Publications by authors named "Cheng-You Jia"

21 Publications

  • Page 1 of 1

MiR-9-1 Suppresses Cell Proliferation and Promotes Apoptosis by Targeting UHRF1 in Lung Cancer.

Technol Cancer Res Treat 2021 Jan-Dec;20:15330338211041191

Shanghai Tenth People's Hospital, 278245Tongji University School of Medicine, Shanghai, China.

Lung cancer is listed as the most common reason for cancer-related death all over the world despite diagnostic improvements and the development of chemotherapy and targeted therapies. MicroRNAs control both physiological and pathological processes including development and cancer. A microRNA-9 to 1 (miR-9 to 1) overexpression model in lung cancer cell lines was established and miR-9 to 1 was found to significantly suppress the proliferation rate in lung cancer cell lines, colony formation in vitro, and tumorigenicity in nude mice of A549 cells. Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) was then identified to direct target of miR-9 to 1. The inhibition of UHRF1 by miR-9 to 1 causes G1 arrest and p15, p16, and p21 were re-expressed in miR-9 to 1 group in mRNA level and protein level. Silence of UHRF1 expression in A549 cells resulted in the similar re-expression of p15, p16, p21 which is similar with miR-9 to 1 infection. Therefore, we concluded that UHRF1 is a new target for miR-9 to 1 to suppress cell proliferation by re-expression of tumor suppressors p15, p16, and p21 mediated by UHRF1.
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http://dx.doi.org/10.1177/15330338211041191DOI Listing
September 2021

Exosomal microRNA-15a from mesenchymal stem cells impedes hepatocellular carcinoma progression via downregulation of SALL4.

Cell Death Discov 2021 Aug 28;7(1):224. Epub 2021 Aug 28.

Department of Radiology, The Fourth Affiliated Hospital of Anhui Medical University, 230012, Hefei, China.

Hepatocellular carcinoma (HCC) is a heterogeneous tumor with an increased incidence worldwide accompanied by high mortality and dismal prognosis. Emerging evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes possess protective effects against various human diseases by transporting microRNAs (miRNAs or miRs). We aimed to explore the role of exosomal miR-15a derived from MSCs and its related mechanisms in HCC. Exosomes were isolated from transduced MSCs and co-incubated with Hep3B and Huh7 cells. miR-15a expression was examined by RT-qPCR in HCC cells, MSCs, and secreted exosomes. CCK-8, transwell, and flow cytometry were used to detect the effects of miR-15a or spalt-like transcription factor 4 (SALL4) on cell proliferative, migrating, invasive, and apoptotic properties. A dual-luciferase reporter gene assay was performed to validate the predicted targeting relationship of miR-15a with SALL4. Finally, in vivo experiments in nude mice were implemented to assess the impact of exosome-delivered miR-15a on HCC. The exosomes from MSCs restrained HCC cell proliferative, migrating, and invasive potentials, and accelerated their apoptosis. miR-15a was expressed at low levels in HCC cells and could bind to SALL4, thus curtailing the proliferative, migrating, and invasive abilities of HCC cells. Exosomes successfully delivered miR-15a to HCC cells. Exosomal miR-15a depressed tumorigenicity and metastasis of HCC tumors in vivo. Overall, exosomal miR-15a from MSCs can downregulate SALL4 expression and thereby retard HCC development.
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http://dx.doi.org/10.1038/s41420-021-00611-zDOI Listing
August 2021

Protein disulfide isomerase inhibits endoplasmic reticulum stress response and apoptosis via its oxidoreductase activity in colorectal cancer.

Cell Signal 2021 Oct 7;86:110076. Epub 2021 Jul 7.

Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China. Electronic address:

Protein disulfide isomerase (PDI), a principal endoplasmic reticulum resident oxidoreductase chaperone, is known to play a role in malignancies. This study aims to explore the molecular mechanism by which PDI regulates endoplasmic reticulum stress and the apoptosis signaling pathway in colorectal cancer (CRC). We determined the expression of PDI in CRC tissues and adjacent normal tissues. Gain- and loss- of function assays were conducted to evaluate the effects of PDI on oxidative stress, endoplasmic reticulum stress, and apoptosis in CRC cells, as reflected by hydrogen peroxide (HO) level and the expression of related proteins. PDI protein expression was upregulated in CRC tissues. Small molecule inhibitor of PDI or PDI knockdown reduced CRC cell viability and induced apoptosis. Overexpression of wild-type PDI augmented the viability of CRC cells and inhibited endoplasmic reticulum stress response and apoptosis. Small molecule inhibitor of PDI or PDI knockdown increased intracellular HO level and activated apoptosis signaling pathway, which could be reversed by wild-type PDI restoration. Moreover, the catalytic active site of C-terminal of PDI was found to be indispensable for the regulatory effects of PDI on HO levels, apoptosis and cell viability in CRC cells. Collectively, PDI inhibits endoplasmic reticulum stress and apoptosis of CRC cells through its oxidoreductase activity, thereby promoting the malignancy of CRC.
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http://dx.doi.org/10.1016/j.cellsig.2021.110076DOI Listing
October 2021

