METTL1-mediated tRNA m7G methylation and translational dysfunction restricts breast cancer tumorigenesis by fueling cell cycle blockade.

BACKGROUND: RNA modifications of transfer RNAs (tRNAs) are critical for tRNA function. Growing evidence has revealed that tRNA modifications are related to various disease processes, including malignant tumors. However, the biological functions of methyltransferase-like 1 (METTL1)-regulated m7G tRNA modifications in breast cancer (BC) remain largely obscure. METHODS: The biological role of METTL1 in BC progression were examined by cellular loss- and gain-of-function tests and xenograft models both in vitro and in vivo. To investigate the change of m7G tRNA modification and mRNA translation efficiency in BC, m7G-methylated tRNA immunoprecipitation sequencing (m7G tRNA MeRIP-seq), Ribosome profiling sequencing (Ribo-seq), and polysome-associated mRNA sequencing were performed. Rescue assays were conducted to decipher the underlying molecular mechanisms. RESULTS: The tRNA m7G methyltransferase complex components METTL1 and WD repeat domain 4 (WDR4) were down-regulated in BC tissues at both the mRNA and protein levels. Functionally, METTL1 inhibited BC cell proliferation, and cell cycle progression, relying on its enzymatic activity. Mechanistically, METTL1 increased m7G levels of 19 tRNAs to modulate the translation of growth arrest and DNA damage 45 alpha (GADD45A) and retinoblastoma protein 1 (RB1) in a codon-dependent manner associated with m7G. Furthermore, in vivo experiments showed that overexpression of METTL1 enhanced the anti-tumor effectiveness of abemaciclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor. CONCLUSION: Our study uncovered the crucial tumor-suppressive role of METTL1-mediated tRNA m7G modification in BC by promoting the translation of GADD45A and RB1 mRNAs, selectively blocking the G2/M phase of the cell cycle. These findings also provided a promising strategy for improving the therapeutic benefits of CDK4/6 inhibitors in the treatment of BC patients.

EIF4A3-mediated circ_0042881 activates the RAS pathway via miR-217/SOS1 axis to facilitate breast cancer progression.

Breast cancer (BC) is one of the most frequent cancer-related deaths in women worldwide. Studies have shown the potential impact of circRNAs in multiple human tumorigeneses. Research on the vital signaling pathways and therapeutic targets of circRNAs is indispensable. Here, we aimed to investigate the clinical implications and underlying mechanisms of circ_0042881 in BC. RT-qPCR validated circ_0042881 was notably elevated in BC tissues and plasma, and closely associated with BC clinicopathological features. Functionally, circ_0042881 significantly accelerated the proliferation, migration, and invasion of BC cells in vitro and tumor growth and metastasis in vivo. Mechanistically, circ_0042881 promoted BC progression by sponging miR-217 to relieve its inhibition effect in son of sevenless 1 (SOS1), which further activated RAS protein and initiated downstream signaling cascades, including MEK/ERK pathway and PI3K/AKT pathway. We also demonstrated that treatment of BAY-293, an inhibitor of SOS1 and RAS interaction, attenuated BC progression induced by circ_0042881 overexpression. Furthermore, Eukaryotic initiation factor 4A-III (EIF4A3) could facilitate circ_0042881 circularization. Altogether, we proposed a novel signaling network in which circ_0042881, induced by EIF4A3, influences the process of BC tumorigenesis and metastasis by miR-217/SOS1 axis.

N6-methyladenosine modification of REG1α facilitates colorectal cancer progression via ß-catenin/MYC/LDHA axis mediated glycolytic reprogramming.

Aerobic glycolysis has been considered as a hallmark of colorectal cancer (CRC). However, the potential functional regulators of glycolysis in CRC remains to be elucidated. In the current study, we found that Regenerating islet-derived protein 1-alpha (REG1α) was significantly increased in both CRC tissues and serum, and positively associated with CRC patients' lymph node metastasis, advanced tumor stage, and unfavorable prognosis. Ectopic expression of REG1α contributed to various tumorigenic properties, including cell proliferation, cell cycle, migration, invasion, and glycolysis. In contrast, REG1α deficiency in CRC cells attenuated malignant properties and glucose metabolism. Mechanically, REG1α promoted CRC proliferation and metastasis via ß-catenin/MYC axis-mediated glycolysis upregulation. Moreover, the malignant behaviors governed by REG1α could be effectively abolished by silencing of Wnt/ß-catenin/MYC axis or glycolysis process using specific inhibitors. Besides, REG1α expression was mediated by METTL3 in an m6A-dependent manner. Overall, our work defines a novel regulatory model of the METTL3/REG1α/ß-catenin/MYC axis in CRC, which indicates that REG1α could function as a novel biomarker and a potential therapeutic target for patients with CRC.

