CA : A Cancer Journal for Clinicians

Prostate cancer (PCa) is one of the most common malignancies in men globally. The aim of the present study was to identify the key genes and pathways involved in the occurrence of PCa. Gene expression profile (GSE55945) was downloaded from Gene Expression Omnibus, and the differentially expressed genes (DEGs) were identified. Subsequently, Gene ontology analysis, KEGG pathway analysis and protein-protein interaction (PPI) analysis of DEGs were performed. Finally, the identified key genes were confirmed by immunohistochemistry. The GO analysis results showed that the DEGs were mainly participated in cell cycle, cell division, cell development and cell junction. The KEGG pathway analysis showed that the DEGs were mainly enriched in proteoglycans in cancer, endocytosis, focal adhesion and hippo signaling pathway. The PPI analysis results showed that RPS21, FOXO1, BIRC5, POLR2H, RPL22L1 and NPM1 were the key genes involved in the occurrence of PCa, and the Module analysis indicated that the occurrence of PCa was associated with cell cycle, oocyte meiosis and ribosome biogenesis. IHC result showed that the expression of RPS21, BIRC5, POLR2H, RPL22L1 and NPM1 were significantly upregulated in PCa, while the expression of FOXO1 was significantly downregulated in PCa, matching with the bioinformatics analysis. Taken together, several key genes and pathways were identified involved in PCa, which might provide the potential biomarker for prognosis, diagnosis and drug targets.

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Identification of the key genes and pathways in prostate cancer

Colorectal cancer, one of the most commonly diagnosed cancers worldwide, is often accompanied by uncontrolled proliferation of tumor cells. Dyskerin pseudouridine synthase 1 (DKC1), screened using the genome-wide RNAi strategy, is a previously unidentified key regulator that promotes colorectal cancer cell proliferation. Enforced expression of DKC1, but not its catalytically inactive mutant D125A, accelerates cell growth in vitro and in vivo. DKC1 knockdown or its inhibitor pyrazofurin attenuates cell proliferation. Proteomics, RNA immunoprecipitation (RIP)-seq, and RNA decay analyses reveal that DKC1 binds to and stabilizes the mRNA of several ribosomal proteins (RPs), including RPL10A, RPL22L1, RPL34, and RPS3. DKC1 depletion significantly accelerates mRNA decay of these RPs, which mediates the oncogenic function of DKC1. Interestingly, these DKC1-regulated RPs also interact with HRAS and suppress the RAS/RAF/MEK/ERK pathway. Pyrazofurin and trametinib combination synergistically restrains colorectal cancer cell growth in vitro and in vivo. Furthermore, DKC1 is markedly upregulated in colorectal cancer tissues compared to adjacent normal tissues. Colorectal cancer patients with higher DKC1 expression has consistently poorer overall survival and progression-free survival outcomes. Taken together, these data suggest that DKC1 is an essential gene and candidate therapeutic target for colorectal cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/advs.202004344

Dual Inhibition of DKC1 and MEK1/2 Synergistically Restrains the Growth of Colorectal Cancer Cells

Prostate cancer (PCa) is one of the most common malignancies in men worldwide. This study was designed to investigate the potential of Ribosomal Protein L22-like1 (RPL22L1) and Ribosomal Protein S21 (RPS21) as diagnostic and prognostic biomarkers for PCa. First, RPL22L1 and RPS21 were screened as the key molecular of PCa by bioinformatics analysis. Subsequently, the prostate tissue samples were stained for antibodies against RPL22L1 and RPS21. The unbiased signal quantification was performed by ImageJ software, and the results showed that the expression of RPL22L1 and RPS21 exhibited significant differences between the PCa tissues and the normal prostate tissues. Receiver-operating characteristics (ROC) curves were prepared, and then the area under the curve (AUC) values of RPL22L1 and RPS21 were calculated as 0.798 and 0.768, and the likelihood ratio (LR) values of RPL22L1 and RPS21 were calculated as 2.86 and 2.53. These data implied that the over-expression of RPL22L1 and RPS21 is associated with the presence of PCa. The further analysis suggested that the expression of RPL22L1 and RPS21 were significantly higher in high Gleason grade than they were in low Gleason grade. In addition, in vitro studies were undertaken to evaluate the roles of RPL22L1 and RPS21 in PCa. The results revealed that these genes promote PCa cell proliferation, migration and invasion, and inhibit PCa cell apoptosis. Taken together, these data showed that RPL22L1 and RPS21 exhibited higher expression in human prostate cancer tissue, and involved in PCa cell proliferation and invasion. This research provided a novel insight into diagnostic and prognostic biomarkers for PCa.

