scholarly journals m6A Modification-Mediated DUXAP8 Regulation of Malignant Phenotype and Chemotherapy Resistance of Hepatocellular Carcinoma Through miR-584-5p/MAPK1/ERK Pathway Axis

2021 ◽  
Vol 9 ◽  
Author(s):  
Zefeng Liu ◽  
Jin Lu ◽  
He Fang ◽  
Jiyao Sheng ◽  
Mengying Cui ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Chemotherapy Resistance ◽  
Tumor Model ◽  
Mechanistic Study ◽  
Xenograft Tumor ◽  
Malignant Phenotype ◽  
Sorafenib Treatment ◽  
Xenograft Tumor Model

Hepatocellular carcinoma (HCC) has a poor prognosis due to its high malignancy, rapid disease progression, and the presence of chemotherapy resistance. Long-stranded non-coding RNAs (lncRNAs) affect many malignant tumors, including HCC. However, their mechanism of action in HCC remains unclear. This study aimed to clarify the role of DUXAP8 in regulating the malignant phenotype and chemotherapy resistance in HCC. Using an in vivo xenograft tumor model, the regulatory functions and mechanisms of lncRNA DUXAP8 in the progression and response of HCC to chemotherapy were explored. It was found that DUXAP8 was significantly upregulated in a patient-derived xenograft tumor model based on sorafenib treatment, which is usually associated with a relatively poor prognosis in patients. In HCC, DUXAP8 maintained its upregulation in the expression by increasing the stability of m6A methylation-mediated RNA. DUXAP8 levels were positively correlated with the proliferation, migration, invasion, and chemotherapy resistance of HCC in vivo and in vitro. In the mechanistic study, it was found that DUXAP8 competitively binds to miR-584-5p through a competing endogenous RNA (ceRNA) mechanism, thus acting as a molecular sponge for miR-584-5p to regulate MAPK1 expression, which in turn activates the MAPK/ERK pathway. These findings can provide ideas for finding new prognostic indicators and therapeutic targets for patients with HCC.

scholarly journals Wnt5b-induced PCP/JNK Activation Promotes PD-L1 Expression and the Malignant Phenotype of Non-small Cell Lung Cancer 

2020 ◽  
Author(s):  
Guangping Wu ◽  
Yuan Luo ◽  
Yusai Xie ◽  
Yang Han ◽  
Di Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumor Model ◽  
Small Cell ◽  
Xenograft Tumor ◽  
Small Cell Lung ◽  
Malignant Phenotype ◽  
Membrane Recruitment ◽  
Xenograft Tumor Model

Abstract Background: Wnt5b is noncanonical Wnt ligand, and programmed-death ligand 1 (PD-L1) is a targeted agent for immunotherapy, but the mechanism by which Wnt5b regulates PD-L1 expression in non-small cell lung cancer (NSCLC) is unclear. Methods: Wnt5b and PD-L1 expressions were detected in NSCLC specimens by immunohistochemistry. The interrelationship connecting Wnt5b with PD-L1 was verified using dual-luciferase assay, immunofluorescence, coimmunoprecipitation, western blot，real-time PCR and xenograft tumor model. Results: Wnt5b and PD-L1 expressions were positively correlated in NSCLC specimens. Five-year survival time in the group with their coexpression was significantly lower than that without coexpression. Under the effect of Wnt5b, Frizzled-3 (Fzd3) initiated Dishevellde-3 (Dvl-3) membrane recruitment via DEP domain by Dvl-3 phosphorylation, contributing to activate PCP/JNK signaling through the small GTPase Rac1, and then upregulate PD-L1 expression and promote the malignant phenotype of NSCLC in vivo and in vitro. After PD-L1 antibody treatment, Wnt5b induced tumor growth was inhibited significantly in xenograft tumor model. Conclusion: We demonstrate a new signal transduction pathway: Wnt5b initiates Dvl-3 membrane recruitment via DEP domain by Fzd3 so as to promote Rac1–PCP/JNK–PD-L1 pathway, which provides a potential target for clinical intervention and immunotherapy in lung cancer.

