Identification and Validation of lncRNA-Related Prognostic Signatures in Cholangiocarcinoma

Abstract Background and Aims: Cholangiocarcinoma (CCA), the second most common hepatobiliary cancer, is associated with poor prognosis. Therefore, there is a need to elucidate on the pathogenic mechanisms of CCA. In this study, we aimed at identifying lncRNA-related prognostic signatures for CCA through bioinformatics analysis and further validated their functions in CCA tumorigenesis and progression.Methods: The RNA-seq data of CCA were downloaded from public databases. Differentially expressed lncRNAs (DElncRNAs) were screened using R packages. Then, candidate OS- and DFS-related DElncRNAs were selected through Kaplan–Meier survival analysis. Furthermore, LASSO regression analyses were performed to establish two prognostic signatures, termed the OS and DFS signatures, respectively. Multivariate COX models and nomograms for overall survival (OS) and disease-free survival (DFS) were established based on OS/DFS signature and clinical data. Hub lncRNAs were identified and enrichment analyses performed to explore their potential functions. Finally, in vitro and in vivo models were used to validate the effects of the hub lncRNAs in CCA tumorigenesis and progression.Results: A total of 925 DElncRNAs were selected, from which six candidate OS-related lncRNAs and 15 candidate DFS-related lncRNAs were identified. The OS and DFS signatures were then established using four lncRNAs, respectively. We found that the OS signature and vascular invasion were significant independent risk factors for OS outcomes of CCA, while the DFS signature, vascular invasion and CA19-9 were significant independent risk factors for DFS outcomes of CCA. MiR4435-2HG and GAPLINC were selected as hub lncRNAs because they were included in both OS and DFS signatures. GO and KEGG enrichment analyses revealed that the two hub lncRNAs were involved in CCA tumorigenesis and progression. Finally, we constructed in vitro and in vivo models and revealed that the lncRNAs, MiR4435-2HG and GAPLINC can prompt CCA proliferation and migration in vitro and in vivo.Conclusions: The established OS and DFS signatures, which were based on DElncRNAs, are independent risk factors for OS and DFS of CCA patients, respectively. MIR4435-2HG and GAPLINC were identified as hub lncRNAs. In vitro and in vivo models revealed that MiR4435-2HG and GAPLINC can prompt CCA progression, which might be novel prognostic biomarkers and therapeutic targets for CCA.

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Diaphanous related formin 3 knockdown suppresses cell proliferation and metastasis of osteosarcoma cells

Discover Oncology ◽

10.1007/s12672-021-00415-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Zehua Zhang ◽

Fei Dai ◽

Fei Luo ◽

Wenjie Wu ◽

Shuai Zhang ◽

...

Keyword(s):

Cell Proliferation ◽

Tumor Therapy ◽

Disease Free Survival ◽

Tumor Stage ◽

Migration And Invasion ◽

Osteosarcoma Cell ◽

Proliferation And Metastasis ◽

New Biomarkers

AbstractOsteosarcoma is a malignant osteoblastic tumor that can gravely endanger the lives and health of children and adolescents. Therefore, there is an urgent need to explore new biomarkers for osteosarcoma and determine new targeted therapies to improve the efficacy of osteosarcoma treatment. Diaphanous related formin 3 (DIAPH3) promotes tumorigenesis in hepatocellular carcinoma and lung adenocarcinoma, suggesting that DIAPH3 may be a target for tumor therapy. To date, there have been no reports on the function of DIAPH3 in osteosarcoma. DIAPH3 protein expression in osteosarcoma tissues and healthy bone tissues adjacent to cancer cells was examined by immunohistochemical staining. DIAPH3 mRNA expression correlates with overall survival and reduced disease-free survival. DIAPH3 protein is upregulated in osteosarcoma tissues, and its expression is significantly associated with tumor size, tumor stage, node metastasis, and distant metastasis. Functional in vitro experiments revealed that DIAPH3 knockdown suppressed cell proliferation and suppressed cell migration and invasion of osteosarcoma cell lines MG-63 and HOS. Functional experiments demonstrated that DIAPH3 knockdown inhibited subcutaneous tumor growth and lung metastasis in vivo. In conclusion, DIAPH3 expression can predict the clinical outcome of osteosarcoma. In addition, DIAPH3 is involved in the proliferation and metastasis of osteosarcoma, and as such, DIAPH3 may be a potential therapeutic target for osteosarcoma.