Construction of a Myc-associated ceRNA network reveals a prognostic signature in hepatocellular carcinoma.

Mol Ther Nucleic Acids 2021 Jun 1;24:1033-1050. Epub 2021 May 1.

Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.

Hepatocellular carcinoma (HCC) remains an extremely lethal disease worldwide. High-throughput methods have revealed global transcriptome dysregulation; however, a comprehensive investigation of the complexity and behavioral characteristics of the competing endogenous RNA (ceRNA) network in HCC is lacking. In this study, we extracted the transcriptome (RNA) sequencing data of 371 HCC patients from The Cancer Genome Atlas platform. With the comparison of the high Myc expression (Myc) tumor and low Myc expression (Myc) tumor groups in HCC, we identified 1,125 differentially expressed (DE) mRNAs, 589 long non-coding RNAs (lncRNAs), and 93 microRNAs (miRNAs). DE RNAs predicted the interactions necessary to construct an associated Myc ceRNA network, including 19 DE lncRNAs, 5 miRNAs, and 72 mRNAs. We identified a significant signature (long intergenic non-protein-coding [LINC] RNA 2691 [LINC02691] and LINC02499) that effectively predicted overall survival and had protective effects. The target genes of microRNA (miR)-212-3p predicted to intersect with DE mRNAs included SEC14-like protein 2 (SEC14L2) and solute carrier family 6 member 1 (SLC6A1), which were strongly correlated with survival and prognosis. With the use of the lncRNA-miRNA-mRNA axis, we constructed a ceRNA network containing four lncRNAs (LINC02691, LINC02499, LINC01354, and NAV2 antisense RNA 4), one miRNA (miR-212-3p), and two mRNAs (SEC14L2 and SLC6A1). Overall, we successfully constructed a mutually regulated ceRNA network and identified potential precision-targeted therapies and prognostic biomarkers.
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http://dx.doi.org/10.1016/j.omtn.2021.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167205PMC
June 2021

MicroRNA-499 serves as a sensitizer for lung cancer cells to radiotherapy by inhibition of CK2α-mediated phosphorylation of p65.

Mol Ther Oncolytics 2021 Jun 3;21:171-182. Epub 2021 Apr 3.

Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.

The present study aimed to define the tumor-suppressive role of microRNA-499 (miR-499) in lung cancer cells and its underlying mechanism. First, qRT-PCR analysis revealed poor expression of miR-499 in clinical samples and cell lines of lung cancer. Next, we performed loss- and gain-of-function experiments for the expression of miR-499 in lung cancer cells exposed to irradiation (IR) to determine the effect of miR-499 expression on cell viability and apoptosis as well as tumor growth. Results showed that overexpression of miR-499 inhibited cell viability, enhanced the radiosensitivity of lung cancer cells, and promoted cell apoptosis under IR. Furthermore, CK2α was verified to be a target of miR-499, and miR-499 was identified to repress p65 phosphorylation by downregulating CK2α expression, which ultimately diminished the survival rate of lung cancer cells under IR. Collectively, the key findings of the study illustrate the tumor-inhibiting function of miR-499 and confirmed that miR-499-mediated CK2α inhibition and altered p65 phosphorylation enhances the sensitivity of lung cancer cells to IR.
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http://dx.doi.org/10.1016/j.omto.2021.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099482PMC
June 2021

microRNA-873 inhibits self-renewal and proliferation of pancreatic cancer stem cells through pleckstrin-2-dependent PI3K/AKT pathway.

Cell Signal 2021 Aug 27;84:110025. Epub 2021 Apr 27.

Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tenth People's Hospital of Tongji University, Shanghai 200072, China. Electronic address:

Recent studies have emphasized microRNAs (miRs) as crucial regulators in the occurrence and development of pancreatic cancer that continues to be one of the deadliest malignancies with few effective therapies. The study aimed to investigate the functional role of miR-873 and its associated mechanism to unravel the biological characteristics of pancreatic cancer stem cells in tumor growth. The expression patterns of pleckstrin-2 (PLEK2) and miR-873 were detected in the pancreatic cancer tissues. Then to further investigate specific role of miR-873, the pancreatic cancer stem cells were treated with miR-873 mimic, PLEK2, small interfering RNA against PLEK2, LY294002 (inhibitor of phosphatidylinositol 3-kinase/protein kinase B [PI3K/AKT] pathway) to detect the relative gene expression as well as their effects on cell self-renewal, proliferation and apoptosis. Finally, the tumor formation in nude mice was measured to verify the preceding results in vivo. Pancreatic cancer tissues exhibited a decline of miR-873 expression and an enhancement of PLEK2 expression. miR-873 targeted PLEK2 and downregulated its expression, leading to inhibition of PI3K/AKT pathway. Overexpressed miR-873 or silenced PLEK2 inhibited the self-renewal and proliferation while promoting the apoptosis of pancreatic cancer stem cells. Tumor formation was inhibited by overexpressed miR-873 or silenced PLEK2 in nude mice. Overall, miR-873 can suppress the self-renewal and proliferation of pancreatic cancer stem cells by blocking PLEK2-dependent PI3K/AKT pathway. Hence, this study contributes to understanding the role of miR-873 in pancreatic cancer stem cells and its underlying molecular mechanisms to aid in the development of effective pancreatic cancer therapeutics.
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http://dx.doi.org/10.1016/j.cellsig.2021.110025DOI Listing
August 2021

MicroRNA-497-5p Is Downregulated in Hepatocellular Carcinoma and Associated with Tumorigenesis and Poor Prognosis in Patients.

Int J Genomics 2021 16;2021:6670390. Epub 2021 Mar 16.

Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China.

Background: MicroRNAs (miRNAs) have been demonstrated to exhibit important regulatory roles in multiple malignancies, including hepatocellular carcinoma (HCC). hsa-miR-497-5p was reported to involve in cancer progression and poor prognosis in many kinds of tumors. However, the expression and its clinical significance of hsa-miR-497-5p in HCC remain unclear.

Methods: In the present study, we investigated the expression of hsa-miR-497-5p in HCC and analyzed the correction of clinical features with prognosis. The expression levels of hsa-miR-497-5p and potential target genes were analyzed in HCC and adjacent noncancerous tissues using The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) datasets. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze hsa-miR-497-5p levels in 328 HCC tissues and 30 paired adjacent noncancer tissues. Overall survival (OS) and progression-free survival (PFS) of patients with HCC were assessed using the Kaplan-Meier method and the log-rank test.

Results: The hsa-miR-497-5p expression levels were decreased, and its target genes ACTG1, CSNK1D, PPP1CC, and BIRC5 were upregulated in HCC tissues compared with normal tissues. Lower levels of hsa-miR-497-5p expression and higher levels of the four target genes were significantly associated with higher tumor diameter. Moreover, patients with lower hsa-miR-497-5p expression and higher target genes levels had shorter OS.

Conclusion: The expression levels of hsa-miR-497-5p may play an important regulatory role in HCC and are closely correlated with HCC progression and poor prognosis in patients. The hsa-miR-497-5p may be a specific therapeutic target for the treatment of HCC.
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http://dx.doi.org/10.1155/2021/6670390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987441PMC
March 2021

microRNA-320b suppresses HNF4G and IGF2BP2 expression to inhibit angiogenesis and tumor growth of lung cancer.

Carcinogenesis 2021 May;42(5):762-771

Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China.

We examined the effect of microRNA-320b (miR-320b) on tumor growth and angiogenesis in lung cancer and also determined its downstream molecular mechanisms. Lung cancer tissues and adjacent non-cancerous tissues were collected from 66 patients with lung cancer. miR-320b expression was experimentally determined to be expressed at low level in cancer tissues. The results of gain-of-function experiments suggested that miR-320b overexpression suppressed cancer cell invasion, tube formation, tumor volume and angiogenesis in xenografted nude mice. Hepatocyte nuclear factor 4 gamma (HNF4G) was identified as a target of miR-320b based on in silico analysis. Dual-luciferase reporter gene assays further identified the binding relationship between HNF4G and miR-320b. Lung cancer tissues exhibited increased expression of HNF4G and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Meanwhile, HNF4G knockdown suppressed IGF2BP2 expression, thereby repressing cancer cell invasion and tube formation. Furthermore, IGF2BP2 modified m6A to increase the expression of thymidine kinase 1 (TK1), thus promoting angiogenesis. In nude mice, restoration of TK1 reversed the suppressive effect of miR-320b overexpression on tumor growth rate and CD31 expression. In conclusion, miR-320b suppresses lung cancer growth and angiogenesis by inhibiting HNF4G, IGF2BP2 and TK1.
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http://dx.doi.org/10.1093/carcin/bgab023DOI Listing
May 2021

Comprehensive analysis to identify DLEU2L/TAOK1 axis as a prognostic biomarker in hepatocellular carcinoma.

