High TRAF6 Expression Is Associated With Esophageal Carcinoma Recurrence and Prompts Cancer Cell Invasion

Esophageal cancer is one of the most common types of cancer, and it has a poor prognosis. The molecular mechanisms of esophageal cancer progression remain largely unknown. In this study, we aimed to investigate the clinical significance and biological function of tumor necrosis factor receptor-associated factor 6 (TRAF6) in esophageal cancer. Expression of TRAF6 in esophageal cancer was examined, and its correlation with clinicopathological factors and patient prognosis was analyzed. A series of functional and mechanism assays were performed to further investigate the function and underlying mechanisms in esophageal cancer. Expression of TRAF6 was highly elevated in esophageal cancer tissues, and patients with high TRAF6 expression have a significantly shorter survival time than those with low TRAF6 expression. Furthermore, loss-of-function experiments showed that knockdown of TRAF6 significantly reduced the migration and invasion abilities of esophageal cancer cells. Moreover, the pro-oncogenic effects of TRAF6 in esophageal cancer were mediated by the upregulation of AEP and MMP2. Altogether, our data suggest that high expression of TRAF6 is significant for esophageal cancer progression, and TRAF6 indicates poor prognosis in esophageal cancer patients, which might be a novel prognostic biomarker or potential therapeutic target in esophageal cancer.

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LncRNA LBX2-AS1 promotes colorectal cancer progression and 5-fluorouracil resistance

Cancer Cell International ◽

10.1186/s12935-021-02209-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yu-Nan Ma ◽

Yong-Gang Hong ◽

Guan-Yu Yu ◽

Si-yuan Jiang ◽

Bo-lun Zhao ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Ex Vivo ◽

Prognostic Indicator ◽

Migration And Invasion ◽

Loss Of Function ◽

Clinical Benefits ◽

Colorectal Cancer Progression

Abstract Background Recent reports suggest that the long non-coding RNA LBX2 antisense RNA 1 (LBX2-AS1) acts as an important regulator in cancer progression, but its significance in colorectal cancer (CRC) remains undetermined. Methods LBX2-AS1 expression levels in CRC were determined from the GEPIA database and CRC tissues to investigate clinical relevance. meRIP-PCR assays investigated the molecular mechanisms underlying the function of m6A in LBX2-AS1. Loss of function experiments was used to define the role of LBX2-AS1 in the progression of CRC. The ceRNA function of LBX2-AS1 was evaluated by RNA immunoprecipitation. In vitro and PDX models were used to determine if LBX2-AS1 promotes 5-fluorouracil resistance. Results Data from the TCGA and our institutional patient cohorts established that LBX2-AS1 levels were significantly upregulated in most CRC tissues relative to normal adjacent colon tissues. Moreover, LBX2-AS1 levels were positively correlated with aggressive disease characteristics, constituting an independent prognostic indicator of overall patient survival. Mechanistic investigations suggested that the increased LBX2-AS1 in CRC was mediated by METTL3-dependent m6A methylation. In vitro experiments indicated that knockdown of LBX2-AS1 inhibited CRC proliferation, migration and invasion with this phenotype linked to LBX2-AS1-mediated regulation of AKT1, acting as a ceRNA to sponge miR-422a. Ex vivo analysis of patient-derived CRC xenografts showed that low LBX2-AS1 expression cases exhibited 5-FU responsiveness and clinical investigations confirmed that low LBX2-AS1 expression was associated with improved clinical benefits from 5-FU therapy. Conclusions Together these results suggest that LBX2-AS1 may serve as a therapeutic target and predictor of 5-FU benefit in CRC patients.

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Long Non-Coding RNA HAGLROS Promotes the Malignant Progression of Bladder Cancer by Regulating the miR-330-5p/SPRR1B Axis

10.21203/rs.3.rs-1213167/v1 ◽

2022 ◽

Author(s):

Shiwei Xiao ◽

Yigang Zuo ◽

Yanan Li ◽

Yinglong Huang ◽

Shi Fu ◽

...