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Double-targeting CDCA8 and E2F1 inhibits the growth and migration of malignant glioma

Cell Death and Disease ◽

10.1038/s41419-021-03405-4 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Xiaoxiong Wang ◽

Heping Wang ◽

Jiajun Xu ◽

Xu Hou ◽

Haoqiang Zhan ◽

...

Keyword(s):

Malignant Glioma ◽

Malignant Tumors ◽

Disease Free Survival ◽

High Grade Glioma ◽

Poor Overall Survival ◽

Survival Prognosis ◽

Who Grade ◽

And Migration

AbstractHigh-grade glioma is the most common and aggressive primary brain tumor in adults with poor therapeutic efficiency and survival prognosis. Cell division cycle associated 8 (CDCA8) has been well known as a cell cycle regulator and tumor promotor in various malignant tumors. However, its biological role in glioma still remains unclear. Our results showed that high level of CDCA8 was significantly correlated with advanced WHO grade and poor overall survival and disease-free survival prognosis. In vitro and in vivo investigations demonstrated that CDCA8 promoted the glioma malignancy by promoting cell proliferation, cell migration, and inhibiting cell apoptosis. Moreover, we found its synergetic biological protein—E2F1 by the gene microarray chip. In this study, we revealed that CDCA8 synergized with E2F1 facilitated the proliferation and migration of glioma. In conclusion, our study provides a novel promising therapeutic targets and prognostic biomarkers for malignant glioma treatment.

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TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

Cell Death and Disease ◽

10.1038/s41419-021-03734-4 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Sha Zhou ◽

Jianhong Peng ◽

Liuniu Xiao ◽

Caixia Zhou ◽

Yujing Fang ◽

...

Keyword(s):

Colorectal Cancer ◽

Disease Free Survival ◽

Free Survival ◽

Epigenetic Regulator ◽

Crc Management ◽

Disease Free ◽

Resistance To Chemotherapy

AbstractResistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). Here, we identified TRIM25 as an epigenetic regulator of oxaliplatin (OXA) resistance in CRC. The level of TRIM25 in OXA-resistant patients who experienced recurrence during the follow-up period was significantly higher than in those who had no recurrence. Patients with high expression of TRIM25 had a significantly higher recurrence rate and worse disease-free survival than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited, while overexpression of TRIM25 increased, CRC cell survival after OXA treatment. In addition, TRIM25 promoted the stem cell properties of CRC cells both in vitro and in vivo. Importantly, we demonstrated that TRIM25 inhibited the binding of E3 ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2, and promoting OXA resistance. Our study contributes to a better understanding of OXA resistance and indicates that inhibitors against TRIM25 might be an excellent strategy for CRC management in clinical practice.

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Biofilm Formation by and Antifungal Susceptibility of Candida Isolates from Urine

Applied and Environmental Microbiology ◽

10.1128/aem.02439-06 ◽

2007 ◽

Vol 73 (6) ◽

pp. 1697-1703 ◽

Cited By ~ 86

Author(s):

N. Jain ◽

R. Kohli ◽

E. Cook ◽

P. Gialanella ◽

T. Chang ◽

...