When N7-methyladenosine modification meets cancer: Emerging frontiers and promising therapeutic opportunities.

N7-methylguanosine (m7G) methylation, one of the most common RNA modifications in eukaryotes, has recently gained considerable attention. The biological functions of m7G modification in RNAs, including tRNA, rRNA, mRNA, and miRNA, remain largely unknown in human diseases. Owing to rapid advances in high-throughput technologies, increasing evidence suggests that m7G modification plays a critical role in cancer initiation and progression. As m7G modification and hallmarks of cancer are inextricably linked together, targeting m7G regulators may provide new possibilities for future cancer diagnoses and potential intervention targets. This review summarizes various detection methods for m7G modification, recent advances in m7G modification and tumor biology regarding their interplay and regulatory mechanisms. We conclude with an outlook on the future of diagnosing and treating m7G-related diseases.

IGF2BP2-induced circRUNX1 facilitates the growth and metastasis of esophageal squamous cell carcinoma through miR-449b-5p/FOXP3 axis.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common digestive malignancies with relatively high morbidity and mortality. Emerging evidence suggests circular RNAs (circRNAs) play critical roles in tumor cell malignancy. However, the biological function and clinical significance of many circRNAs in ESCC remain elusive. METHODS: The expression level and clinical implication of circRUNX1 in ESCC tissues were evaluated using qRT-PCR. In vitro and in vivo functional studies were conducted to investigate the underlying biological effects of circRUNX1 on ESCC cell growth and metastasis. Moreover, bioinformatics analysis, RNA sequencing (RNA-seq), RNA immunoprecipitation (RIP) assays, dual-luciferase reporter assays, and rescue experiments were performed to explore the relationships between circRUNX1, miR-449b-5p, Forkhead box protein P3 (FOXP3), and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). RESULTS: CircRUNX1 was found to be significantly up-regulated in ESCC tissues and associated with TNM stage and differentiation grade. Functionally, circRUNX1 promoted ESCC cell proliferation and metastasis in vitro and in vivo. CircRUNX1 enhanced FOXP3 expression by competitively sponging miR-449b-5p. Notably, both miR-449b-5p mimics and FOXP3 knockdown restored the effects of circRUNX1 overexpression on cell proliferation and metastasis. Furthermore, IGF2BP2 binding to circRUNX1 prevented its degradation. CONCLUSIONS: IGF2BP2 mediated circRUNX1 functions as an oncogenic factor to facilitate ESCC progression through the miR-449b-5p/FOXP3 axis, implying that circRUNX1 has the potential to be a promising diagnostic marker and therapeutic target for ESCC patients.

Novel insights into m6A modification of coding and non-coding RNAs in tumor biology: From molecular mechanisms to therapeutic significance.

Accumulating evidence has revealed that m6A modification, the predominant RNA modification in eukaryotes, adds a novel layer of regulation to the gene expression. Dynamic and reversible m6A modification implements sophisticated and crucial functions in RNA metabolism, including generation, splicing, stability, and translation in messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs). Furthermore, m6A modification plays a determining role in producing various m6A-labeling RNA outcomes, thereby affecting several functional processes, including tumorigenesis and progression. Herein, we highlighted current advances in m6A modification and the regulatory mechanisms underlying mRNAs and ncRNAs in distinct cancer stages. Meanwhile, we also focused on the therapeutic significance of m6A regulators in clinical cancer treatment.

