Targeting BC200/miR218-5p Signaling Axis for Overcoming Temozolomide Resistance and Suppressing Glioma Stemness

Background: Glioblastoma (GB) is one of the most common (~30%) and lethal cancers of the central nervous system. Although new therapies are emerging, chemoresistance to treatment is one of the major challenges in cancer treatment. Brain cytoplasmic 200 (BC200) RNA, also known as BCYRN1, is a long noncoding RNA (lncRNA) that has recently emerged as one of the crucial members of the lncRNA family. BC200 atypical expression is observed in many human cancers. BC200 expression is higher in invasive cancers than in benign tumors. However, the clinical significance of BC200 and its effect on GB multiforme is still unexplored and remains unclear. Methods: BC200 expression in GB patients and cell lines were investigated through RT-qPCR, immunoblotting, and immunohistochemistry analysis. The biological importance of BC200 was investigated in vitro and in vivo through knockdown and overexpression. Bioinformatic analysis was performed to determine miRNAs associated with BC200 RNA. Results: Our findings revealed that in GB patients, BC200 RNA expression was higher in blood and tumor tissues than in normal tissues. BC200 RNA expression have a statistically significant difference between the IDH1 and P53 status. Moreover, the BC200 RNA expression was higher than both p53, a prognostic marker of glioma, and Ki-67, a reliable indicator of tumor cell proliferation activity. Overexpression and silencing of BC200 RNA both in vitro and in vivo significantly modulated the proliferation, self-renewal, pluripotency, and temozolomide (TMZ) chemo-resistance of GB cells. It was found that the expressions of BC200 were up-regulated and that of miR-218-5p were down-regulated in GB tissues and cells. miR-218-5p inhibited the expression of BC200. Conclusions: This study is the first to show that the molecular mechanism of BC200 promotes GB oncogenicity and TMZ resistance through miR-218-5p expression modulation. Thus, the noncoding RNA BC200/miR-218-5p signaling circuit is a potential clinical biomarker or therapeutic target for GB.

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LINC00958 promotes the proliferation of TSCC via miR-211-5p/CENPK axis and activating the JAK/STAT3 signaling pathway

Cancer Cell International ◽

10.1186/s12935-021-01808-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Bo Jia ◽

Junfeng Dao ◽

Jiusong Han ◽

Zhijie Huang ◽

Xiang Sun ◽

...

Keyword(s):

Noncoding Rna ◽

Xenograft Model ◽

Tumor Xenograft ◽

Luciferase Reporter ◽

Cell Cycle Regulators ◽

Normal Tissues ◽

Stat3 Signaling ◽

Long Intergenic Noncoding Rna

Abstract Background Tongue squamous cell carcinoma (TSCC) is one of the most common oral tumors. Recently, long intergenic noncoding RNA 00958 (LINC00958) has been identified as an oncogene in human cancers. Nevertheless, the role of LINC00958 and its downstream mechanisms in TSCC is still unknown. Methods The effect of LINC00958 on TSCC cells proliferation and growth were assessed by CCK-8, colony formation, 5-Ethynyl-2′-deoxyuridline (EdU) assay and flow cytometry assays in vitro and tumor xenograft model in vivo. Bioinformatics analysis was used to predict the target of LINC00958 in TSCC, which was verified by RNA immunoprecipitation and luciferase reporter assays. Results LINC00958 was increased in TSCC tissues, and patients with high LINC00958 expression had a shorter overall survival. LINC00958 knockdown significantly decreased the growth rate of TSCC cells both in vitro and in vivo. In mechanism, LINC00958 acted as a ceRNA by competitively sponging miR-211-5p. In addition, we identified CENPK as a direct target gene of miR-211-5p, which was higher in TSCC tissues than that in adjacent normal tissues. Up-regulated miR-211-5p or down-regulated CENPK could abolish LINC00958-induced proliferation promotion in TSCC cells. Furthermore, The overexpression of CENPK promoted the expression of oncogenic cell cycle regulators and activated the JAK/STAT3 signaling. Conclusions Our findings suggested that LINC00958 is a potential prognostic biomarker in TSCC.

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A novel hypoxic long noncoding RNA KB-1980E6.3 maintains breast cancer stem cell stemness via interacting with IGF2BP1 to facilitate c-Myc mRNA stability

Oncogene ◽

10.1038/s41388-020-01638-9 ◽

2021 ◽

Author(s):

Pengpeng Zhu ◽

Fang He ◽

Yixuan Hou ◽

Gang Tu ◽

Qiao Li ◽

...

