Xenograft Growth Invivo Research Articles

RETRACTION: Expression of Adrenomedullin in Human Colorectal Tumors and Its Role in Cell Growth and Invasion InVitro and in Xenograft Growth InVivo.

E. Nouguerède, C. Berenguer, S. Garcia, B. Bennani, C. Delfino, I. Nanni, L. Dahan, M. Gasmi, J.-F. Seitz, P.-M. Martin and L. Ouafik, "Expression of Adrenomedullin in Human Colorectal Tumors and Its Role in Cell Growth and Invasion Invitro and in Xenograft Growth InVivo," Cancer Medicine 2, no. 2 (2013): 196-207, https://doi.org/10.1002/cam4.51. The above article, published online on 29 January 2013 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the Journal Editor-in-Chief, Stephen Tait; and John Wiley & Sons Ltd. The retraction has been agreed due to duplication of elements found between Figure2i and 2m and also between Figure2c, 2g, and 2k. Theauthors provided a replacement Figure2 to correct the duplications. However, the editors have lost confidence in the data and conclusions presented in this article as well as the new figure provided.

The Deubiquitinase USP22-Stabilized COL17A1 Promotes Lung Adenocarcinoma Progression.

Lung adenocarcinoma (LUAD) is a highly aggressive and rapidly fatal malignancy worldwide. Collagen XVII (COL17A1) has been implicated in various protumorigenic processes. However, the functions and mechanisms of COL17A1 in LUAD progression still remain elusive. COL17A1 and ubiquitin-specific protease 22 (USP22) mRNA analysis was performed by quantitative PCR, and their protein levels were detected by immunoblotting and immunohistochemistry. The functional influence was evaluated by determining cell viability, proliferation, apoptosis, invasion, migration, and ferroptosis invitro, as well as xenograft growth invivo. Co-immunoprecipitation (Co-IP) and IP experiments were used to examine the USP22/COL17A1 interaction and COL17A1 deubiquitination. Cycloheximide treatment was used to analyze COL17A1 protein stability. COL17A1 and USP22 were upregulated in human LUAD tissues and cell lines. Functionally, COL17A1 knockdown acted for the suppression of LUAD cell growth, invasion, and migration as well as promotion of cell apoptosis and ferroptosis invitro. COL17A1 knockdown could diminish the tumorigenicity of LUAD cells invivo. Mechanistically, USP22 stabilized and upregulated COL17A1 by enhancing the deubiquitination of COL17A1. Additionally, reexpression of COL17A1 could reverse USP22 silencing-induced phenotype changes of LUAD cells invitro. Our findings demonstrate that USP22-stabilized COL17A1 possesses oncogenic activity in LUAD. We propose that USP22 and COL17A1 would be potential targets for the establishment of therapeutic approaches against LUAD.

FAM86A methylation of eEF2 links mRNA translation elongation to tumorigenesis

eEF2 post-translational modifications (PTMs) can profoundly affect mRNA translation dynamics. However, the physiologic function of eEF2K525 trimethylation (eEF2K525me3), a PTM catalyzed by the enzyme FAM86A, is unknown. Here, we find that FAM86A methylation of eEF2 regulates nascent elongation to promote protein synthesis and lung adenocarcinoma (LUAD) pathogenesis. The principal physiologic substrate of FAM86A is eEF2, with K525me3 modeled to facilitate productive eEF2-ribosome engagement during translocation. FAM86A depletion in LUAD cells causes 80S monosome accumulation and mRNA translation inhibition. FAM86A is overexpressed in LUAD and eEF2K525me3 levels increase through advancing LUAD disease stages. FAM86A knockdown attenuates LUAD cell proliferation and suppression of the FAM86A-eEF2K525me3 axis inhibits cancer cell and patient-derived LUAD xenograft growth invivo. Finally, FAM86A ablation strongly attenuates tumor growth and extends survival in KRASG12C-driven LUAD mouse models. Thus, our work uncovers an eEF2 methylation-mediated mRNA translation elongation regulatory node and nominates FAM86A as an etiologic agent in LUAD.

Suppression of DRP1‑mediated mitophagy increases the apoptosis of hepatocellular carcinoma cells in the setting of chemotherapy.