Keyword(s):

Risk Factors ◽

Growth Medium ◽

Biofilm Formation ◽

Chart Review ◽

Antifungal Susceptibility ◽

Retrospective Chart Review ◽

Urine Samples ◽

Rpmi Medium

ABSTRACT Biofilm formation (BF) in the setting of candiduria has not been well studied. We determined BF and MIC to antifungals in Candida spp. isolates grown from urine samples of patients and performed a retrospective chart review to examine the correlation with risk factors. A total of 67 Candida spp. isolates were grown from urine samples from 55 patients. The species distribution was C. albicans (54%), C. glabrata (36%), and C. tropicalis (10%). BF varied greatly among individual Candida isolates but was stable in sequential isolates during chronic infection. BF also depended on the growth medium and especially in C. albicans was significantly enhanced in artificial urine (AU) compared to RPMI medium. In nine of the C. albicans strains BF was 4- to 10-fold higher in AU, whereas in three of the C. albicans strains and two of the C. glabrata strains higher BF was measured in RPMI medium than in AU. Determination of the MICs showed that planktonic cells of all strains were susceptible to amphotericin B (AMB) and caspofungin (CASPO) and that three of the C. glabrata strains and two of the C. albicans strains were resistant to fluconazole (FLU). In contrast, all biofilm-associated adherent cells were resistant to CASPO and FLU. The biofilms of 14 strains (28%) were sensitive to AMB (MIC50 of <1 μg/ml). Correlation between degree of BF and MIC of AMB was not seen in RPMI grown biofilms but was present when grown in AU. A retrospective chart review demonstrated no correlation of known risk factors of candiduria with BF in AU or RPMI. We conclude that BF is a stable characteristic of Candida strains that varies greatly among clinical strains and is dependent on the growth medium. Resistance to AMB is associated with higher BF in AU, which may represent the more physiologic medium to test BF. Future studies should address whether in vitro BF can predict treatment failure in vivo.

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GLRX3, a novel cancer stem cell-related secretory biomarker of pancreatic ductal adenocarcinoma

BMC Cancer ◽

10.1186/s12885-021-08898-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jung Hyun Jo ◽

Sun A Kim ◽

Jeong Hoon Lee ◽

Yu Rang Park ◽

Chanyang Kim ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Cancer Progression ◽

Biomarker Discovery ◽

Disease Free Survival ◽

Tumor Formation ◽

Ductal Adenocarcinoma ◽

Curative Surgery ◽

In Vitro Proliferation

Abstract Background Cancer stem cells (CSCs) are implicated in carcinogenesis, cancer progression, and recurrence. Several biomarkers have been described for pancreatic ductal adenocarcinoma (PDAC) CSCs; however, their function and mechanism remain unclear. Method In this study, secretome analysis was performed in pancreatic CSC-enriched spheres and control adherent cells for biomarker discovery. Glutaredoxin3 (GLRX3), a novel candidate upregulated in spheres, was evaluated for its function and clinical implication. Results PDAC CSC populations, cell lines, patient tissues, and blood samples demonstrated GLRX3 overexpression. In contrast, GLRX3 silencing decreased the in vitro proliferation, migration, clonogenicity, and sphere formation of cells. GLRX3 knockdown also reduced tumor formation and growth in vivo. GLRX3 was found to regulate Met/PI3K/AKT signaling and stemness-related molecules. ELISA results indicated GLRX3 overexpression in the serum of patients with PDAC compared to that in healthy controls. The sensitivity and specificity of GLRX3 for PDAC diagnosis were 80.0 and 100%, respectively. When GLRX3 and CA19–9 were combined, sensitivity was significantly increased to 98.3% compared to that with GLRX3 or CA19–9 alone. High GLRX3 expression was also associated with poor disease-free survival in patients receiving curative surgery. Conclusion Overall, these results indicate GLRX3 as a novel diagnostic marker and therapeutic target for PDAC targeting CSCs.

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Nomogram for Predicting COVID-19 Disease Progression Based on Single-Center Data: Observational Study and Model Development (Preprint)

10.2196/preprints.19588 ◽

2020 ◽

Author(s):

Tao Fan ◽

Bo Hao ◽

Shuo Yang ◽

Bo Shen ◽

Zhixin Huang ◽

...