Mol Ther Nucleic Acids 2021 Mar 1;23:702-718. Epub 2021 Jan 1.

National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, China.

Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors that are harmful to human health. Increasing evidence has underscored the critical role of the competitive endogenous RNA (ceRNA) regulatory networks among various human cancers. However, the complexity and behavior characteristics of the ceRNA network in HCC were still unclear. In this study, we aimed to clarify a phosphatase and tensin homolog (PTEN)-related ceRNA regulatory network and identify potential prognostic markers associated with HCC. The expression profiles of three RNAs (long non-coding RNAs [lncRNAs], microRNAs [miRNAs], and mRNAs) were extracted from The Cancer Genome Atlas (TCGA) database. The DLEU2L-hsa-miR-100-5p/ hsa-miR-99a-5p-TAOK1 ceRNA network related to the prognosis of HCC was obtained by performing bioinformatics analysis. Importantly, we identified the DLEU2L/TAOK1 axis in the ceRNA by using correlation analysis, and it appeared to become a clinical prognostic model by Cox regression analysis. Furthermore, methylation analyses suggested that the abnormal upregulation of the DLEU2L/TAOK1 axis likely resulted from hypomethylation, and immune infiltration analysis showed that the DLEU2L/TAOK1 axis may have an impact on the changes in the tumor immune microenvironment and the development of HCC. In summary, the current study constructing a ceRNA-based DLEU2L/TAOK1 axis might be a novel important prognostic factor associated with the diagnosis and prognosis of HCC.
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http://dx.doi.org/10.1016/j.omtn.2020.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851426PMC
March 2021

Systematic analysis using a bioinformatics strategy identifies SFTA1P and LINC00519 as potential prognostic biomarkers for lung squamous cell carcinoma.

Am J Transl Res 2021 15;13(1):168-182. Epub 2021 Jan 15.

Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai 200072, China.

Lung cancer has high incidence and mortality rates, in which lung squamous cell carcinoma (LUSC) is a primary type of non-small cell lung carcinoma (NSCLC). The aim of our study was to discover long non-coding RNAs (lncRNAs) associated with diagnose and prognosis for LUSC. RNA sequencing data obtained from LUSC samples were extracted from The Cancer Genome Atlas database (TCGA). Two prognosis-associated lncRNAs (including SFTA1P and LINC00519) were selected from LUSC samples, and the expression levels were also verified to be associated abnormal in LUSC clinical samples. Our findings demonstrate that lncRNAs SFTA1P and LINC00519 exert important functions in human LUSC and may serve as new targets for LUSC diagnosis and therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847518PMC
January 2021

Identified GNGT1 and NMU as Combined Diagnosis Biomarker of Non-Small-Cell Lung Cancer Utilizing Bioinformatics and Logistic Regression.

Dis Markers 2021 6;2021:6696198. Epub 2021 Jan 6.

Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.

Non-small-cell lung cancer (NSCLC) is one of the most devastating diseases worldwide. The study is aimed at identifying reliable prognostic biomarkers and to improve understanding of cancer initiation and progression mechanisms. RNA-Seq data were downloaded from The Cancer Genome Atlas (TCGA) database. Subsequently, comprehensive bioinformatics analysis incorporating gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and the protein-protein interaction (PPI) network was conducted to identify differentially expressed genes (DEGs) closely associated with NSCLC. Eight hub genes were screened out using Molecular Complex Detection (MCODE) and cytoHubba. The prognostic and diagnostic values of the hub genes were further confirmed by survival analysis and receiver operating characteristic (ROC) curve analysis. Hub genes were validated by other datasets, such as the Oncomine, Human Protein Atlas, and cBioPortal databases. Ultimately, logistic regression analysis was conducted to evaluate the diagnostic potential of the two identified biomarkers. Screening removed 1,411 DEGs, including 1,362 upregulated and 49 downregulated genes. Pathway enrichment analysis of the DEGs examined the Ras signaling pathway, alcoholism, and other factors. Ultimately, eight prioritized genes (GNGT1, GNG4, NMU, GCG, TAC1, GAST, GCGR1, and NPSR1) were identified as hub genes. High hub gene expression was significantly associated with worse overall survival in patients with NSCLC. The ROC curves showed that these hub genes had diagnostic value. The mRNA expressions of GNGT1 and NMU were low in the Oncomine database. Their protein expressions and genetic alterations were also revealed. Finally, logistic regression analysis indicated that combining the two biomarkers substantially improved the ability to discriminate NSCLC. GNGT1 and NMU identified in the current study may empower further discovery of the molecular mechanisms underlying NSCLC's initiation and progression.
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http://dx.doi.org/10.1155/2021/6696198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806402PMC
January 2021

