mouse xenograft model
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2022 ◽  
Author(s):  
Jia-fu Feng ◽  
Jun Wang ◽  
Gang Xie ◽  
Yao-dong Wang ◽  
Xiao-han Li ◽  
...  

Abstract Objective: This study is to investigate the regulation of long non-coding RNA (lncRNA) SNHG12 promoter methylation modification by KMT2B and the mechanism of SNHG12 in the development of renal cell carcinoma (RCC) involving E2F1/CEP55 axis.Methods: TCGA and GEO databases were used to predict the involvement of SNHG12 in RCC. Knockdown of SNHG12/E2F1/CEP55 was performed. Next, SNHG12 expression and other mRNAs were analyzed by RT-qPCR. Subsequently, CCK-8 was used to detect cell proliferation. Wound healing test and Transwell assay was used to detect cell migration and invasion, respectively. The vascularization of HUVEC was explored by in vitro pseudotubule formation. CHIP was used to detect H3K4me3 in SNHG12 promoter region. The binding of E2F1 and CEP55 promoter region was analyzed with CHIP and dual luciferase reporter assay. RIP was used to detect the binding of SNHG12 and E2F1. Finally, the effect of SNHG12 on the tumor formation and angiogenesis of RCC was assessed in nude mouse xenograft model.Results: Bioinformatics analysis showed that SNHG12 was highly expressed in RCC tissues and cells, and it was related to the poor prognosis of RCC patients. SNHG12 knockdown significantly inhibited RCC cell proliferation, migration, and invasion and HUVEC angiogenesis. KMT2B up-regulated SNHG12 through modifying H3K4me3 in its promoter region. In addition, SNHG12 promoted CEP55 expression by recruiting the transcription factor E2F1. Knockdown of SNHG12 blocked E2F1 recruitment, thereby down-regulating the expression of CEP55, and inhibited tumor formation and angiogenesis of RCC cells in nude mice.Conclusion: KMT2B up-regulates SNHG12 via the modification of H3K4me3 in its promoter region. SNHG12 recruits E2F1 to promote the expression of CEP55, and ultimately promotes RCC cell proliferation, migration, and invasion and HUVEC angiogenesis.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Lei Zhang ◽  
Jing Zhang ◽  
Pengfei Li ◽  
Ting Li ◽  
Zhiqin Zhou ◽  
...  

AbstractMacrophage-derived exosomes (Mφ-Exo) have multidimensional involvement in tumor initiation, progression, and metastasis, but their regulation in hepatocellular carcinoma (HCC) is not fully understood. RBPJ has been implicated in macrophage activation and plasticity. In this study we assess the role of exosomes derived from RBPJ-overexpressed macrophages (RBPJ+/+ Mφ-Exo) in HCC. The circular RNA (circRNA) profiles in RBPJ+/+ Mφ-Exo and THP-1-like macrophages (WT Mφ)-Exo was evaluated using circRNA microarray. CCK-8, Transwell, and flow cytometry analyses were used to evaluate the function of Mφ-Exo-circRNA on HCC cells. Luciferase reporter assays, RNA immunoprecipitation, and Pearson’s correlation analysis were used to confirm interactions. A nude mouse xenograft model was used to further analyze the functional significance of Mφ-Exo-cirRNA in vivo. Our results shown that hsa_circ_0004658 is upregulated in RBPJ+/+ Mφ-Exo compared to WT Mφ-Exo. RBPJ+/+ Mφ-Exo and hsa_circ_0004658 inhibits proliferation and promotes apoptosis in HCC cells, whereas hsa_circ_0004658 knockdown stimulated cell proliferation and migration but restrained apoptosis in vitro and promotes tumor growth in vivo. The effects of RBPJ+/+ Mφ-Exo on HCC cells can be reversed by the hsa_circ_0004658 knockdown. Mechanistic investigations revealed that hsa_circ_0004658 acts as a ceRNA of miR-499b-5p, resulting in the de-repression of JAM3. These results indicate that exosome circRNAs secreted from RBPJ+/+ Mφ inhibits tumor progression through the hsa_circ_0004658/miR-499b-5p/JAM3 pathway and hsa_circ_0004658 may be a diagnostic biomarker and potential target for HCC therapy.