Keyword(s):

Bladder Cancer ◽

Molecular Mechanisms ◽

Subcellular Fractionation ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Sequencing Analysis ◽

Loss Of Function ◽

Invasion And Migration ◽

Potential Biomarker ◽

Underlying Mechanisms

Abstract BackgroundBladder cancer (BC) is the most common genitourinary malignancy worldwide, and its aetiology and pathogenesis remain unclear. Long noncoding RNAs can play vital roles in gene expression and diverse biological processes, especially in cancers. Accumulating evidence has shown that HAGLROS, a novel lncRNA, is closely related to the occurrence and progression of various cancers. However, the biological functions and underlying mechanisms of HAGLROS in BC remain unknown.MethodsThe relative expression of HAGLROS in BC was determined by bioinformatics analysis, transcriptome sequencing analysis and qRT–PCR. Gain- or loss-of-function assays were performed to study the biological roles of HAGLROS in BC. A CCK-8 assay was used to detect BC cell proliferation. BC cell invasion and migration were investigated by wound healing and Transwell assays. The cell cycle was analysed by flow cytometry assay. Western blot analysis and immunohistochemistry were performed to evaluate SPRR1B expression. The differential expression of candidate genes and their relationships were evaluated in data retrieved from the starBase database, the GEIPIA database, the Lnc2Cancer database and the LncBase database. FISH assays, subcellular fractionation assays and luciferase reporter assays were performed to explore the underlying molecular mechanisms of HAGLROS.ResultsHAGLROS expression is significantly upregulated in BC tissues and cells, and increasing HAGLROS expression was related to high pathologic grade. HAGLROS enhances the proliferation, migration and invasion of BC. Furthermore, SPRR1B is obviously upregulated and miR-330-5p is significantly downregulated in BC. Mechanistically, we found that HAGLROS is mainly located in the cytoplasm and positively regulates SPRR1B expression by sponging miR-330-5p, playing an oncogenic role in BC pathogenesis.ConclusionsThe present study demonstrates that HAGLROS is significantly overexpressed and plays an oncogenic role by regulating the miR-330-5p/SPRR1B axis in BC. HAGLROS may serve as a potential biomarker for the diagnosis and treatment of BC.

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Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors

Cancers ◽

10.3390/cancers12082210 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2210

Author(s):

Shu-Chun Chang ◽

Wayne Hsu ◽

Emily Chia-Yu Su ◽

Chin-Sheng Hung ◽

Jeak Ling Ding

Keyword(s):

Cancer Progression ◽

Tumor Suppressors ◽

Ex Vivo ◽

E3 Ligase ◽

Migration And Invasion ◽

Loss Of Function ◽

Protein Levels ◽

Signaling Axis ◽

Underlying Mechanisms ◽

Gain Loss

The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation, which is critically modulated by the E3 ubiquitin ligase. However, the underlying mechanisms and key factors involved in BRCA formation and disease advancement remains under-explored. By retrospective studies of BRCA patient tissues; and gene knockdown and gain/loss-of-function studies, we uncovered a novel E3 ligase, FBXL8, in BRCA. A signature expression profile of F-box factors that specifically target and degrade proteins involved in cell death/survival, was identified. FBXL8 emerged as a prominent member of the F-box factors. Ex vivo analysis of 1349 matched BRCA tissues indicated that FBXL8 promotes cell survival and tumorigenesis, and its level escalates with BRCA progression. Knockdown of FBXL8 caused: (i) intrinsic apoptosis, (ii) inhibition of cell migration and invasion, (iii) accumulation of two tumor-suppressors, CCND2 and IRF5, and (iv) downregulation of cancer-promoting cytokines/chemokines; all of which curtailed the tumor microenvironment and displayed potential to suppress cancer progression. Co-IP study suggests that two tumor-suppressors, CCND2 and IRF5 are part of the immune-complex of FBXL8. The protein levels of CCND2 and IRF5 inversely correlated with FBXL8 expression, implying that FBXL8 E3 ligase was associated with the degradation of CCND2 and IRF5. Altogether, we propose the exploitation of the ubiquitin signaling axis of FBXL8-CCND2-IRF5 for anti-cancer strategies and potential therapeutics.

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Novel Findings of Anti-cancer Property of Propofol

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520617666170912120327 ◽

2018 ◽

Vol 18 (2) ◽

pp. 156-165 ◽

Cited By ~ 8

Author(s):

Jiaqiang Wang ◽

Chien-shan Cheng ◽

Yan Lu ◽

Xiaowei Ding ◽

Minmin Zhu ◽

...