Targeting Long Non-coding RNA to Therapeutically Regulate Gene Expression in Cancer.

Mol Ther Nucleic Acids 2020 Sep 10;21:712-724. Epub 2020 Jul 10.

Department of Radiology, The Fourth Affiliated Hospital of Anhui Medical University, Hefei 230012, China; Cancer Institute, Nantong Tumor Hospital, Nantong 226631, China; Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China. Electronic address:

Long-chain non-coding RNAs (lncRNAs) are RNA molecules with a length greater than 200 nt and no function of encoding proteins. lncRNAs play a precise regulatory function at different levels of transcription and post-transcription, and they interact with various regulatory factors to regulate gene expression, and then participate in cell growth, differentiation, apoptosis, and other life processes. In recent years, studies have shown that the abnormal expression of lncRNAs is closely related to the occurrence and development of tumors, which is expected to become an effective biomarker in tumor diagnosis. The sequencing analysis of mutations in the whole tumor genome suggests that mutations in non-coding regions may play an important role in the occurrence and development of tumors. Therefore, in-depth study of lncRNAs is helpful to clarify the molecular mechanism of tumor occurrence and development and to provide new targets for tumor diagnosis and treatment. This review introduces the molecular mechanism and clinical application prospect of lncRNAs affecting tumor development from the perspective of gene expression and regulation.
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http://dx.doi.org/10.1016/j.omtn.2020.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412722PMC
September 2020

Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with Deficiency.

Mol Ther Oncolytics 2020 Mar 11;16:147-157. Epub 2020 Jan 11.

Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.

Functional elimination of p53 is a common feature of a large percentage of human malignancies. Here, we report the development of a pharmacological strategy aimed at restoring p53 function and its use for targeted therapy in p53-deficient mice. Specific inhibition of deubiquitinases ubiquitin-specific peptidase 14 (USP14) resulted in durable tumor regressions of autochthonous lymphomas and sarcomas in p53-deficient mice without affecting normal tissues, and therapeutic response was correlated with an increase in the ubiquitination of constitutive photomorphogenesis 9 (COP9) signalosome subunit 5 (COPS5), a key negative regulatory effector for p53. Inhibition of USP14 resulted in durable tumor regression through COPS5 deubiquitilation and a p53-dependent and -independent regulation mechanism by USP14. This series highlights the utility of proteasome deubiquitinating activity inhibition as a novel treatment paradigm for p53-deficient cancers. In addition, it provides preliminary evidence that inhibition of USP14 resulted in durable tumor regression through COPS5 deubiquitilation and p53-dependent and -independent regulation mechanism by USP14. These findings suggest that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target for patients with p53 deficiency.
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http://dx.doi.org/10.1016/j.omto.2019.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005481PMC
March 2020

Prognostic implications of decreased microRNA-101-3p expression in patients with non-small cell lung cancer.

Oncol Lett 2018 Dec 9;16(6):7048-7056. Epub 2018 Oct 9.

Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China.