2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Cheng Zeng ◽  
Shaojun Ye ◽  
Yu Chen ◽  
Qu Zhang ◽  
Yan Luo ◽  
...  

Hepatocellular carcinoma (HCC) is the most prevalent type of hepatic carcinoma. Long noncoding RNAs (lncRNAs) are considered crucial regulators of gene expression; however, their functions in HCC are not well understood. Thus, the present study is aimed at elucidating the functions of the lncRNA HOXA-AS3 in HCC. The functions of the HOXA-AS3/miR-455-5p/programmed death-ligand 1 (PD-L1) axis were investigated in vitro via qRT-PCR and dual-luciferase reporter assays. The effect of HOXA-AS3 expression on tumor growth and metastasis was assessed using a mouse xenograft model. High HOXA-AS3 expression was observed in the HCC cell lines. Furthermore, overexpression of HOXA-AS3 in HCC cells enhanced proliferation, migration, and invasion, regulated the cell cycle, and retarded apoptosis. We also identified an miR-455-5p binding site in HOXA-AS3. By sponging miR-455-5p, HOXA-AS3 increased the expression of PD-L1. Additionally, both the inhibition of PD-L1 and overexpression of miR-455-5p reversed the effects on cell proliferation and invasion triggered by the overexpression of HOXA-AS3. In conclusion, HOXA-AS3 modulated the functions of HCC cells through the miR-455-5p/PD-L1 axis. Therefore, HOXA-AS3 may be a novel therapeutic target for HCC.


Author(s):  
Takeyoshi Eda ◽  
Masayasu Okada ◽  
Ryosuke Ogura ◽  
Yoshihiro Tsukamoto ◽  
Yu Kanamaru ◽  
...  

Multimodal therapy including surgery, radiation treatment and temozolomide (TMZ) is performed on glioblastoma (GBM). However, the prognosis is still poor and there is an urgent need to develop effective treatments to improve survival. Molecular biological analysis was conducted to exam-ine the signal activation patterns at GBM specimens and remains an open problem. Advanced macrolides, such as azithromycin, reduce the phosphorylation of p70 ribosomal protein S6 kinase (p70S6K), a downstream mammalian target of rapamycin (mTOR) effector, and suppress the proliferation of T-cells. We focused on its unique profile and screened for the antitumor activity of approved macrolide antibiotics. Clindamycin (CLD) reduced the viability of GBM cells in vitro. We assessed the effects of the candidate macrolide on the mTOR pathway through Western blotting. CLD attenuated p70S6K phosphorylation in a dose dependent manner. These effects of on GBM cells were enhanced by co-treatment with TMZ. Furthermore, CLD inhibited the expression of O6-methylguanine-DNA methyltransferase (MGMT) protein in cultured cells. In the mouse xenograft model, CLD and TMZ co-administration significantly suppressed the tumor growth and markedly decreased the number of Ki-67 (clone MIB-1) positive cells within the tumor. These results suggest that CLD suppresses GBM cell growth by the inhibiting mTOR signaling. Moreover, CLD and TMZ showed promising synergistic antitumor activity.


2021 ◽  
Author(s):  
Dongya Sheng ◽  
Bei Zhao ◽  
Wenjing Zhu ◽  
Tiantian Wang ◽  
yu peng