Keyword(s):

General Anesthesia ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Intravenous Anesthetic ◽

The Past ◽

Anti Cancer ◽

Underlying Mechanisms ◽

Recent Attention

Background: Propofol, a widely used intravenous anesthetic agent, is traditionally applied for sedation and general anesthesia. Explanation: Recent attention has been drawn to explore the effect and mechanisms of propofol against cancer progression in vitro and in vivo. Specifically, the proliferation-inhibiting and apoptosis-inducing properties of propofol in cancer have been studied. However, the underlying mechanisms remain unclear. Conclusion: This review focused on the findings within the past ten years and aimed to provide a general overview of propofol's malignance-modulating properties and the potential molecular mechanisms.

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TEAD4 modulated LncRNA MNX1-AS1 contributes to gastric cancer progression partly through suppressing BTG2 and activating BCL2

Molecular Cancer ◽

10.1186/s12943-019-1104-1 ◽

2020 ◽

Vol 19 (1) ◽

Cited By ~ 12

Author(s):

You Shuai ◽

Zhonghua Ma ◽

Weitao Liu ◽

Tao Yu ◽

Changsheng Yan ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Mechanistic Model ◽

Ectopic Expression ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Tissue Samples ◽

Reporter Assays

Abstract Background Gastric cancer (GC) is the third leading cause of cancer-related mortality globally. Long noncoding RNAs (lncRNAs) are dysregulated in obvious malignancies including GC and exploring the regulatory mechanisms underlying their expression is an attractive research area. However, these molecular mechanisms require further clarification, especially upstream mechanisms. Methods LncRNA MNX1-AS1 expression in GC tissue samples was investigated via microarray analysis and further determined in a cohort of GC tissues via quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Cell proliferation and flow cytometry assays were performed to confirm the roles of MNX1-AS1 in GC proliferation, cell cycle regulation, and apoptosis. The influence of MNX1-AS1 on GC cell migration and invasion was explored with Transwell assays. A xenograft tumour model was established to verify the effects of MNX1-AS1 on in vivo tumourigenesis. The TEAD4-involved upstream regulatory mechanism of MNX1-AS1 was explored through ChIP and luciferase reporter assays. The mechanistic model of MNX1-AS1 in regulating gene expression was further detected by subcellular fractionation, FISH, RIP, ChIP and luciferase reporter assays. Results It was found that MNX1-AS1 displayed obvious upregulation in GC tissue samples and cell lines, and ectopic expression of MNX1-AS1 predicted poor clinical outcomes for patients with GC. Overexpressed MNX1-AS1 expression promoted proliferation, migration and invasion of GC cells markedly, whereas decreased MNX1-AS1 expression elicited the opposite effects. Consistent with the in vitro results, MNX1-AS1 depletion effectively inhibited the growth of xenograft tumour in vivo. Mechanistically, TEAD4 directly bound the promoter region of MNX1-AS1 and stimulated the transcription of MNX1-AS1. Furthermore, MNX1-AS1 can sponge miR-6785-5p to upregulate the expression of BCL2 in GC cells. Meanwhile, MNX1-AS1 suppressed the transcription of BTG2 by recruiting polycomb repressive complex 2 to BTG2 promoter regions. Conclusions Our findings demonstrate that MNX1-AS1 may be able to serve as a prognostic indicator in GC patients and that TEAD4-activatd MNX1-AS1 can promote GC progression through EZH2/BTG2 and miR-6785-5p/BCL2 axes, implicating it as a novel and potent target for the treatment of GC.

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LINC01089 functions as a ceRNA for miR-152-3p to inhibit non‐small lung cancer progression through regulating PTEN

Cancer Cell International ◽

10.1186/s12935-021-01846-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Huixian Zhang ◽

Hao Zhang ◽

Xingya Li ◽

Siyuan Huang ◽

Qianqian Guo ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Progression ◽

Expression Level ◽

Cell Counting ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Loss Of Function ◽