To investigate the expression level of microRNA-101-3p (miR-101-3p) and its possible association with progression, prognosis and chemotherapy in patients with non-small cell lung cancer (NSCLC), the Gene Expression Omnibus (GEO) database was used. Quantitative polymerase chain reaction was used to verify the expression in 327 NSCLC and 42 adjacent normal lung tissues, of which 42 viable tissues were paired with nearby normal lung tissues. Based on the Cox regression model, univariate and multivariate analyses were used to address the factors that had effects on overall survival (OS) and disease-free survival (DFS) rate. Data from the GEO database demonstrated that the miR-101-3p expression in NSCLC was downregulated, compared with normal lung cancer. Survival analysis through univariate and multivariate models indicated that the miR-101-3p expression level was a crucial risk factor for OS and DFS in patients with NSCLC. A number of clinical parameters were determined to be associated with miR-101-3p expression, including tumor diameter, lymph node metastasis and tumor-node-metastasis stage. Adjuvant chemotherapy with high expression of miR-101-3p was determined to increase OS and DFS in patients with NSCLC, compared with patients with de novo or low expression of miR-101-3p. The present results demonstrated that miR-101-3p expression levels were associated with NSCLC progression and prognosis, which indicated that miR-101-3p may serve as a biomarker for patients with NSCLC who have received adjuvant chemotherapy.
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http://dx.doi.org/10.3892/ol.2018.9559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256371PMC
December 2018

MicroRNA‑mRNA integrated analysis based on a case of well‑differentiated thyroid cancer with both metastasis and metastatic recurrence.

Oncol Rep 2018 Dec 26;40(6):3803-3811. Epub 2018 Sep 26.

Department of Orthopedics, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.

The incidence of well‑differentiated thyroid cancer (WDTC) is rapidly increasing. Poor survival follows distant metastasis (DM) and recurrence. In the present study, we aimed to analyze the expression alterations in different stages of WDTC and the regulatory mechanism of DM and the recurrence of DM. A male patient diagnosed with follicular thyroid cancer and distant metastasis in the eleventh thoracic vertebrae received total thyroidectomy and the removal of a metastatic lesion. A local relapse was found in the vertebrae after four‑time iodine‑131 treatment. We performed mRNA and microRNA microarray on the paracancerous, cancerous, metastatic and metastatic recurrent tissue. In combination with the data of The Cancer Genome Atlas (TCGA), we used bioinformatics approaches to analyze the common alterations and microRNA‑mRNA interactions among the processes of tumorigenesis and metastasis. Metastatic lesions and recurrent lesions were used to investigate the molecular mechanism of tumor evolution and recurrence in this case. A total of four mRNAs and two microRNAs were newly found to be related to patient survival in WDTC. The microRNA‑mRNA interactions were predicted for the overlapped mRNAs and microRNAs. Lineage deregulation of genes, such as C‑X‑C motif chemokine receptor 4 (CXCR4) and thyroglobulin (TG) were found from the tumorigenic stage to the metastatic stage. The ribosome pathway was highly enriched in the bone metastasis compared with the cancerous tissue. The downstreaming effects of p53 were impaired in the recurrent lesion due to deregulation of several functional genes. The integrated analysis with TCGA data indicated several prognostic markers and regulatory networks for potential treatment. Our results also provided possible molecular mechanisms in which the ribosome and p53 pathways may respectively contribute to bone metastasis and local recurrence of metastasis.
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http://dx.doi.org/10.3892/or.2018.6739DOI Listing
December 2018

Tumor suppressive microRNA-124a inhibits stemness and enhances gefitinib sensitivity of non-small cell lung cancer cells by targeting ubiquitin-specific protease 14.

Cancer Lett 2018 07 24;427:74-84. Epub 2018 Apr 24.

Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China. Electronic address:

Increasing evidence has shown that microRNAs (miRNAs) play a significant functional role by directly regulating respective targets in cancer stem cell (CSC)-induced non-small cell lung cancer (NSCLC) progression and resistance to therapy. In this study, we found that hsa-miR-124a was downregulated during spheroid formation of the NSCLC cell lines SPC-A1 and NCI-H1650 and NSCLC tissues compared with normal lung cells and tissues. Patients with lower hsa-miR-124a expression had shorter overall survival (OS) and progression free survival (PFS). Moreover, ubiquitin-specific protease 14 (USP14) was confirmed to be a direct target of hsa-miR-124a. Furthermore, concomitant low hsa-miR-124a expression and high USP14 expression were correlated with a shorter median OS and PFS in NSCLC patients. Cellular functional analysis verified that the tumor suppressor hsa-miR-124a negatively regulated cell growth and self-renewal, and promoted apoptosis and gefitinib sensitivity of lung cancer stem cells by suppressing its target gene USP14. Our results provide the first evidence that USP14 is a direct target of hsa-miR-124a, and that hsa-miR-124a inhibits stemness and enhances the gefitinib sensitivity of NSCLC cells by targeting USP14. Thus, hsa-miR-124a and USP14 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC.
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http://dx.doi.org/10.1016/j.canlet.2018.04.022DOI Listing
July 2018

Identification of miR‑124a as a novel diagnostic and prognostic biomarker in non‑small cell lung cancer for chemotherapy.