Current advances and future perspectives on the functional roles and clinical implications of circular RNAs in esophageal squamous cell carcinoma: more influential than expected.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive gastrointestinal cancers with high incidence and mortality. Therefore, it is necessary to identify novel sensitive and specific biomarkers for ESCC detection and treatment. Circular RNAs (circRNAs) are a type of noncoding RNAs featured by their covalently closed circular structure. This special structure makes circRNAs more stable in mammalian cells, coupled with their great abundance and tissue specificity, suggesting circRNAs may present enormous potential to be explored as valuable prognostic and diagnostic biomarkers for tumor. Mounting studies verified the critical roles of circRNAs in regulating ESCC cells malignant behaviors. Here, we summarized the current progresses in a handful of aberrantly expressed circRNAs, and elucidated their biological function and clinical significance in ESCC, and introduced a series of databases for circRNA research. With the improved advancement in high-throughput sequencing and bioinformatics technique, new frontiers of circRNAs will pave the path for the development of precision treatment in ESCC.

Long non-coding RNA BBOX1-AS1 exacerbates esophageal squamous cell carcinoma development by regulating HOXB7/ß-catenin axis.

Mounting evidence suggests that long non-coding RNAs play a critical role in the occurrence and development of human malignancies. Nonetheless, it remains unknown whether Gamma-Butyrobetaine Hydroxylase 1-Antisense RNA 1 (BBOX1-AS1) participates in the regulation of esophageal squamous cell carcinoma (ESCC) carcinogenesis. Herein, we validated that BBOX1-AS1 was notably overexpressed in ESCC tissues compared to the adjacent non-tumor tissues and significantly correlated with tumor sizes. BBOX1-AS1 enhanced the malignant behavior of ESCC cells in vitro, such as cell proliferation, migration, and invasion. In addition, knockdown of BBOX1-AS1 augmented the proportion of apoptotic cells in ESCC cells. Mechanistically, BBOX1-AS1 regulated HOXB7 expression, and rescue experiments indicated that silencing of HOXB7 could abolish the malignant phenotypes mediated by BBOX1-AS1 to a certain extent. Moreover, HOXB7 participated in the activation of the Wnt/ß-catenin signaling pathway. In summary, our findings substantiated that BBOX1-AS1 could activate the Wnt/ß-catenin pathway by upregulating HOXB7 expression to promote ESCC progression, providing a rationale to develop novel therapeutic approaches.

Integrative analysis of key candidate genes and signaling pathways in ovarian cancer by bioinformatics.

BACKGROUND: Ovarian cancer is one of the most common gynecological tumors, and among gynecological tumors, its incidence and mortality rates are fairly high. However, the pathogenesis of ovarian cancer is not clear. The present study aimed to investigate the differentially expressed genes and signaling pathways associated with ovarian cancer by bioinformatics analysis. METHODS: The data from three mRNA expression profiling microarrays (GSE14407, GSE29450, and GSE54388) were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes between ovarian cancer tissues and normal tissues were identified using R software. The overlapping genes from the three GEO datasets were identified, and profound analysis was performed. The overlapping genes were used for pathway and Gene Ontology (GO) functional enrichment analysis using the Metascape online tool. Protein-protein interactions were analyzed with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). Subnetwork models were selected using the plugin molecular complex detection (MCODE) application in Cytoscape. Kaplan-Meier curves were used to analyze the univariate survival outcomes of the hub genes. The Human Protein Atlas (HPA) database and Gene Expression Profiling Interactive Analysis (GEPIA) were used to validate hub genes. RESULTS: In total, 708 overlapping genes were identified through analyses of the three microarray datasets (GSE14407, GSE29450, and GSE54388). These genes mainly participated in mitotic sister chromatid segregation, regulation of chromosome segregation and regulation of the cell cycle process. High CCNA2 expression was associated with poor overall survival (OS) and tumor stage. The expression of CDK1, CDC20, CCNB1, BUB1B, CCNA2, KIF11, CDCA8, KIF2C, NDC80 and TOP2A was increased in ovarian cancer tissues compared with normal tissues according to the Oncomine database. Higher expression levels of these seven candidate genes in ovarian cancer tissues compared with normal tissues were observed by GEPIA. The protein expression levels of CCNA2, CCNB1, CDC20, CDCA8, CDK1, KIF11 and TOP2A were high in ovarian cancer tissues, which was further confirmed via the HPA database. CONCLUSION: Taken together, our study provided evidence concerning the altered expression of genes in ovarian cancer tissues compared with normal tissues. In vivo and in vitro experiments are required to verify the results of the present study.