Keyword(s):

Risk Factors ◽

Regression Analysis ◽

Clinical Characteristics ◽

Cox Regression ◽

Disease Onset ◽

Lasso Regression ◽

Prediction Ability ◽

Calibration Curves ◽

Independent Risk Factors ◽

Critical Patients

BACKGROUND In late December 2019, a pneumonia caused by SARS-CoV-2 was first reported in Wuhan and spread worldwide rapidly. Currently, no specific medicine is available to treat infection with COVID-19. OBJECTIVE The aims of this study were to summarize the epidemiological and clinical characteristics of 175 patients with SARS-CoV-2 infection who were hospitalized in Renmin Hospital of Wuhan University from January 1 to January 31, 2020, and to establish a tool to identify potential critical patients with COVID-19 and help clinical physicians prevent progression of this disease. METHODS In this retrospective study, clinical characteristics of 175 confirmed COVID-19 cases were collected and analyzed. Univariate analysis and least absolute shrinkage and selection operator (LASSO) regression were used to select variables. Multivariate analysis was applied to identify independent risk factors in COVID-19 progression. We established a nomogram to evaluate the probability of progression of the condition of a patient with COVID-19 to severe within three weeks of disease onset. The nomogram was verified using calibration curves and receiver operating characteristic curves. RESULTS A total of 18 variables were considered to be risk factors after the univariate regression analysis of the laboratory parameters (P<.05), and LASSO regression analysis screened out 10 risk factors for further study. The six independent risk factors revealed by multivariate Cox regression were age (OR 1.035, 95% CI 1.017-1.054; P<.001), CK level (OR 1.002, 95% CI 1.0003-1.0039; P=.02), CD4 count (OR 0.995, 95% CI 0.992-0.998; P=.002), CD8 % (OR 1.007, 95% CI 1.004-1.012, P<.001), CD8 count (OR 0.881, 95% CI 0.835-0.931; P<.001), and C3 count (OR 6.93, 95% CI 1.945-24.691; P=.003). The areas under the curve of the prediction model for 0.5-week, 1-week, 2-week and 3-week nonsevere probability were 0.721, 0.742, 0.87, and 0.832, respectively. The calibration curves showed that the model had good prediction ability within three weeks of disease onset. CONCLUSIONS This study presents a predictive nomogram of critical patients with COVID-19 based on LASSO and Cox regression analysis. Clinical use of the nomogram may enable timely detection of potential critical patients with COVID-19 and instruct clinicians to administer early intervention to these patients to prevent the disease from worsening.

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CTPS1 promotes malignant progression of triple-negative breast cancer with transcriptional activation by YBX1

Journal of Translational Medicine ◽

10.1186/s12967-021-03206-5 ◽

2022 ◽

Vol 20 (1) ◽

Author(s):

Yuxiang Lin ◽

Jie Zhang ◽

Yan Li ◽

Wenhui Guo ◽

Lili Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Triple Negative Breast Cancer ◽

Transcriptional Activation ◽

Triple Negative ◽

Pearson Correlation ◽

Disease Free Survival ◽

Luciferase Reporter

Abstract Background Cytidine nucleotide triphosphate synthase 1 (CTPS1) is a CTP synthase which play critical roles in DNA synthesis. However, its biological regulation and mechanism in triple-negative breast cancer (TNBC) has not been reported yet. Methods The expression of CTPS1 in TNBC tissues was determined by GEO, TCGA databases and immunohistochemistry (IHC). The effect of CTPS1 on TNBC cell proliferation, migration, invasion, apoptosis and tumorigenesis were explored in vivo and in vitro. In addition, the transcription factor Y-box binding protein 1 (YBX1) was identified by bioinformatics methods, dual luciferase reporter and chromatin immunoprecipitation (CHIP) assays. Pearson correlation analysis was utilized to assess the association between YBX1 and CTPS1 expression. Results CTPS1 expression was significantly upregulated in TNBC tissues and cell lines. Higher CTPS1 expression was correlated with a poorer disease-free survival (DFS) and overall survival (OS) in TNBC patients. Silencing of CTPS1 dramatically inhibited the proliferation, migration, invasion ability and induced apoptosis of MDA-MB-231 and HCC1937 cells. Xenograft tumor model also indicated that CTPS1 knockdown remarkably reduced tumor growth in mice. Mechanically, YBX1 could bind to the promoter of CTPS1 to promote its transcription. Furthermore, the expression of YBX1 was positively correlated with CTPS1 in TNBC tissues. Rescue experiments confirmed that the enhanced cell proliferation and invasion ability induced by YBX1 overexpression could be reversed by CTPS1 knockdown. Conclusion Our data demonstrate that YBX1/CTPS1 axis plays an important role in the progression of TNBC. CTPS1 might be a promising prognosis biomarker and potential therapeutic target for patients with triple-negative breast cancer.

