exosomal LINC00355 promoted the proliferation, migration and invasion of gastric cancer cell lines. RNA sequence analysis demonstrated that LINC00355 knockdown downregulated histone deacetylase HDAC3 and upregulated TP53INP1. Mechanistic investigation indicated that exosomal LINC00355 interacted with HDAC3 to suppress TP53INP1 transcription, which promoted epithelial-mesenchymal transition (EMT). SIGNIFICANCE: Exosomal LINC00355 plays a pivotal role in regulating EMT to induce the malignant progression of GC. Exosomal LINC00355 could be a promising biomarker in the early diagnosis and prognosis of GC.

A novel long non-coding RNA LINC00355 promotes proliferation of lung adenocarcinoma cells by down-regulating miR-195 and up-regulating the expression of CCNE1.

Lung adenocarcinoma is the most common subtype of non-small-cell lung cancer affecting people all over the globe. Recent studies have indicated that long non-coding RNAs (lncRNAs) possess the ability to regulate gene expression. Initially, we uncovered increased LINC00355 expressions in lung adenocarcinoma tissues and cells. Functionally, our findings demonstrated that LINC00355 silencing suppressed the proliferation in vitro and in vivo. In addition, we found that LINC00355 negatively regulated miR-195 in lung adenocarcinoma cells. Simultaneously, silencing LINC00355 by shRNA resulted in suppressed proliferation, colony formation and promoted cell cycle arrest and apoptosis via miR-195. Moreover, silencing LINC00355 by shRNA inhibited the cyclin E1 (CCNE1) gene expression via miR-195 in lung adenocarcinoma cells. Collectively, this study demonstrates the novel lncRNA LINC00355 in regulatory network of CCNE1 via miR-195 in lung adenocarcinoma, highlighting LINC00355 as a new target for the treatment of lung adenocarcinoma.

Long Non-Coding RNA LINC00355 Promotes the Development and Progression of Colorectal Cancer by Elevating Guanine Nucleotide Exchange Factor T Expression via RNA Binding Protein lin-28 Homolog A.

BACKGROUND: Our previous study showed that guanine nucleotide exchange factor T (GEFT) was highly expressed in colorectal cancer (CRC) tissues and CRC patients with high GEFT expression had a poor prognosis, and suggested the close link of GEFT expression and CRC tumorigenesis/metastasis. In this text, the roles and upstream regulatory mechanisms of GEFT in the development and progression of CRC were further investigated. METHODS: Expression levels of GEFT mRNA and LINC00355 was measured by RT-qPCR assay. Protein levels of lin-28 homologue A (LIN28A) and GEFT were determined by western blot assay. Cell proliferative, migratory, and invasive capacities were assessed by CCK-8, Transwell migration and invasion assays, respectively. The effect of GEFT knockdown on CRC tumorigenesis was examined by mouse xenograft experiments in vivo. GEFT mRNA stability was examined by actinomycin D assay. The relationships of LINC000355, LIN28A, and GEFT were explored by RNA pull down and RIP assays. RESULTS: GEFT was highly expressed in CRC tissues and cell lines. GEFT knockdown inhibited CRC cell proliferation, migration, and invasion, and hindered CRC xenograft tumor growth. GEFT overexpression alleviated the detrimental effects of LINC00355 loss on CRC cell proliferation, migration, and invasion. LINC00355 promoted GEFT expression and enhanced GEFT mRNA stability via LIN28A. LIN28A knockdown weakened the promotive effect of LINC00355 on CRC cell proliferation, migration, and invasion. CONCLUSION: LINC00355 facilitated CRC tumorigenesis and progression by increasing GEFT expression via LIN28A, deepening our understanding on roles and upstream regulatory mechanisms of GEFT in CRC development and progression.

LINC00355:8 promotes cell proliferation and migration with invasion via the MiR-6777-3p/Wnt10b axis in Hepatocellular Carcinoma.

Background: Recent studies have reported that various long non-coding RNAs (lncRNAs) promote hepatocellular carcinoma (HCC) progression, and our previous study indicated that lncRNA LINC00355:8 is overexpressed in HCC. However, the role of LINC00355:8 in HCC is unclear. The primary aim of this study was to explore the biological role of LINC00355:8 in HCC. Methods: Microarray analysis was performed to explore the aberrantly expressed lncRNAs in HCC compared with precancerous tissues. Real-time PCR and in situ hybridization were used to investigate the expression of LINC00355:8 in HCC tissues. CCK8, EdU, colony formation, wound healing and transwell assays were performed to analyse cell proliferation, migration and invasion. A xenograft tumour model was established to analyse the effect of LINC00355:8 on tumour growth in vivo. Luciferase assays were utilized to explore the binding sites between miR-6777-3p and other genes, such as LINC00355:8 and Wnt10b. After cell transfection, the protein expression levels of Wnt10b, ß-catenin, E-cadherin, N-cadherin, c-Myc and Snail were determined by Western blotting. Results: The present study revealed that LINC00355:8 was significantly upregulated in HCC, promoted HCC cell proliferation, migration and invasion in vitro and enhanced tumour growth in vivo. LINC00355:8 regulated miR-6777-3p expression by acting as a ceRNA, and the expression of Wnt10b was negatively modulated by miR-6777-3p. Moreover, LINC00355:8 could activate the Wnt/ß-catenin signalling pathway and promote EMT progression by inhibiting the miR-6777-3p/Wnt10b interaction in HCC. Conclusion: Our findings indicate that LINC00355:8 activates Wnt10b and promotes HCC progression via the suppression of miR-6777-3p, which may provide novel therapeutic targets for HCC.

LINC00355 promoted the progression of lung squamous cell carcinoma through regulating the miR-466/LYAR axis

LINC00355 has been reported aberrantly over-expressed and associated with poor prognosis in various types of cancer. However, reports regarding the effect of LINC00355 on lung squamous cell carcinoma (SCC) are rare. This study aimed to explore the function of LINC00355 in the development and progression of lung SCC and reveal the underlying mechanism. The expression and subcellular location of LINC00355 were determined by qRT-PCR and RNA-FISH, respectively. The lung SCC cell growth was analyzed by CCK-8 assay, transwell invasion, wound healing, colony formation, and flow cytometry assays. Reactive oxygen species level was evaluated by DCFH-DA probes. Bioinformatics online websites, luciferase reporter assay, RNA binding protein immunoprecipitation (RIP), and RNA pull-down assays were utilized to investigate the interaction among LINC00355, miR-466, and Ly-1 antibody reactive clone (LYAR). The results showed that LINC00355 was upregulated in lung SCC and was positively associated with poor overall survival in lung SCC patients. LINC00355 was mainly located in the cytoplasm of SCC cells. Additionally, LINC0035 functioned as a competing endogenous RNA (ceRNA) to target miR-466, and LYAR was identified as a direct target of miR-466. LINC00355 expression negatively correlated with miR-466 level, and positively correlated with LYAR level. Mechanistically, knockdown of LINC00355 inhibited cell proliferation, migration and invasion, promoted cell apoptosis in vitro, and suppressed tumor growth in vivo through targeting miR-466, and thus down-regulated LYAR expression. These findings provide a new sight for understanding the molecular mechanism of lung SCC and indicate that LINC00355 may serve as a potential biomarker for the diagnosis and treatment of lung SCC.