Identification of candidate diagnostic and prognostic biomarkers for human prostate cancer: RPL22L1 and RPS21.

Neuroblastoma is a common childhood cancer with almost a third of those affected still dying, thus new therapeutic strategies need to be explored. Current experimental therapies focus mostly on inhibiting oncogenic transcription factor signalling. Although LIN28B, DICER and other RNA-binding proteins (RBPs) have reported roles in neuroblastoma development and patient outcome, the role of RBPs in neuroblastoma is relatively unstudied. In order to elucidate novel RBPs involved in MYCN-amplified and other high-risk neuroblastoma subtypes, we performed differential mRNA expression analysis of RBPs in a large primary tumour cohort (n = 498). Additionally, we found via Kaplan-Meier scanning analysis that 685 of the 1483 tested RBPs have prognostic value in neuroblastoma. For the top putative oncogenic candidates, we analysed their expression in neuroblastoma cell lines, as well as summarised their characteristics and existence of chemical inhibitors. Moreover, to help explain their association with neuroblastoma subtypes, we reviewed candidate RBPs' potential as biomarkers, and their mechanistic roles in neuronal and cancer contexts. We found several highly significant RBPs including RPL22L1, RNASEH2A, PTRH2, MRPL11 and AFF2, which remain uncharacterised in neuroblastoma. Although not all RBPs appear suitable for drug design, or carry prognostic significance, we show that several RBPs have strong rationale for inhibition and mechanistic studies, representing an alternative, but nonetheless promising therapeutic strategy in neuroblastoma treatment.

Identification of RNA-Binding Proteins as Targetable Putative Oncogenes in Neuroblastoma

Double minute chromosomes (DMs) have important implications for cancer progression because oncogenes frequently amplified on them. We previously detected a functionally undefined gene amplified on DMs, Ribosomal L22-like1 (RPL22L1). The relationship between RPL22L1 and cancer progression is unknown. Here, RPL22L1 was characterized for its role in ovarian cancer (OC) metastasis and its underlying mechanism was examined. DNA copy number and mRNA expression of RPL22L1 in OC cells was analyzed using data obtained from The Cancer Genome Atlas and the Gene Expression Omnibus database. An immunohistochemical analysis of clinical OC specimens was performed and the relationships between expression level and clinicopathological factors were evaluated. Additionally, in vivo and in vitro assays were performed to understand the role of RPL22L1 in OC. RPL22L1 expression was higher in OC specimens than in normal tissues, and its expression level was highly positively correlated with invasion and lymph node metastasis (P < 0.05). RPL22L1 over-expression significantly enhanced intraperitoneal xenograft tumor development in nude mice and promoted invasion and migration in vitro. Additionally, RPL22L1 knockdown remarkably inhibited UACC-1598 cells invasion and migration. Further, RPL22L1 over-expression up-regulated the mesenchymal markers vimentin, fibronectin, and α-SMA, reduced expression of the epithelial markers E-cadherin, α-catenin, and β-catenin. RPL22L1 inhibition reduced expression of vimentin and N-cadherin. These results suggest that RPL22L1 induces epithelial-to-mesenchymal transition (EMT). Our data showed that the DMs amplified gene RPL22L1 is critical in maintaining the aggressive phenotype of OC and in triggering cell metastasis by inducing EMT. It could be employed as a novel prognostic marker and/or effective therapeutic target for OC.

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Jin-yan Yan

Papers

Ribosomal L22-like1 (RPL22L1) Promotes Ovarian Cancer Metastasis by Inducing Epithelial-to-Mesenchymal Transition.