Protein Coding ◽

Tensin Homolog ◽

Pten Mrna

Abstract Background Long non-coding RNAs (lncRNAs) have been reported to exert crucial functions in regulating the progression of human cancers. However, the function and mechanism of long intergenic non-protein coding RNA 01089 (LINC01089) in non-small cell lung cancer (NSCLC) have not been revealed. Methods The expression level of LINC01089, microRNA (miRNA, miR)-152-3p and phosphatase and tensin homolog deleted onc hromosome ten (PTEN) mRNA was detected by quantitative real-time PCR (qRT-PCR). After gain-of-function and loss-of-function models were established with NSCLC cell lines, the proliferation, migration and invasion of NSCLC cells were detected by cell counting kit-8 (CCK-8) assay, scratch healing assay, Transwell assay, respectively. Dual luciferase reporter assay was employed to validate the binding relationship between miR-152-3p and LINC01089 or the 3’UTR of PTEN. Western blot was used to detect PTEN expression in NSCLC cells after LINC01089 and miR-152-3p were selectively modulated. Results LINC01089 was down-regulated in NSCLC tissues and cells. Functional experiments showed that knockdown of LINC01089 could promote the proliferation, migration and invasion of NSCLC cells, while over-expression of LINC01089 had the opposite effects. miR-152-3p was identified as a functional target for LIN01089, and miR-152-3p could reverse the function of LINC01089. Additionally, LINC01089 could up-regulate the expression level of PTEN via repressing miR-152-3p. Conclusions Down-regulation of LINC01089 promoted the progression of NSCLC through regulating miR-152-3p/PTEN axis.

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Decreased level of miR-1301 promotes colorectal cancer progression via activation of STAT3 pathway

Biological Chemistry ◽

10.1515/hsz-2020-0301 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Fangfang Yang ◽

Hua Wang ◽

Bianbian Yan ◽

Tong Li ◽

Lulu Min ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Migration ◽

Cancer Progression ◽

Luciferase Assay ◽

Migration And Invasion ◽

Loss Of Function ◽

Aberrant Expression ◽

Cell Migration And Invasion ◽

Lovo Cells ◽

Colorectal Cancer Progression

Abstract The molecular pathogenesis of colorectal cancer (CRC) has been widely investigated in recent years. Accumulating evidence has indicated that microRNA (miRNA) dysregulation participates in the processes of driving CRC initiation and progression. Aberrant expression of miR-1301 has been found in various tumor types. However, its role in CRC remains to be elucidated. In the present study, we identified miR-1301 was enriched in normal colorectal tissues and significantly down-regulated in CRC. Decreased level of miR-1301 strongly correlated with aggressive pathological characteristics, including advanced stage and metastasis. Bioinformatics and dual luciferase assay demonstrated that STAT3 is a direct target of miR-1301. Gain and loss-of-function assays showed that miR-1301 had no effect on cell proliferation. Overexpression of miR-1301 suppressed cell migration and invasion capacity of pSTA3-positive LoVo cells, but not pSTAT3-negative SW480 cells, while inhibition of miR-1301 consistently promoted cell migration and invasion in both cell lines. Additionally, miR-1301 inhibition restored the suppressed migration and invasion of STAT3- knockdown LoVo cells. MiR-1301 functioned as a tumor suppressor to modulate the IL6/STAT3 signaling pathway. In summary, this study highlights the significant role of miR- 1301/STAT3 axis in CRC metastasis.

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Wnt5a Signaling in Normal and Cancer Stem Cells

Stem Cells International ◽

10.1155/2017/5295286 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 8

Author(s):

Yan Zhou ◽

Thomas J. Kipps ◽

Suping Zhang

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Migration And Invasion ◽

Target Cells ◽

Dependent Manner ◽

Self Renewal ◽

Surface Receptors ◽

Canonical Wnt

Wnt5a is involved in activating several noncanonical Wnt signaling pathways, which can inhibit or activate canonical Wnt/β-catenin signaling pathway in a receptor context-dependent manner. Wnt5a signaling is critical for regulating normal developmental processes, including stem cell self-renewal, proliferation, differentiation, migration, adhesion, and polarity. Moreover, the aberrant activation or inhibition of Wnt5a signaling is emerging as an important event in cancer progression, exerting both oncogenic and tumor suppressive effects. Recent studies show the involvement of Wnt5a signaling in regulating normal and cancer stem cell self-renewal, cancer cell proliferation, migration, and invasion. In this article, we review recent findings regarding the molecular mechanisms and roles of Wnt5a signaling in stem cells in embryogenesis and in the normal or neoplastic breast or ovary, highlighting that Wnt5a may have different effects on target cells depending on the surface receptors expressed by the target cell.