scholarly journals Circular RNA circ-CDYL sponges miR-1180 to elevate yes-associated protein in multiple myeloma

2020 ◽  
Vol 245 (11) ◽  
pp. 925-932 ◽  
Author(s):  
Fang Chen ◽  
Xiaohui Wang ◽  
Shuang Fu ◽  
Shaokun Wang ◽  
Yu Fu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Model ◽  
Circular Rna ◽  
Xenograft Tumor ◽  
Functional Assays ◽  
Xenograft Tumor Model ◽  
Therapeutic Possibility ◽  
Plasma Depletion ◽  
Potential Therapeutic Intervention

The covalently closed circular RNA has recently been proposed as a pivotal player in tumorigenesis. In the current study, we found that circ-CDYL was notably elevated in multiple myeloma tissue and plasma samples and had good diagnostic and prognostic efficacy. Functional assays showed that circ-CDYL enhanced the viability and DNA synthesis of multiple myeloma cells and inhibited apoptosis. Mechanically, cytoplasmic circ-CDYL was co-localized with miR-1180, and circ-CDYL absorbed miR-1180 to upregulate yes-associated protein (YAP), thereby facilitating multiple myeloma progression. Importantly, we further confirmed the existence of this circ-CDYL/miR-1180/YAP regulatory axis in vivo by using the xenograft tumor model. Taken together, our data demonstrate that circ-CDYL is novel promoter of multiple myeloma, and targeting circ-CDYL and its associated network implicates the therapeutic possibility for multiple myeloma patients. Impact statement Multiple myeloma (MM) is an extremely complex and heterogeneous disease, and its pathogenesis is poorly understood. Here, we described an important MM-related circular RNA (circRNA), circ-CDYL. It was remarkably increased in both MM cells and plasma. Depletion of circ-CDYL evidently stunted MM growth. Circ-CDYL could absorb miR-1180 and alleviated the repression of miR-1180 on YAP, leading to increased YAP expression, ultimately triggering MM uncontrolled growth. Therefore, our findings advance the understanding of MM pathogenesis, and also raise the possibility of considering circ-CDYL as a potential therapeutic intervention for MM.

scholarly journals mTORC2 promotes cell survival through c-Myc–dependent up-regulation of E2F1

2015 ◽  
Vol 211 (1) ◽  
pp. 105-122 ◽  
Author(s):  
Zhipeng Zou ◽  
Juan Chen ◽  
Anling Liu ◽  
Xuan Zhou ◽  
Qiancheng Song ◽  
...  
Keyword(s):  
Cell Survival ◽  
Tumor Model ◽  
Xenograft Tumor ◽  
In Vivo Experiments ◽  
Xenograft Tumor Model ◽  
Cancer Cell Survival ◽  
Consequent Reduction ◽  
Dependent Mechanism

Previous studies have reported that mTORC2 promotes cell survival through phosphorylating AKT and enhancing its activity. We reveal another mechanism by which mTORC2 controls apoptosis. Inactivation of mTORC2 promotes binding of CIP2A to PP2A, leading to reduced PP2A activity toward c-Myc serine 62 and, consequently, enhancement of c-Myc phosphorylation and expression. Increased c-Myc activity induces transcription of pri-miR-9-2/miR-9-3p, in turn inhibiting expression of E2F1, a transcriptional factor critical for cancer cell survival and tumor progression, resulting in enhanced apoptosis. In vivo experiments using B cell–specific mTORC2 (rapamycin-insensitive companion of mTOR) deletion mice and a xenograft tumor model confirmed that inactivation of mTORC2 causes up-regulation of c-Myc and miR-9-3p, down-regulation of E2F1, and consequent reduction in cell survival. Conversely, Antagomir-9-3p reversed mTORC1/2 inhibitor–potentiated E2F1 suppression and resultant apoptosis in xenograft tumors. Our in vitro and in vivo findings collectively demonstrate that mTORC2 promotes cell survival by stimulating E2F1 expression through a c-Myc– and miR-9-3p–dependent mechanism.