Keyword(s):

Breast Cancer ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Underlying Mechanism ◽

Rapid Expansion ◽

Breast Cancer Patients ◽

Coding Region ◽

Signaling Axis

AbstractThe hostile hypoxic microenvironment takes primary responsibility for the rapid expansion of breast cancer tumors. However, the underlying mechanism is not fully understood. Here, using RNA sequencing (RNA-seq) analysis, we identified a hypoxia-induced long noncoding RNA (lncRNA) KB-1980E6.3, which is aberrantly upregulated in clinical breast cancer tissues and closely correlated with poor prognosis of breast cancer patients. The enhanced lncRNA KB-1980E6.3 facilitates breast cancer stem cells (BCSCs) self-renewal and tumorigenesis under hypoxic microenvironment both in vitro and in vivo. Mechanistically, lncRNA KB-1980E6.3 recruited insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to form a lncRNA KB-1980E6.3/IGF2BP1/c-Myc signaling axis that retained the stability of c-Myc mRNA through increasing binding of IGF2BP1 with m6A-modified c-Myc coding region instability determinant (CRD) mRNA. In conclusion, we confirm that lncRNA KB-1980E6.3 maintains the stemness of BCSCs through lncRNA KB-1980E6.3/IGF2BP1/c-Myc axis and suggest that disrupting this axis might provide a new therapeutic target for refractory hypoxic tumors.

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LINC00958 promotes the proliferation of TSCC via miR-211-5p/CENPK axis and activating the JAK/STAT3 signaling pathway

10.21203/rs.3.rs-78207/v2 ◽

2021 ◽

Author(s):

Bo Jia ◽

Junfeng Dao ◽

Jiusong Han ◽

Zhijie Huang ◽

Xiang Sun ◽

...

Keyword(s):

Noncoding Rna ◽

Xenograft Model ◽

Tumor Xenograft ◽

Luciferase Reporter ◽

Cell Cycle Regulators ◽

Normal Tissues ◽

Stat3 Signaling ◽

Long Intergenic Noncoding Rna

Abstract Background: Tongue squamous cell carcinoma (TSCC) is one of the most common oral tumors. Recently, long intergenic noncoding RNA 00958 (LINC00958) has been identified as an oncogene in human cancers. Nevertheless, the role of LINC00958 and its downstream mechanisms in TSCC is still unknown. Methods: The expression levels of LINC00958 in human TSCC tissues and adjacent normal tissues were detected. The effect of LINC00958 on TSCC cells proliferation and growth were assessed by CCK-8, colony formation, 5-Ethynyl-2’-deoxyuridline (EdU) assay, and flow cytometry assays in vitro and tumor xenograft model in vivo. Bioinformatics analysis was used to predict the target of LINC00958 in TSCC, which was verified by RNA immunoprecipitation and luciferase reporter assays. Results: We found LINC00958 was increased in TSCC tissues, and patients with high LINC00958 expression had a shorter overall survival. LINC00958 knockdown significantly decreased the growth rate of TSCC cells both in vitro and in vivo . In mechanism, LINC00958 acted as a competing endogenous RNA (ceRNA) by competitively sponging miR-211-5p. In addition, we identified centromere protein K (CENPK) as a direct target gene of miR-211-5p, which was higher in TSCC tissues than that in adjacent normal tissues. Up-regulated miR-211-5p or down-regulated CENPK could abolish LINC00958-induced proliferation promotion in TSCC cells. Conclusion: Furthermore, CENPK promoted the expression of oncogenic cell cycle regulators and activated the JAK/STAT3 signaling. Our findings suggest that LINC00958 is a potential prognostic biomarker in TSCC.

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circLMTK2 acts as a sponge of miR-150-5p and promotes proliferation and metastasis in gastric cancer

Molecular Cancer ◽

10.1186/s12943-019-1081-4 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 15

Author(s):

Sen Wang ◽

Dong Tang ◽

Wei Wang ◽

Yining Yang ◽

Xiaoqing Wu ◽

...