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Long noncoding RNA SNHG25 promotes the malignancy of endometrial cancer by sponging microRNA-497-5p and increasing FASN expression

Journal of Ovarian Research ◽

10.1186/s13048-021-00906-w ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Yuhua He ◽

Shuifang Xu ◽

Yi Qi ◽

Jinfang Tian ◽

Fengying Xu

Keyword(s):

Endometrial Cancer ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Fatty Acid Synthase ◽

Molecular Mechanisms ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Study Cohort ◽

Loss Of Function ◽

Ec Cells

Abstract Background Small nucleolar RNA host gene 25 (SNHG25), a long noncoding RNA, has been well-studied in epithelial ovarian cancer. However, the specific functions of SNHG25 in endometrial cancer (EC) have not been studied yet. In this study, we aimed to elucidate the clinical significance of SNHG25 in EC and determine the regulatory activity of SNHG25 on the tumor-associated EC phenotype. We also thoroughly explored the molecular mechanisms underlying SNHG25 function in EC. Methods Gene expression was measured using quantitative real-time polymerase chain reaction. The detailed functions of SNHG25 in EC were examined by performing loss-of-function experiments. Moreover, the regulatory mechanisms involving SNHG25, microRNA-497-5p, and fatty acid synthase (FASN) were unveiled using the luciferase reporter assay and RNA immunoprecipitation. Results We observed a high level of SNHG25 in EC using the TCGA dataset and our study cohort. Patients with a high SNHG25 level had shorter overall survival than those with a low SNHG25 level. SNHG25 deficiency resulted in tumor-repressing activities in EC cells by decreasing cell proliferation, migration, and invasion and promoting cell apoptosis. Furthermore, the function of SNHG25 depletion in impairing tumor growth in vivo was confirmed. SNHG25 sequestered miR-497-5p as a competing endogenous RNA in EC and consequently positively regulated FASN expression. Thus, the decrease in miR-497-5p or increase in FASN could neutralize the modulatory actions of SNHG25 knockdown in EC cells. Conclusions The depletion of SNHG25 impedes the oncogenicity of EC by targeting the miR-497-5p/FASN axis. The newly elucidated SNHG25/miR-497-5p/FASN pathway may be a promising target for the molecular-targeted management of EC.

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Cooperation of SRPK2, Numb and p53 in the malignant biology and chemosensitivity of colorectal cancer

Bioscience Reports ◽

10.1042/bsr20191488 ◽

2020 ◽

Vol 40 (1) ◽

Author(s):

Guosen Wang ◽

Weiwei Sheng ◽

Jingtong Tang ◽

Xin Li ◽

Jianping Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Migration ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Migration And Invasion ◽

Chemical Agent ◽

Cell Migration And Invasion ◽

Agent Treatment ◽

Hct116 Cells

Abstract Serine-arginine protein kinase 2 (SRPK2) is aberrantly expressed in human malignancies including colorectal cancer (CRC). However, little is known about the molecular mechanisms, and the role of SRPK2 in chemosensitivity remains unexplored in CRC. We recently showed that SRPK2 promotes pancreatic cancer progression by down-regulating Numb and p53. Therefore, we investigated the cooperation between SRPK2, Numb and p53 in the cell migration, invasion and chemosensitivity of CRC in vitro. Here, we showed that SRPK2 expression was higher in CRC tumors than in nontumor tissues. SRPK2 expression was positively associated with clinicopathological characteristics of CRC patients, including tumor differentiation, T stage, N stage and UICC stage. Additionally, SRPK2 had no association with mutant p53 (mtp53) in SW480 and SW620 cells, but negatively regulated Numb and wild-type p53 (wtp53) in response to 5-fluorouracil or cisplatin treatment in HCT116 cells. Moreover, SRPK2, Numb and p53 coimmunoprecipitated into a triple complex with or without the treatment of 5-fluorouracil in HCT116 cells, and p53 knockdown reversed the up-regulation of wtp53 induced by SRPK2 silencing with chemical agent treatment. Furthermore, overexpression of SRPK2 increased cell migration and invasion and decreased chemosensitivity to 5-fluorouracil or cisplatin in HCT116 cells. Conversely, SRPK2 silencing decreased cell migration and invasion and increased chemosensitivity to 5-fluorouracil or cisplatin, yet these effects could be reversed by p53 knockdown under chemical agent treatment. These results thus reveal a novel role of SRPK2-Numb-p53 signaling in the progression of CRC and demonstrate that SRPK2 is a potential therapeutic target for CRC clinical therapy.

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