ANP32A promotes the proliferation, migration and invasion of hepatocellular carcinoma by modulating the HMGA1/STAT3 pathway

2020 ◽  
Author(s):  
Zilu Tian ◽  
Zhiyi Liu ◽  
Xiaokang Fang ◽  
Kuan Cao ◽  
Bin Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nude Mice ◽  
High Mobility ◽  
Tumor Model ◽  
Migration And Invasion ◽  
Xenograft Tumor ◽  
Stat3 Pathway ◽  
Xenograft Tumor Model ◽  
Rna Immunoprecipitation ◽  
Hcc Cells

Abstract ANP32A (acidic leucine-rich nuclear phosphoprotein-32A) has been reported to play an essential role in the development and progression of various human cancers. However, its expression pattern and possible mechanism in human hepatocellular carcinoma (HCC) remain to be elucidated. In this study, we used western blot and immunohistochemical staining to detect protein expression. The effects of ANP32A on the proliferation, migration and invasion of HCC cells were examined using 5-ethynyl-20-deoxyuridine (EdU), colony formation, CCK-8, and transwell assays. RT-qPCR was performed to detect mRNA expression. The interaction between ANP32A and the high mobility group A1 (HMGA1) mRNA was assessed using RNA immunoprecipitation (RIP). The tumorigenicity of ANP32A was assessed by establishing a xenograft tumor model in Balb/c nude mice. We found that the ANP32A protein was expressed at high levels in patients with HCC, which was associated with a poor prognosis. Functional experiments revealed that the silencing of ANP32A inhibited the proliferation, migration, and invasion of HCC cells, whereas overexpression of ANP32A promoted these processes. Further investigations indicated that ANP32A bound the HMGA1 mRNA and maintained its stability to promote the expression of HMGA1, thereby increasing the expression and activation of STAT3. Finally, a xenograft tumor model of Balb/c nude mice confirmed the tumorigenicity of ANP32A. This study found that ANP32A is up-regulated in patients with HCC and may accelerate the proliferation, migration, and invasion of HCC cells by modulating the HMGA1/STAT3 pathway.

scholarly journals Construction of Hierarchical-Targeting pH-Sensitive Liposomes to Reverse Chemotherapeutic Resistance of Cancer Stem-like Cells

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1205
Author(s):  
Shuang Ba ◽  
Mingxi Qiao ◽  
Li Jia ◽  
Jiulong Zhang ◽  
Xiuli Zhao ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Chemotherapy Resistance ◽  
Tumor Model ◽  
Ph Sensitive ◽  
Mitochondrial Targeting ◽  
Tumor Treatment ◽  
Chemotherapeutic Resistance ◽  
Xenograft Tumor Model ◽  
Tumor Region

Cancer stem-like cells (CSLCs) have been considered to be one of the main problems in tumor treatment owing to high tumorigenicity and chemotherapy resistance. In this study, we synthesized a novel mitochondria-target derivate, triphentlphosphonium-resveratrol (TPP-Res), and simultaneously encapsulated it with doxorubicin (Dox) in pH-sensitive liposomes (PSL (Dox/TPP-Res)), to reverse chemotherapeutic resistance of CSLCs. PSL (Dox/TPP-Res) was approximately 165 nm in size with high encapsulation efficiency for both Dox and TPP-Res. Cytotoxicity assay showed that the optimal synergistic effect was the drug ratio of 1:1 for TPP-Res and Dox. Cellular uptake and intracellular trafficking assay indicated that PSL (Dox/TPP-Res) could release drugs in acidic endosomes, followed by mitochondrial targeting of TPP-Res and nucleus transports for Dox. The mechanisms for reversing the resistance in CSLCs were mainly attributed to a synergistic effect for reduction of mitochondrial membrane potential, activation of caspase cascade reaction, reduction of ATP level and suppression of the Wnt/β-catenin pathway. Further, in vivo assay results demonstrated that the constructed liposomes could efficiently accumulate in the tumor region and possess excellent antineoplastic activity in an orthotopic xenograft tumor model with no evident systemic toxicity. The above experimental results determined that PSL (Dox/TPP-Res) provides a new method for the treatment of heterogenecity tumors.