Keyword(s):

Gastric Cancer ◽

Bioinformatic Analysis ◽

Migration And Invasion ◽

Circular Rnas ◽

Normal Tissues ◽

Tumour Metastasis ◽

Genome Wide ◽

Proliferation And Metastasis

Abstract Background As a novel class of non-coding RNAs, circular RNAs (circRNAs) are key regulators of the development and progression of different cancers. However, little is known about the function and biological mechanism of circLMTK2, also named hsa_circ_0001725, in gastric cancer (GC) tumourigenesis. Methods circLMTK2 was identified in ten paired cancer specimens and adjacent normal tissues by RNA sequencing and genome-wide bioinformatic analysis and verified by quantitative real-time PCR (qRT-PCR). Knockdown or exogenous expression of circLMTK2 combined with in vitro and in vivo assays were performed to prove the functional significance of circLMTK2. The molecular mechanism of circLMTK2 was demonstrated by searching the CircNet database and confirmed by RNA in vivo precipitation assays, western blotting, luciferase assays and rescue experiments. Results circLMTK2 was frequently upregulated in GC tissues, and high circLMTK2 expression was associated with poor prognosis, lymph node metastasis and poor TNM stage in GC patients. Functionally, circLMTK2 overexpression promoted GC cell proliferation and tumourigenicity in vitro and in vivo. Furthermore, ectopic circLMTK2 expression enhanced GC cell migration and invasion in vitro and tumour metastasis in vivo. In addition, we demonstrated that circLMTK2 could sponge miR-150-5p, thus indirectly regulating the c-Myc expression and contributing to GC tumourigenesis. Conclusion Our findings demonstrate that circLMTK2 functions as a tumour promoter in GC through the miR-150-5p/c-Myc axis and could thus be a prognostic predictor and therapeutic target for GC.

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LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer

Molecular Cancer ◽

10.1186/s12943-019-1105-0 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 20

Author(s):

Yun Wang ◽

Jia-Huan Lu ◽

Qi-Nian Wu ◽

Ying Jin ◽

De-Shen Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Therapeutic Target ◽

Noncoding Rna ◽

Aerobic Glycolysis ◽

Poor Overall Survival ◽

Normal Tissues ◽

In Vivo Experiments ◽

Long Intergenic Noncoding Rna

Abstract Background Long noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) progression and could be a potential therapeutic target. Methods We screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact with LINRIS (Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells with LINRIS inhibited were tested in vitro and in vivo. Results LINRIS was upregulated in CRC tissues from patients with poor overall survival (OS), and LINRIS inhibition led to the impaired CRC cell line growth. Moreover, knockdown of LINRIS resulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N6-methyladenosine (m6A) ‘reader’. LINRIS blocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown of LINRIS attenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription of LINRIS could be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition of LINRIS suppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models. Conclusion LINRIS is an independent prognostic biomarker for CRC. The LINRIS-IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.

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Circular RNA _0008278 acts as a sponge of miR-378 and promotes proliferation and metastasis in gastric cancer

10.21203/rs.3.rs-335561/v1 ◽

2021 ◽

Author(s):

Xuan Li ◽

Haisheng Qian ◽

Hao Dong ◽

Yini Dang ◽

Lei Peng ◽

...

Keyword(s):

Gastric Cancer ◽

Bioinformatic Analysis ◽

Potential Method ◽

Circular Rna ◽

Migration And Invasion ◽

Normal Tissues ◽

Tumour Metastasis ◽

Regulatory Molecule

Abstract Background: Circular RNA (circRNA) is rising as an indispensable regulatory molecule in the progression of various kinds of malignant growth. However, little is known about the capacity and instruments of circRNA_0008727 in gastric cancer (GC). Our point was to recognize a novel circRNA-microRNA-mRNA useful system in gastric cancer. Method: CircRNA_0008278 was identified in three paired cancer specimens and adjacent normal tissues by RNA sequencing and genome-wide bioinformatic analysis and verified by quantitative real-time PCR (qRT-PCR). Knockdown or exogenous expression of circRNA_0008278 combined with in vitro and in vivo assays were performed to prove the functional significance of circRNA_0008278. The molecular mechanism of circRNA_0008278 was demonstrated by searching the CircNet database and confirmed by RNA in vivo precipitation assays, western blotting, luciferase assays and rescue experiments.Results: CircRNA_0008278 was frequently upregulated in GC tissues, and high circRNA_0008278 expression was associated with poor prognosis, lymph node metastasis and poor TNM stage in GC patients. Functionally, circRNA_0008278 overexpression promoted GC cell proliferation and tumourigenicity in vitro and in vivo. Furthermore, circRNA_0008278 over-expression enhanced GC cell migration and invasion in vitro and tumour metastasis in vivo. In addition, we demonstrated that circRNA_0008278 could sponge miR-378, thus indirectly regulating theYY1 expression and contributing to GC tumourigenesis.Conclusion: Our findings demonstrate that circRNA_0008278 functions as a tumour promoter in GC, and a new pathway circRNA_0008278/miR-378/YY1 which may be potential method for gastric cancer treatment.