ANXA1 enhances tumor proliferation and migration by regulating epithelial-mesenchymal transition and IL-6/JAK2/STAT3 pathway in papillary thyroid carcinoma.

Background: Annexin A1 (ANXA1) was discovered to show various effects during tumor initiation and development in a tumor-specific manner. However, the function of ANXA1 in papillary thyroid carcinoma (PTC) has not been reported. Methods: Bioinformatic analyses, RT-PCR and immunohistochemistry were employed to determine the ANXA1 expression level in PTC. Both gain- and loss-of-function studies, including CCK-8, EdU assay, transwell experiment and wound-healing assay were used to investigate the role of ANXA1 in PTC progression. GSEA enrichment analysis was utilized to explore the potential mechanisms of ANXA1 mediated downstream signaling, and ELISA, RT-PCR and western blot were used to confirm the relevance. Results: ANXA1 expression was prominently upregulated in PTC tumor tissues. Ectopic expression of ANXA1 expedited PTC cell proliferation, migration and invasion, whereas ANXA1 knockdown exhibited the opposing trends. Mechanistic investigations showed that ANXA1 regulated epithelial-mesenchymal transition (EMT) and activated the IL-6/JAK2/STAT3 pathway to contribute to PTC malignant behaviors. In particular, loss of ANXA1 retarded tumor burden and suppressed lung metastasis in vivo. Conclusions: In conclusion, our findings identified ANXA1 as a pivotal oncogene during PTC carcinogenesis and ANXA1 might function as a promising therapeutic target and prognostic marker for PTC.

METTL3 restrains papillary thyroid cancer progression via m6A/c-Rel/IL-8-mediated neutrophil infiltration.

Growing evidence indicates that N6-methyladenosine (m6A) is the most pervasive RNA modification in eukaryotic cells. However, the specific role of METTL3 in papillary thyroid carcinoma (PTC) initiation and development remains elusive. Here we found that downregulation of METTL3 was correlated with malignant progression and poor prognosis in PTC. A variety of gain- and loss-of-function studies clarified the effect of METTL3 on regulation of growth and metastasis of PTC cells in vitro and in vivo. By combining RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (meRIP-seq), our mechanistic studies pinpointed c-Rel and RelA as downstream m6A targets of METTL3. Disruption of METTL3 elicited secretion of interleukin-8 (IL-8), and elevated concentrations of IL-8 promoted recruitment of tumor-associated neutrophils (TANs) in chemotaxis assays and mouse models. Administration of the IL-8 antagonist SB225002 substantially retarded tumor growth and abolished TAN accumulation in immunodeficient mice. Our findings revealed that METTL3 played a pivotal tumor-suppressor role in PTC carcinogenesis through c-Rel and RelA inactivation of the nuclear factor κB (NF-κB) pathway by cooperating with YTHDF2 and altered TAN infiltration to regulate tumor growth, which extends our understanding of the relationship between m6A modification and plasticity of the tumor microenvironment.

Aberrant SLC6A14 Expression Promotes Proliferation and Metastasis of Colorectal Cancer via Enhancing the JAK2/STAT3 Pathway.

BACKGROUND: Solute carrier family 6 member 14 (SLC6A14) is a high-capacity amino acid transporter in mammalian cells. It has gained increasing attention for its potential involvement in the progression and metabolic reprogramming of various malignant tumors. However, the role of SLC6A14 in colorectal cancer (CRC) remains unclear. METHODS: Real-time polymerase chain reaction (qRT-PCR), immunoblotting and immunohistochemistry were carried out to detect the expression level of SLC6A14 in human CRC tissues and CRC-derived cell lines. HCT-116 and Caco-2 cell lines were selected to conduct in vitro functional studies. Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, cell migration and invasion assays were performed to investigate the role of SLC6A14 in CRC cells. Besides, azoxymethane/dextran sulfate sodium salt (AOM/DSS)-induced CRC and tumor xenograft models were constructed to explore the effects of SLC6A14 blockade or overexpression during tumor progression in vivo. RESULTS: SLC6A14 was substantially increased in human CRC samples and higher levels of SLC6A14 was correlated with advanced tumor stage, lymph node metastasis and dismal survival of CRC patients. SLC6A14 markedly promoted cell growth, inhibited cell apoptosis, and exacerbated migration and invasion of CRC cells in vitro. Mechanistically, SLC6A14 aggravated these malignant phenotypes through activating JAK2/STAT3 signaling pathway, and inhibiting JAK2/STAT3 signaling with specific inhibitors could reverse SLC6A14-mediated tumorigenic effects. Besides, two different animal studies verified the tumor-promoting effect of SLC6A14 in CRC. CONCLUSION: Our data illustrated the crucial function of SLC6A14 during CRC progression, suggesting SLC6A14/JAK2/STAT3 axis may serve as novel therapeutic targets for patients with CRC.