Abstract Background: Scutellaria barbata D.Don (SBD) is derived from the dried whole plant of Labiate that has been widely used to treat patients with multiple cancer. It was previously reported that the ethanol extract of SBD is able to promote apoptosis, and inhibit cell proliferation and angiogenesis in cancer.Materials and methods: CCK8, Edu assays and colony formation assay were performed to assess the effect of SBD on PCa cell growth. Effect of SBD on apoptosis and cell cycle was detected by flow cytometry. Transwell and wounding healing assay were performed to detected the invasion and migration activities of PCa cells. Western blot was employed to detect the protein expression. 2RRV1 mouse xenograft model was established to detect the effect of SBD on prostate cancer. Angiogenesis was analysed by coculturing PCa cell lines and HUVECs.Results: The results showed that SBD induced a significant decrease in cell viability and clonogenic growth in a dose-dependent manner. SBD induced cell apoptosis and cell cycle G2/M phase arrest by inactivating PI3K/AKT signalling pathway. Treatment with SBE also significantly decreased the cell migration and invasion via phenotypic inversion of EMT that was characterized by the increased expression of E-cadherin and Vimentin, and decreased expression of N-cadherin, which could be partially attributed to inhibiting PI3K/AKT signalling pathway. Subsequently, using AKT inhibitor MK2206, we performed that PI3K/AKT are also involved in cell apoptosis and metastasis of PCa cells stimulated by SBE. In addition, to its direct effects on PCa cells, SBD also exhibited anti-angiogenic properties. SBD alone or conditioned media from SBD-treated PCa cells inhibited HUVEC tube formation on Matrigel without affecting HUVEC viability. Furthermore, 22RV1 xenograft C57BL/6 mice treated with SBE in vivo showed a significant decrease in tumour size and tumour weight without toxicity. In addition, administration with medium- or high-dose of SBE significantly inhibited the cell proliferation and promoted the damage of tumour tissues.Conclusions: Collectively, our in vitro and in vivo findings suggest that SBE had the potential to develop into a safe and potent alternative therapy for PCa patients.


2021 ◽  
Author(s):  
Jia Liu ◽  
Qijin Wu ◽  
Ruiyu Song ◽  
Wen Miao ◽  
Yuting Ma ◽  
...  

Abstract Background: Prostate cancer is the leading cause of disease and death in men. Long non-coding RNAs (lncRNAs), microRNA (miRNAs) and mRNAs networks mediate prostate cancer progression. Here, we aim to investigate functions of lncRNA AC008972.1/miR-143-3p/thousand-and-one-amino acid 2 kinase (TAOK2) in prostate cancer. Methods: The expression levels of lncRNA AC008972.1, miR-143-3p and TAOK2 are detected in prostate cancer tissues and cell lines by RT-qPCR. PC3 and LNCaP cells are used to establish lncRNA AC008972.1-knockdown, miR-143-3p-overexpressing, and TAOK2-down-regulated cells. Cell viability is examined by MTT and cell proliferation is detected by clone formation assay. Cell migration and invasion are tested by wound scratch assay and transwell chamber assay. The rate of apoptosis was analyzed by flow cytometry. The protein expression is detected by western blot assay. The target is validated by RNA binding protein immunoprecipitation (RIP) assay and dual luciferase activity assay. A mouse xenograft model was conducted to investigate the oncogenic effect of lncRNA AC008972.1 on prostate cancer. Results: High expression of lncRNA AC008972.1 was associated with low overall survival in prostate cancer. Down-regulation of lncRNA AC008972.1 delayed prostate cancer process by inhibiting cell viability, proliferation, migration and invasion, as well as altering protein expression,whereas cell apoptosis was markedly promoted. LncRNA AC008972.1 negatively regulated miR-143-3p expression and miR-143-3p overexpression promoted prostate cancer process in vitro. TAOK2 expression was decreased by miR-143-3p through the complementary targeting of TAOK2 mRNA. Down-regulation of lncRNA AC008972.1 mitigated prostate cancer process in vitro based on miR-143-3p/TAOK2 node. Furthmore, the data of xenograft model experiment showed that inhibition of lncRNA AC008972.1 suppressed tumor growth in vivo. Conclusions: Collectively, knockdown of lncRNA AC008972.1 inhibits prostate cancer cell growth based on down-regulation of TAOK2 induced by miR-143-3p. Here, we identify that lncRNA AC008972.1 exerts essential roles in the progression of prostate cancer and serves as a novel therapeutic target for prostate cancer.


Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1877
Author(s):  
Jong-Kwang Kim ◽  
Jaehun Jung ◽  
Dong-Hoon Shin ◽  
Hye-Jin You ◽  
Seho Cha ◽  
...  

Androgen exerts its functions by binding with an androgen receptor (AR). It can activate many signaling pathways that are important to the progression of castration-resistant prostate cancer (CRPC). Here, we characterized the rapid proteomic changes seen at 5, 15, 30, and 60 min after the androgen treatment of VCaP cells via the tandem mass tag (TMT) labeling strategy. A total of 5529 proteins were successfully identified and quantified. Dynamic time profiling of protein expression patterns allowed us to identify five protein clusters involved in various stages of androgen-initiated signal transmission and processing. More details of protein functions and localization patterns, and our elucidation of an AR-interacting protein network, were obtained. Finally, we validated the expression level of AR-regulated proteins known to be significantly regulated in CRPC patients using the mouse xenograft model and patient samples. Our work offers a systematic analysis of the rapid proteomic changes induced by androgen and provides a global view of the molecular mechanisms underlying CRPC progression.


2021 ◽  
Author(s):  
Bin Zhou ◽  
Jinghao Lei ◽  
Qiang Wang ◽  
Tengfei Qu ◽  
Lichao Cha ◽  
...  

Abstract The mortality rate of pancreatic cancer (PC) remains high due to late diagnosis, early metastasis, and difficulty of complete resection. The online databases showed that potassium voltage-gated channel subfamily H member 2 (KCNH2) was highly expressed in pancreatic tumor tissues and was closely related to the poor survival of patients with PC. However, the mechanism of action of KCNH2 in PC is still unclear. In the present study, for the first time, we explored the regulatory effect of KCNH2 in PC. The results showed that KCNH2 was upregulated in PC compared with normal pancreatic tissues. High KCNH2 expression was associated with low tissue differentiation, high malignancy, and poor prognosis of PC. Moreover, knockdown of KCNH2 inhibited the proliferation and apoptosis of PC cells, as well as the epithelial-mesenchymal transition process, thereby promoting PC cell migration and invasion. In addition, KCNH2 knockdown inhibited the progression and metastasis of PC in a mouse xenograft model. In conclusion, these findings highlighted the potential of KCNH2 as a targeted molecule in the treatment of PC.


2021 ◽  
Author(s):  
Zhou Lu Wei ◽  
Wang Juan ◽  
Dou Tong ◽  
Li Xiao Juan ◽  
Liu Yi Sa ◽  
...  

Abstract Purpose: This study is to investigate the effect and mechanism of curcumol on ERα36 positive breast cancer cells, and the relationship between curcumol’s target protein nucleolin (NCL) and ERα36. Methods: The anti-tumor effect of curcumol were quantified via MTT assay, colony formation and cycle arrest respectively. The expression of ERα36, NCL and the proteins involved in PI3K/AKT signaling were evaluated by western blotting. The interaction between two proteins were detected using co-immunoprecipitation (Co-IP) and immunofluorescence assay. Mouse xenograft model was established to verify the role of ERα36 in breast cancer cells and curcumol’s effect on ERα36 positive cancer cells. Results: Curcumol inhibited the cell growth, caused cell cycle arrest, decreased cell cycle related-proteins and inactivated PI3K/AKT pathway in ERα36 positive breast cancer cells. There is a positive correlation between NCL and ERα36 in breast cancer cells. In addition, ERα36 bound to NCL, the two proteins were distributed in the nucleus, cytoplasm and on the plasma membrane, where their expression were obviously decreased by curcumol. Moreover, NCL silenced by NCL siRNA blocked the cell cycle progress and inhibited the activation of PI3K/AKT in MDA-MB-231 cells, while overexpressed ERα36 increased the expression of NCL, promoted cell cycle progress and enhanced the activity of PI3K/AKT in MCF-7 cells. NCL knockdown or ERα36 overexpressed all attenuated the effect of curcumol on breast cancer cells. Conclusion: Curcumol reduced the proliferation of breast cancer cells by targeting NCL/ERα36 and inactivated PI3K/AKT pathway.


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