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CircBCBM1 Promotes Breast Cancer Brain Metastasis via miR-125a/BRD4 Axis

10.21203/rs.3.rs-130879/v1 ◽

2020 ◽

Author(s):

Bo Fu ◽

Wei Liu ◽

Peng Li ◽

Li Pan ◽

Ke Li ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Luciferase Reporter ◽

Circular Rnas ◽

Breast Cancer Patients ◽

Breast Cancer Brain Metastasis ◽

Tumorigenesis And Progression ◽

And Migration

Abstract Background: Accumulating evidence indicates that circular RNAs (circRNAs) play critical roles in tumorigenesis and progression of various cancers. We previously identified a novel upregulated circRNA, circBCBM1 (hsa_circ_0001944), in the context of breast cancer brain metastasis. However, the potential biological function and molecular mechanism of circBCBM1 in breast cancer brain metastasis remain largely unknown.Methods: In this reserch, we validated the expression and characterization of circBCBM1 through RT-qPCR, Sanger sequencing, RNase R assay and fluorescence in situ hybridization (FISH). Functional experiments were performed to determine the effect of circBCBM1 on growth and metastasis of 231-BR cells both in vitro and in vivo. The regulatory mechanisms among circBCBM1, miR-125a (has-miR-125a-5p), and BRD4 (bromodomain containing 4) were investigated by RNA immunoprecipitation (RIP), RNA pull-down, luciferase reporter assay and western blot. Results: Our findings demonstrated that circBCBM1 is a stable and cytoplasmic circRNA. Functionally, silencing of circBCBM1 led to decreased proliferation and migration of 231-BR cells whereas elevated circBCBM1 expression showed reverse effects in vitro. These findings were confirmed in vivo in mouse models, as knockdown of circBCBM1 significantly decreased growth and brain metastases of 231-BR cells. Mechanistically, circBCBM1 functions as an endogenous miR-125a sponge to inhibit miR-125a activity, resulting in the upregulation of BRD4 expression and subsequent upregulation of MMP9 (matrix metallopeptidase 9) through Sonic hedgehog (SHH) signaling pathway. Importantly, circBCBM1 was markedly upregulated in the breast cancer brain metastasis cells and clinical tissue and plasma samples; besides, the overexpression of circBCBM1 in primary cancerous tissues was associated with shorter brain metastasis-free survival (BMFS) of breast cancer patients.Conclusions: These findings indicate that circBCBM1 is involved in breast cancer brain metastasis via circBCBM1/miR-125a/BRD4 axis, which sheds light on the pathogenic mechanism of circBCBM1 and provides translational evidence that circBCBM1 may serve as a novel diagnostic or prognostic biomarker and potential therapeutic target for breast cancer brain metastasis.