LncRNA FAM83A-AS1 promotes ESCC progression by regulating miR-214/CDC25B axis.

Background: Recent researches have pinpointed that long non-coding RNA (lncRNA) was tightly related to the carcinogenesis. However, the function of lncRNA in esophageal cell squamous carcinoma (ESCC) remains to be explored. In the current study, we assessed the expression pattern and the biological function of FAM83A-AS1 in ESCC. Methods: qRT-PCR was used to detect the expression of FAM83A-AS1, miR-214, and CDC25B expression in ESCC tissues and cell lines. CCK-8, transwell, apoptosis and cell cycle assays were performed to define the function of FAM83A-AS1 in ESCC cells. Furthermore, the regulation of miR-214 by FAM83A-AS1 was defined by qRT- PCR and rescue assays. In addition, the association between CDC25B, miR-214, CDC25B was confirmed by qRT-PCR. Results: Here, we discovered that FAM83A-AS1 was strongly expressed in ESCC tissues. FAM83A-AS1 abundance was associated with TNM stages and the differentiation grade of ESCC patients. The receiver operating characteristic curve (ROC) analysis indicated the high accuracy of FAM83A-AS1 in ESCC diagnosis. Functionally, inhibiting FAM83A-AS1 repressed cell proliferation, migration, and invasion in ESCC. In addition, we found that FAM83A-AS1 accelerated the cell cycle while inhibited cell apoptosis. Mechanistically, we found that FAM83A-AS1 regulated miR-214 expression, and there was a negative correlation between miR-214 and FAM83A-AS1 in ESCC. Rescue assay indicated that miR-214 could impair the suppressing effect of cell migration induced by FAM83A-AS1 depletion. Furthermore, CDC25B was a direct target of miR-214, and FAM83A-AS1 enhanced CDC25B expression while miR-214 positively CDC25B expression in ESCC. Conclusions: Collectively, we concluded that FAM83A-AS1 facilitated ESCC progression by regulating the miR-214/CDC25B axis. Our study showed FAM83A-AS1 may act as a promising target for ESCC diagnosis and therapy.

LncRNA LOXL1-AS1 promotes esophageal squamous cell carcinoma progression by targeting DESC1.

Recently, ample evidence indicated that numerous aberrantly expressed long non-coding RNAs (lncRNAs) participated in the development of multiple malignancies. However, the expression and function of lncRNA LOXL1-AS1 in mediating esophageal squamous cell carcinoma (ESCC) carcinogenesis remains largely elusive. Here we validated that LOXL1-AS1 was significantly upregulated in ESCC tissues compared with the corresponding adjacent non-neoplastic tissues, and LOXL1-AS1 expression was positively correlated with ESCC patients' lymph node metastasis. Besides, LOXL1-AS1 knockdown impaired ESCC cells proliferation, migration and invasion capabilities in vitro. Furthermore, inhibiting LOXL1-AS1 in ESCC cells increased the percentage of cells at the G1 phase, accompanied by reducing in S phase in contrast to scramble control, and silencing of LOXL1-AS1 evoked ESCC cell apoptosis. From high throughput RNA sequencing (RNA-seq) analysis, we identified that differentially expressed in squamous cell carcinoma 1 (DESC1) was a critical downstream target of LOXL1-AS1. Taken together, we demonstrated the function and mechanism of LOXL1-AS1 in contributing ESCC progression for the first time, and indicated LOXL1-AS1 may be a novel therapeutic biomarker of ESCC.

Protective and anti-inflammatory role of REG1A in inflammatory bowel disease induced by JAK/STAT3 signaling axis.