The efficacy of chemotherapy for hepatocellular carcinoma (HCC) remains unsatisfactory, primarily due to inherent self‑defense mechanisms (e.g., mitophagy and autophagy). In the present study, we aimed to explore the pro‑apoptotic effects of targeting mitophagy to potentiate the efficacy of chemotherapy for HCC. HCC cells were subjected to cisplatin, after which cisplatin‑induced mitophagy was quantified by immunofluorescence. Mdivi‑1, a specific dynamin‑related protein1 (DRP1) inhibitor, was used to study the role of DRP1 in cisplatin‑induced HCC mitophagy. The synergistic effect of cisplatin and the DRP1 inhibitor on HCC was assessed invitro and invivo. Accordingly, cisplatin induced mitophagy in surviving HCC cells by activating DRP1. The DRP1 inhibitor (Mdivi‑1) increased the apoptosis of cisplatin‑treated HCC cells by targeting mitophagy. Mechanistically, Mdivi‑1 upregulated Bax and downregulated Bcl‑xL, leading to an increase in mitochondrial membrane permeability and subsequent release of cytochromec from mitochondria into the cytosol, thereby aggravating cisplatin‑induced apoptosis in HCC cells. Moreover, Mdivi‑1 acted synergistically with cisplatin to suppress HCC xenograft growth invivo. Our results indicate that targeting cisplatin‑mediated mitophagy increases HCC apoptosis via DRP1 inhibition, providing preclinical proof of concept for combination therapy targeting mitophagy to potentiate the efficacy of chemotherapy.

Suppression of the SDF‑1/CXCR4/β‑catenin axis contributes to bladder cancer cell growth inhibition invitro and invivo.

Previous studies have found that the activation of stromal cell‑derived factor‑1 (SDF‑1)/CXC chemokine receptor‑4 (CXCR4)/β‑catenin signaling is associated with biological malignant potential in cancers. However, its function has been rarely reported in the progression of bladder cancer (BCa). The aim of the present study was to investigate the association of SDF‑1/CXCR4 signaling and β‑catenin in regards to BCa cell proliferation, colony formation, migration and invasion. The methods used were MTS, colony formation, and Transwell migration and invasion assays which were performed in SW780 cells following treatment with the CXCR4 antagonist AMD3465, SDF‑1, the β‑catenin antagonist FH535, AMD3465+SDF‑1 or FH535+SDF‑1. The mRNA and protein levels were assayed by RT‑qPCR and western blotting, respectively. The effect of AMD3465 on SW780 cell xenograft growth invivo was evaluated using a nude mouse model. According to our results, human BCa SW780 cells were identified as having high expression of CXCR4 and β‑catenin. Subsequently, we found that both CXCR4 and β‑catenin antagonists could significantly inhibit the proliferation, colony formation, migration and invasion of SW780 cells. Notably, SDF‑1 could reverse the inhibitory effects of AMD3465 and FH535 on proliferation, colony formation, migration and invasion in SW780 cells. In AMD3465‑treated SW780 cells, the expression of c‑myc was significantly upregulated, and E‑cadherin was downregulated in the presence of SDF‑1. Furthermore, the tumor volume and average weight in the AMD3465‑treated group were evidently less than these parameters in the control group, indicating that AMD3465 can inhibit SW780 cell growth invivo. In conclusion, targeting the SDF‑1/CXCR4/β‑catenin axis may be a potential therapeutic target for suppressing BCa progression.

Not So Fast: Cultivating miRs as Kinks in the Chain of the Cell Cycle

In this issue of Cancer Cell, Hydbring and colleagues define a novel class of microRNAs (miRNAs), deemed "cell-cycle-targeting miRNAs," that target several cyclins/CDKs, reduce tumor cell growth, and induce apoptosis. These miRNAs effectively suppressed chemoresistant patient-derived xenograft growth invivo, and efficacy could be prospectively predicted with an expression-based algorithm.

Single-Agent Inhibition of Chk1 Is Antiproliferative in Human Cancer Cell Lines In Vitro and Inhibits Tumor Xenograft Growth In Vivo

Chk1 is a serine/threonine kinase that plays several important roles in the cellular response to genotoxic stress. Since many current standard-of-care therapies for human cancer directly damage DNA or inhibit DNA synthesis, there is interest in using small molecule inhibitors of Chk1 to potentiate their clinical activity. Additionally, Chk1 is known to be critically involved in cell cycle progression of unperturbed cells. Therefore, it is plausible that treatment with a Chkl inhibitor alone could also be an efficacious cancer therapy. Here we report that Chk1-A, a potent and highly selective small molecule inhibitor of Chk1, is antiproliferative as a single agent in a variety of human cancer cell lines in vitro. The inhibition of proliferation is associated with collapse of DNA replication and apoptosis. Rapid decreases in inhibitory phosphorylation of CDKs and a concomitant increase in CDK kinase activity and chromatin loading of Cdc45 suggest that the antiproliferative and proapoptotic activity of Chk1-A is at least in part due to deregulation of DNA synthesis. We extend these in vitro studies by demonstrating that Chk1-A inhibits the growth of tumor xenografts in vivo in a treatment regimen that is well tolerated. Together, these results suggest that single-agent inhibition of Chk1 may be an effective treatment strategy for selected human malignancies.