Nano-Encapsulation of Plitidepsin: In Vivo Pharmacokinetics, Biodistribution, and Efficacy in a Renal Xenograft Tumor Model

2013 ◽  
Vol 31 (4) ◽  
pp. 983-991 ◽  
Author(s):  
Hugo Oliveira ◽  
Julie Thevenot ◽  
Elisabeth Garanger ◽  
Emmanuel Ibarboure ◽  
Pilar Calvo ◽  
...  
Keyword(s):  
Tumor Model ◽  
Xenograft Tumor ◽  
Xenograft Tumor Model ◽  
In Vivo Pharmacokinetics

scholarly journals In vivo anticancer activity of a rhodium metalloinsertor in the HCT116 xenograft tumor model

2020 ◽  
Vol 117 (30) ◽  
pp. 17535-17542
Author(s):  
Stephanie D. Threatt ◽  
Timothy W. Synold ◽  
Jun Wu ◽  
Jacqueline K. Barton
Keyword(s):  
Chemotherapy Resistance ◽  
Tumor Model ◽  
Pharmacokinetic Studies ◽  
Xenograft Tumor ◽  
Delivery Methods ◽  
Dna Mutations ◽  
Anticancer Effects ◽  
Dna Mismatches ◽  
In Vivo Analysis

Mismatch repair (MMR) deficiencies are a hallmark of various cancers causing accumulation of DNA mutations and mismatches, which often results in chemotherapy resistance. Metalloinsertor complexes, including [Rh(chrysi)(phen)(PPO)]Cl2(Rh-PPO), specifically target DNA mismatches and selectively induce cytotoxicity within MMR-deficient cells. Here, we present an in vivo analysis of Rh-PPO, our most potent metalloinsertor. Studies with HCT116 xenograft tumors revealed a 25% reduction in tumor volume and 12% increase in survival with metalloinsertor treatment (1 mg/kg; nine intraperitoneal doses over 20 d). When compared to oxaliplatin, Rh-PPO displays ninefold higher potency at tumor sites. Pharmacokinetic studies revealed rapid absorption of Rh-PPO in plasma with notable accumulation in the liver compared to tumors. Additionally, intratumoral metalloinsertor administration resulted in enhanced anticancer effects, pointing to a need for more selective delivery methods. Overall, these data show that Rh-PPO inhibits xenograft tumor growth, supporting the strategy of using Rh-PPO as a chemotherapeutic targeted to MMR-deficient cancers.

scholarly journals A Novel Anti-EGFR mAb Ame55 with Lower Toxicity and Better Efficacy than Cetuximab When Combined with Irinotecan

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Weiyi Qiu ◽  
Chang Zhang ◽  
Shuang Wang ◽  
Xiaoyan Yu ◽  
Qiong Wang ◽  
...  
Keyword(s):  
Tumor Model ◽  
Phage Library ◽  
Lovo Cell ◽  
Xenograft Tumor ◽  
Cynomolgus Monkeys ◽  
Lower Affinity ◽  
Egfr Inhibition ◽  
Xenograft Tumor Model

To improve efficacy and minimize toxicity of EGFR inhibition treatment, we developed Ame55, a novel anti-EGFR IgG1 with lower affinity to EGFR than cetuximab (C225) from a human phage library. Ame55 had lower bioactivity than cetuximab in vitro but similar antitumor efficacy as cetuximab in vivo. Moreover, Ame55 was more efficacious than cetuximab in a Lovo cell xenograft tumor model when combined with irinotecan (CPT-11). Ame55 concentrates in the mouse xenograft tumor and has less toxicity than cetuximab in cynomolgus monkeys in an overdose study.

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