Regenerating islet-derived protein 1-alpha (REG1A) was abnormally upregulated in a series of gastrointestinal inflammatory disorders. However, the potential biological function and underlying regulatory mechanisms of the increased REG1A in inflammatory bowel disease (IBD) pathogenesis remain to be fully elucidated. In this study, we uncovered that REG1A was substantially increased in the inflamed colorectal tissues of IBD patients. And the aberrantly expressed REG1A in intestinal epithelial cells (IEC) prominently inhibited inflammatory responses, promoted cell proliferation and suppressed epithelial apoptosis. Mechanically, IL-6 and IL-22 markedly activated REG1A transcription through triggering JAK/STAT3 signaling pathway. In addition, overexpression of REG1A in mice by systematic delivery of REG1A lentivirus remarkably alleviated DSS-induced inflammatory injury and maintained the integrity of intestinal mucosal barrier. Taken together, our data demonstrated that the novel proliferative factor REG1A controlled by IL-6/IL-22-JAK-STAT3 signaling may provide a promising therapeutic target for patients with IBD.

LncRNA MIR205HG Drives Esophageal Squamous Cell Carcinoma Progression by Regulating miR-214/SOX4 Axis.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a common and fatal malignancy, which has posed a great challenge to public health, especially in China. Dysregulation of long non-coding RNAs is involved in the occurrence, development, invasion, and metastasis of multiple cancers including ESCC. However, little is known about the function of MIR205HG in ESCC. METHODS: We used qRT-PCR to detect the expression level of MIR205HG, miR-214, and SOX4 in human ESCC tissues and cell lines. Loss-of-functional assays were performed to test the impact of MIR205HG on cell proliferation, metastasis, and apoptosis process via CCK-8, transwell, and flow cell cytometry assays. Additionally, the downstream molecular mechanism of MIR205HG in ESCC was explored. RESULTS: Here, we found MIR205HG was substantially up-regulated in ESCC, and there was a positive correlation between MIR205HG expression and tumor size and lymphatic metastasis of ESCC patients. Inhibition of MIR205HG attenuated cell proliferation, migration, and invasion. Silencing MIR205HG increased G1 phase cell counts and decreased S phase cell counts, along with increased apoptotic cell populations. Notably, the rescue assays indicated that miR-214 could partly reverse the influence of MIR205HG on ESCC cell migration. We also found that SOX4 was a direct target mRNA of miR-214, and MIR205HG could act as a molecular sponge to regulate SOX4 expression in ESCC. CONCLUSION: Taken together, our findings demonstrate that MIR205HG promotes ESCC progression by regulating the miR-214/SOX4 axis. MIR205HG may be a novel candidate target for ESCC diagnosis and therapy.

LncRNA MIR31HG functions as a ceRNA to regulate c-Met function by sponging miR-34a in esophageal squamous cell carcinoma.

Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) function as essential regulators in the development and progression of multiple tumors. However, the molecular mechanisms of MIR31HG in regulating ESCC progression remain unknown. Here, we confirmed that MIR31HG facilitated ESCC cells proliferation in vivo. Besides, MIR31HG knockdown increases the percentage of cells at the G1 phase, along with reduced arrest in S phase and MIR31HG overexpression exhibits the opposite effects. Overexpressed MIR31HG decreases the percentage of apoptotic ESCC cells. Interestingly, MIR31HG can function as a competing endogenous RNA by sponging miR-34a. The rescue experiments demonstrated that MIR31HG function is partially reversed by inhibiting miR-34a. In addition, we found c-Met is a target gene of miR-34a and is indirectly regulated by MIR31HG. Taken together, our findings revealed that MIR31HG promotes ESCC progression by regulating miR-34a/ c-Met axis and may provide a new prospective for exploration and understanding of the biological effects of esophageal squamous cell carcinoma.

lncRNA SNHG3 acts as a novel Tumor Suppressor and regulates Tumor Proliferation and Metastasis via AKT/mTOR/ERK pathway in Papillary Thyroid Carcinoma.