Mol Med Rep 2017 Jul 17;16(1):238-246. Epub 2017 May 17.

Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China.

Previous studies have suggested that dysregulation of microRNA (miR) -124a is associated with various types of human cancer. However, there are few studies reporting the level of miR‑124a expression in non‑small cell lung cancer (NSCLC). The present study investigated the association between miR‑124a and NSCLC by analyzing the differential expression of miR‑124a in NSCLC using the GEO database, as well as subsequently performing reverse transcription‑quantitative polymerase chain reaction analysis on 160 NSCLC biopsies, 32 of which were paired with adjacent normal tissues. The results indicated that mir‑124a expression levels were decreased in NSCLC tumor biopsies compared with adjacent normal tissues. The overall survival (OS) in patients with a high expression of miR‑124a was prolonged relative to patients with low expression of miR‑124a. The expression levels of miR‑124a were associated with clinical characteristics, including lymph‑node metastasis, tumor differentiation, tumor node metastasis (TNM) stage and diameter. Frequently, lymph‑node metastasis, TNM stage, diameter and lack of chemotherapy have been associated with a worse prognosis in patients. In addition, the present study identified that high expression of miR‑124awith chemotherapy may increase OS. In conclusion, the current study demonstrated that miR‑124a was downregulated in NSCLC, and miR‑124a was a potential prognostic tumor biomarker response to chemotherapy.
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http://dx.doi.org/10.3892/mmr.2017.6595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482144PMC
July 2017

Association of glutathione S-transferase M1, T1, and P1 polymorphisms with renal cell carcinoma: evidence from 11 studies.

Tumour Biol 2014 Apr 15;35(4):3867-73. Epub 2013 Dec 15.

Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, People's Republic of China.

The glutathione S-transferases (GSTs) are a gene superfamily of phase II metabolic enzymes that has attracted a considerable attention as a candidate gene for renal cell carcinoma (RCC) based on its enzyme function as a key factor in biotransformation pathways. In the past decade, a number of case-control studies were conducted to investigate the association of GST genetic polymorphisms and RCC risk. However, studies on the association between GST (GSTM1, GSTT1, and GSTP1) polymorphisms and RCC remain to be conflicting. To derive a more precise estimation of the relationship, a meta-analysis of 2,189 cases and 3,817 controls from 11 case-control studies was performed. Overall, the summarized odds ratio for RCC of the GSTM1 null and GSTT1 null polymorphisms was 1.02 (95% confidence interval (CI) 0.91-1.15, P = 0.70) and 1.28 (95% CI 0.96-1.72, P = 0.09), respectively. No significant results were observed in heterozygous and homozygous genotypes when compared with wild-type genotype for GSTP1 I105V polymorphism. However, the GSTM1-GSTT1 interaction analysis showed that the dual null genotype of GSTM1/GSTT1 was significantly associated with an increased RCC risk (odds ratio (OR) = 1.42, 95% CI 1.14-1.76, P = 0.001). In the stratified analyses by ethnicity, significant gene-disease association was obtained among Asians for GSTT1 and GSTP1 polymorphisms. In our meta-analysis, the associations between variations of GSTs and RCC may vary in different ethnic populations, and the interaction between unfavorable GST genotypes may exist.
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http://dx.doi.org/10.1007/s13277-013-1513-5DOI Listing
April 2014

MicroRNA-223 regulates FOXO1 expression and cell proliferation.

FEBS Lett 2012 Apr 8;586(7):1038-43. Epub 2012 Mar 8.

Department of Children's Health Care, Yu Ying Children's Hospital, Wenzhou Medical College, Wenzhou, PR China.

In HCT116 colorectal cancer cells, HeLa cervical cancer cells and HuH-7 hepatoma cells, miR-223 is expressed at a low level. Through infection with lentivirus containing miR-223 precursor, miR-223 [corrected] was overexpressed in all these cells. Interestingly, the expression levels of FOXO1 mRNA and protein, and phosphorylation levels became significantly lower than those of their control. FOXO1 was down-regulated mainly in the cytoplasm, while the nuclear FOXO1 level became relatively high compared to the cytoplasm. As the unphosphorylated active form of FOXO1 increased in the cells, cyclin D1/p21/p27 were up-regulated at either mRNA or protein level. Proliferation of the cells was also greatly inhibited when miR-223 was over-expressed. Therein, our data suggest that miR-223 regulates FOXO1 expression and cell proliferation.
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http://dx.doi.org/10.1016/j.febslet.2012.02.050DOI Listing
April 2012

MiR-223 suppresses cell proliferation by targeting IGF-1R.