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PNO1 promotes cell proliferation in prostate cancer

10.21203/rs.2.17848/v2 ◽

2020 ◽

Author(s):

Jianpeng Hu ◽

Feilun Cui ◽

Zhipeng Xv ◽

Jian Tan ◽

Zhengyu Wang

Keyword(s):

Prostate Cancer ◽

Rna Splicing ◽

Bioinformatic Analysis ◽

In Vitro Assays ◽

Multiple Cancer ◽

Translational Initiation ◽

Normal Tissues ◽

Potential Biomarker

Abstract BackgroundProstate cancer (PCa) is one of the most commonly diagnosed cancers. The functions of PNO1 in yeasts were involved in regulating ribosome and proteasome biogenesis. Human PNO1 is crucial to the site 3 cleavage at the 3ʹ-end of 18S pre-rRNA. Previous studies indicated that PNO1 may be related to the progression of cancers. However, the functions of PNO1 in PCa remained unclear. MethodsThe present study evaluated the expression levels of PNO1 in PCa by using GSE45016, GSE55945 and GSE17951 datasets. Then, in vivo and in vitro assays were conducted to detect the biological functions of PNO1 in PCa. Microarray and bioinformatic analysis were carried out to detect the downstream targets and pathways regulated by PNO1.ResultsThe present study for the first time demonstrated PNO1 was up-regulated in PCa samples compared to normal tissues. ShRNA mediated knockdown of PNO1 significantly suppressed PCa proliferation and clone formation, however, induced PCa apoptosis. Microarray analysis and bioinformatics analysis revealed PNO1 was involved in regulating multiple cancer related biological processes, such as regulation of DNA repair, single organismal cell-cell adhesion, translational initiation, RNA splicing, transcription, and positive regulation of mRNA catabolic process. OF note, in vivo results showed PNO1 knockdown remarkably reduced the PCa growth rate. ConclusionsDespite more in-depth research is still required, this study showed PNO1 could serve as a potential biomarker for PCa.

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Exosomal PD-L1 and N-cadherin predict pulmonary metastasis progression for osteosarcoma patients

Journal of Nanobiotechnology ◽

10.1186/s12951-020-00710-6 ◽

2020 ◽

Vol 18 (1) ◽

Cited By ~ 1

Author(s):

Jun Wang ◽

Hongliang Zhang ◽

Xin Sun ◽

Xiaofang Wang ◽

Tingting Ren ◽

...

Keyword(s):

Pulmonary Metastasis ◽

Characteristic Curve ◽

Bioinformatic Analysis ◽

Benign Tumors ◽

Cancer Pathogenesis ◽

Healthy Donors ◽

Close Relationship ◽

Serum Exosomes

Abstract Background Recent studies indicated that exosomal programmed death-ligand 1 (PD-L1) derived from cancers could induce immunosuppression and tumor pathogenesis. However, it is unclear how exosomes influence osteosarcoma (OS) progression and whether PD-L1 also exists in serum exosomes (Sr-exosomes) of patients with osteosarcoma. We examined serum exosomes from 70 OS patients, 9 patients with benign tumors and 22 healthy donors. OS-derived exosomes were functionally evaluated in vivo and in vitro. Results The characteristics of exosomes derived from OS patient serum and OS cell lines were confirmed by several methods. We found OS patients had a higher level of exosomal PD-L1 compared to healthy donors. Meanwhile, OS patients with pulmonary metastasis also showed a relatively higher level of exosomal PD-L1 than patients without metastasis. Next, bioinformatic analysis demonstrated that Sr-exosomes isolated from OS patients may involve in the important process of immune function and cancer pathogenesis for OS patients. Co-expression network centered with PD-L1 among Sr-exosomal differently expressed mRNA demonstrated exosomal N-cadherin had a close relationship with exosomal PD-L1 expression. Then, we confirmed higher level of Sr-exosomal N-cadherin in OS patients with pulmonary metastasis compared to ones without metastasis. Furthermore, we elucidated osteosarcoma-derived exosomes and exosomal-PD-L1 promoted the pulmonary metastasis in metastatic models. ROC (Receiver Operating Characteristic Curve) analysis showed AUC (Area Under Curve) of 0.823 for exosomal PD-L1, 0.806 for exosomal N-cadherin and 0.817 for exosomal N-cadherin/E-cadherin to distinguish OS patients with pulmonary metastasis from ones without metastasis. Conclusions Osteosarcoma stimulates pulmonary metastasis by releasing exosomes, that carry PD-L1 and N-cadherin. Detection of exosomal PD-L1 and N-cadherin from serum of OS patients may predict pulmonary metastasis progression for OS patients.