The incidence of papillary thyroid carcinoma (PTC) has been increased rapidly in recent decades. Long noncoding RNAs (lncRNA) are a class of non-protein-coding transcripts and play critical roles in regulating gene expression and influence biological behaviors of multiple cancers, including PTC. Here, we discovered that lncRNA SNHG3 was significantly downregulated in PTC tissues and cell lines, the expression of SNHG3 was negatively correlated with the TNM stage and poor prognosis of PTC patients. Functional studies illustrated that the depletion of SNHG3 via CRISPR/Cas9 technology promoted the proliferation, migration and invasion abilities of PTC cells. Tumor xenograft models confirmed the tumor-promoting role of silenced SNHG3 in vivo. Further mechanistic analyses revealed that knockout of SNHG3 activated the AKT/mTOR/ERK pathway in PTC cell lines and the mTOR inhibitor AZD8055 abrogated the tumor-promoting effect induced by SNHG3 inhibition. Taken together, our findings identified a lncRNA SNHG3 that functions its tumor-suppressor role during PTC development and SNHG3 might serve as a promising candidate for target therapy of PTC.

Long Non-coding RNA ITIH4-AS1 Accelerates the Proliferation and Metastasis of Colorectal Cancer by Activating JAK/STAT3 Signaling.

Accumulating evidence has uncovered long non-coding RNAs (lncRNAs) as central regulators in the pathogenesis of diverse human cancers including colorectal cancer (CRC). The present study discovered that a novel lncRNA ITIH4 antisense RNA 1 (ITHI4-AS1) was frequently under-expressed in most normal human tissues, including colon tissues. Therefore, we aimed to investigate the role of ITHI4-AS1 in CRC. Interestingly, a significant overexpression of ITIH4-AS1 was observed in CRC cell lines relative to normal NCM460 cells. Also, we investigated the facilitating role of ITIH4-AS1 in CRC cell growth and metastasis both in vitro and in vivo. Additionally, we explained that ITIH4-AS1 upregulation in CRC was attributed to downregulation or even depletion of RE1 silencing transcription factor (REST), a presently identified transcriptional repressor for ITIH4-AS1. Meanwhile, the contribution of ITIH4-AS1 to CRC development was validated to rely on the activation of the JAK/STAT3 pathway. More importantly, we verified that FUS interacted with both ITIH4-AS1 and STAT3, and that ITIH4-AS1 evoked nuclear translocation of phosphorylated (p)-STAT3 in CRC through recruiting FUS. In summary, our findings unveiled for the first time that REST downregulation-enhanced ITIH4-AS1 exerts pro-tumor functions in CRC through FUS-dependent activation of the JAK/STAT3 pathway, implying that targeting ITIH4-AS1 may be a novel effective strategy for CRC therapy.

LncRNA MNX1-AS1 promotes progression of esophageal squamous cell carcinoma by regulating miR-34a/SIRT1 axis.

BACKGROUND: Long non-coding RNAs (lncRNAs) are powerful factors influencing the tumorigenesis and metastasis of multiple carcinomas. LncRNA MNX1-AS1 plays critical roles in the progression of tumor formation according to recent research, while its roles in esophageal squamous cell carcinoma (ESCC) remains unknown. METHODS: The expression levels of lncRNA MNX1-AS1 were examined in ESCC tissues by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The role of lncRNA MNX1-AS1 was performed by WST-1 proliferation assays, migration and invasion assays. Besides, the molecular mechanism of lncRNA MNX1-AS1 was verified by online bioinformatics, qRT-PCR and rescue assays. RESULTS: MNX1-AS1 was signifcantly upregulated in ESCC tissues. It was conformed that high MNX1-AS1 expression was associated with ESCC lymph node metastasis. Moreover, we found that knockdown of MNX1-AS1 apparently suppressed the cell proliferation, migration, and invasion capacity. Flow cytometry analysis showed MNX1-AS1 regulated ESCC cell cycle and apoptosis progression. Mechanism analysis revealed that miR-34a inhibitor could rescue the influence of inhibiting MNX1-AS1 on ESCC cells migration by serving as competing endogenous RNA (ceRNAs). Furthermore, we found that miR-34a specifically targeted SIRTI. CONCLUSIONS: Taken together, we demonstrated that lncRNA MNX1-AS1/miR-34a/SIRT1 regulatory axis could play an important role in ESCC progression, and MNX1-AS1 may act as a novel potential biomarker for esophageal squamous cell carcinoma.