PLoS One 2011 2;6(11):e27008. Epub 2011 Nov 2.

Department of Biochemistry and Molecular Biology, Key Lab of Glycoconjugate Research, Ministry of Public Health, Shanghai Medical College, Fudan University, Shanghai, China.

To study the roles of microRNA-223 (miR-223) in regulation of cell growth, we established a miR-223 over-expression model in HeLa cells infected with miR-223 by Lentivirus pLL3.7 system. We observed in this model that miR-223 significantly suppressed the proliferation, growth rate, colony formation of HeLa cells in vitro, and in vivo tumorigenicity or tumor formation in nude mice. To investigate the mechanisms involved, we scanned and examined the potential and putative target molecules of miR-223 by informatics, quantitative PCR and Western blot, and found that insulin-like growth factor-1 receptor (IGF-1R) was the functional target of miR-223 inhibition of cell proliferation. Targeting IGF-1R by miR-223 was not only seen in HeLa cells, but also in leukemia and hepatoma cells. The downstream pathway, Akt/mTOR/p70S6K, to which the signal was mediated by IGF-1R, was inhibited as well. The relative luciferase activity of the reporter containing wild-type 3'UTR(3'untranslated region) of IGF-1R was significantly suppressed, but the mutant not. Silence of IGF-1R expression by vector-based short hairpin RNA resulted in the similar inhibition with miR-223. Contrarily, rescued IGF-1R expression in the cells that over-expressed miR-223, reversed the inhibition caused by miR-223 via introducing IGF-1R cDNA that didn't contain the 3'UTR. Meanwhile, we also noted that miR-223 targeted Rasa1, but the downstream molecules mediated by Rasa1 was neither targeted nor regulated. Therefore we believed that IGF-1R was the functional target for miR-223 suppression of cell proliferation and its downstream PI3K/Akt/mTOR/p70S6K pathway suppressed by miR-223 was by targeting IGF-1R.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0027008PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206888PMC
March 2012

3'-Sulfo-Le(x) is important for regulation of integrin subunit alphaV.

Biochemistry 2010 Sep;49(36):7811-20

Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, China.

Carbohydrate structures with a 3'-sulfo betaGal linkage, such as 3'-sulfo-Le(x), can be synthesized by Gal:3-O-sulfotransferase-2 (Gal3ST-2) catalysis, but little is known about their roles in many biological processes. To investigate the role of Gal3ST-2 and its product 3'-sulfo-Le(x), we depleted Gal3ST-2 via siRNA and added exogenous Lewis-x trisaccharide 3'-sulfate sodium salt in human SMMC7721 hepatoma cells. After siRNA transfection, a striking morphological change in SMMC7721 hepatoma cells from polygon to shuttle shape and a significant decrease in the level of adhesion to sL-selectin, HUVEC, fibronectin, vitronectin, and fibrinogen were observed. The expression of integrin subunit alphaV was markedly downregulated, and 3'-sulfated subunit alphaV almost disappeared in the transfectants. The level of cell surface integrin alphaVbeta3 was reduced simultaneously, although total subunit beta3 underwent almost no change. After treatment with exogenous Lewis-x 3'-sulfate, cellular integrin subunit alphaV was upregulated and the level of cell surface integrin alphaVbeta3 was elevated. Interestingly, knockdown of Gal3ST-2 expression effectively inhibited cell proliferation, and the result was significantly correlated with the decrease in the levels of ILK, phosphorylated AKT, and ERK. On the other hand, treatment with Lewis-x trisaccharide 3'-sulfate sodium salt greatly upregulated the phosphorylation of AKT and ERK. Our results also indicated that downregulation of Gal3ST-2 via siRNA transfection was associated with the decrease in the level of expression of anti-apoptotic protein, Bcl-2, with a consequent decrease in the ratios for Bcl-2 to Bax. By exposure to Lewis-x trisaccharide 3'-sulfate sodium salt, the apoptotic response of cells was inhibited. Therefore, Gal3ST-2 and its product, 3'-sulfo-Le(x), were involved in regulation of integrin subunit alphaV and might be associated with cancer cell regulation.
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http://dx.doi.org/10.1021/bi101040kDOI Listing
September 2010
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