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Dual PI3 K/mTOR inhibition reduces prostate cancer bone engraftment altering tumor-induced bone remodeling

Tumor Biology ◽

10.1177/1010428318771773 ◽

2018 ◽

Vol 40 (4) ◽

pp. 101042831877177 ◽

Cited By ~ 2

Author(s):

Andrea Mancini ◽

Alessandro Colapietro ◽

Simona Pompili ◽

Andrea Del Fattore ◽

Simona Delle Monache ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Therapeutic Potential ◽

Disease Free Survival ◽

Bone Lesions ◽

Metastatic Progression ◽

Mtor Inhibition ◽

Osteoblast Activity

Morbidity in advanced prostate cancer patients is largely associated with bone metastatic events. The development of novel therapeutic strategies is imperative in order to effectively treat this incurable stage of the malignancy. In this context, Akt signaling pathway represents a promising therapeutic target able to counteract biochemical recurrence and metastatic progression in prostate cancer. We explored the therapeutic potential of a novel dual PI3 K/mTOR inhibitor, X480, to inhibit tumor growth and bone colonization using different in vivo prostate cancer models including the subcutaneous injection of aggressive and bone metastatic (PC3) and non-bone metastatic (22rv1) cell lines and preclinical models known to generate bone lesions. We observed that X480 both inhibited the primary growth of subcutaneous tumors generated by PC3 and 22rv1 cells and reduced bone spreading of PCb2, a high osteotropic PC3 cell derivative. In metastatic bone, X480 inhibited significantly the growth and osteolytic activity of PC3 cells as observed by intratibial injection model. X480 also increased the bone disease-free survival compared to untreated animals. In vitro experiments demonstrated that X480 was effective in counteracting osteoclastogenesis whereas it stimulated osteoblast activity. Our report provides novel information on the potential activity of PI3 K/Akt inhibitors on the formation and progression of prostate cancer bone metastases and supports a biological rationale for the use of these inhibitors in castrate-resistant prostate cancer patients at high risk of developing clinically evident bone lesions.

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KIF4A Regulates the Progression of Pancreatic Ductal Adenocarcinoma through Proliferation and Invasion

BioMed Research International ◽

10.1155/2021/8249293 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Jing Chen ◽

Cui-Cui Zhao ◽

Fei-Ran Chen ◽

Guo-Wei Feng ◽

Fei Luo ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Pancreatic Ductal Adenocarcinoma ◽

Disease Free Survival ◽

High Expression ◽

Ductal Adenocarcinoma ◽

Migration And Invasion

Background. Pancreatic cancer is a malignant tumor of the digestive tract, which is difficult to diagnose and treat due to bad early diagnosis. We aimed to explore the role of kinesin superfamily 4A (KIF4A) in pancreatic ductal adenocarcinoma (PDAC). Methods. We first used the bioinformatic website to screen the data of pancreatic cancer in TCGA, and KIF4A protein was detected among the 86 specimens of patients in our hospital combined with clinic-pathological characteristics and survival analysis. KIF4A loss-expression cell lines were established by RNA interference (RNAi). In addition, we performed in vitro cell assays to detect the changes in cell proliferation, migration, and invasion. The proteins involved in the proliferation and metastasis of cancer cells were also detected by western blot. The above results could be proved in vivo. Further, the correlation between KIF4A and CDC5L was analyzed by TCGA and IHC data. Results. We first found a high expression of KIF4A in pancreatic cancer, suggesting a role of KIF4A in the development of pancreatic cancer. KIF4A was found to be differentially expressed ( P < 0.05 ) among the 86 specimens of patients in our hospital and was significantly associated with PDAC TNM stages and tumor size. High KIF4A expression also significantly worsened overall survival (OS) and disease-free survival rate (DFS) ( P < 0.05 , respectively). In addition, cell proliferation, migration, and invasion were inhibited by the KIF4A-shRNA group compared with the control ( P < 0.05 , respectively). In the end, knockdown of KIF4A could inhibit tumor development and metastasis in vivo. Further, the positive correlation between KIF4A and CDC5L existed, and KIF4A might promote pancreatic cancer proliferation by affecting CDC5L expression. Conclusion. In conclusion, the high expression level of KIF4A in PDAC was closely related to poor clinical and pathological status, lymphatic metastasis, and vascular invasion. KIF4A might be involved in promoting the development of PDAC in vitro and in vivo, which might be a new therapeutic target of PDAC.

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