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Long Noncoding RNA HAGLROS Promotes Cell Invasion and Metastasis by Sponging miR-152 and Upregulating ROCK1 Expression in Osteosarcoma

Computational and Mathematical Methods in Medicine ◽

10.1155/2020/7236245 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Kaifeng Zhou ◽

Jun Xu ◽

Xiaofan Yin ◽

Jiangni Xia

Keyword(s):

Noncoding Rna ◽

Molecular Mechanisms ◽

Luciferase Reporter ◽

Tissue Samples ◽

Normal Tissues ◽

Tumor Growth And Metastasis ◽

And Migration ◽

Proliferation And Invasion

Background. Long noncoding RNAs (lncRNAs) played a crucial role in a number of biological processes. lncRNA HAGLROS was demonstrated to facilitate cell proliferation and migration in various cancers. However, the functions and molecular mechanisms of HAGLROS in osteosarcoma remained to be elucidated. Methods. qRT-PCR assay was used to detect the relative expression of HAGLROS in osteosarcoma tissue samples and cells. CCK-8 and Transwell assays were performed to assess the effects of HAGLROS on OS cells proliferation and invasion. Luciferase reporter assay verified the interaction between ROCK1 and miR-152. Results. In our study, we found that the expression of HAGLROS increased osteosarcoma samples and cell lines compared with normal tissues and cells. HAGLROS knockdown inhibited certain functions of U2OS and SW1353 cells in vitro. Moreover, HAGLROS depletion inhibited tumor growth and metastasis in vivo. Mechanically, we found that HAGLROS sponged miR-152 to promote ROCK1 expression in U2OS and SW1353 cells. Conclusion. In summary, our study indicated that HAGLROS could promote osteosarcoma progression by sponging miR-152 to promote ROCK1 expression. The results showed HAGLROS/miR-152/ROCK1 axis might act as a novel therapeutic strategy for osteosarcoma.

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PNO1 promotes cell proliferation in prostate cancer

10.21203/rs.2.17848/v1 ◽

2019 ◽

Author(s):

Jianpeng Hu ◽

Feilun Cui ◽

Zhipeng Xv ◽

Jian Tan ◽

Zhengyu Wang

Keyword(s):

Prostate Cancer ◽

Rna Splicing ◽

Bioinformatic Analysis ◽

In Vitro Assays ◽

Multiple Cancer ◽

Translational Initiation ◽

Normal Tissues ◽

Potential Biomarker

Abstract Background Prostate cancer (PCa) is one of the most commonly diagnosed cancers. The functions of PNO1 in yeasts were involved in regulating ribosome and proteasome biogenesis. However, its roles in PCa remained largely unclear. Methods The present study evaluated the expression levels of PNO1 in PCa by using GSE45016, GSE55945 and GSE17951 datasets. Then, in vivo and in vitro assays were conducted to detect the biological functions of PNO1 in PCa. BALB/c mice were used for in vivo assay in this study. Microarray and bioinformatic analysis were carried out to detect the downstream targets and pathways regulated by PNO1. Results The present study for the first time demonstrated PNO1 was up-regulated in PCa samples compared to normal tissues. ShRNA mediated knockdown of PNO1 significantly suppressed PCa proliferation and clone formation, however, induced PCa apoptosis. Microarray analysis and bioinformatics analysis revealed PNO1 was involved in regulating multiple cancer related biological processes, such as regulation of DNA repair, single organismal cell-cell adhesion, translational initiation, RNA splicing, transcription, and positive regulation of mRNA catabolic process. OF note, in vivo results showed PNO1 knockdown remarkably reduced the PCa growth rate. Conclusions Despite more in-depth research is still required, this study showed PNO1 could serve as a potential biomarker for PCa.

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