Pseudouridine is the most abundant RNA modification, yet except for a few well-studied cases, little is known about the modified positions and their function(s). Here, we develop Ψ-seq for transcriptome-wide quantitative mapping of pseudouridine. We validate Ψ-seq with spike-ins and de novo identification of previously reported positions and discover hundreds of unique sites in human and yeast mRNAs and snoRNAs. Perturbing pseudouridine synthases (PUS) uncovers which pseudouridine synthase modifies each site and their target sequence features. mRNA pseudouridinylation depends on both site-specific and snoRNA-guided pseudouridine synthases. Upon heat shock in yeast, Pus7p-mediated pseudouridylation is induced at >200 sites, and PUS7 deletion decreases the levels of otherwise pseudouridylated mRNA, suggesting a role in enhancing transcript stability. rRNA pseudouridine stoichiometries are conserved but reduced in cells from dyskeratosis congenita patients, where the PUS DKC1 is mutated. Our work identifies an enhanced, transcriptome-wide scope for pseudouridine and methods to dissect its underlying mechanisms and function.

Transcriptome-wide Mapping Reveals Widespread Dynamic-Regulated Pseudouridylation of ncRNA and mRNA

MicroRNAs (miRNAs), small non-coding RNAs (ncRNAs) of about 22 nucleotides in size, play important roles in gene regulation, and their dysregulation is implicated in human diseases including cancer. A variety of miRNAs could take roles in the cancer progression, participate in the process of tumor immune, and function with miRNA sponges. During the last two decades, the connection between miRNAs and various cancers has been widely researched. Based on evidence about miRNA, numerous potential cancer biomarkers for the diagnosis and prognosis have been put forward, providing a new perspective on cancer screening. Besides, there are several miRNA-based therapies among different cancers being conducted, advanced treatments such as the combination of synergistic strategies and the use of complementary miRNAs provide significant clinical benefits to cancer patients potentially. Furthermore, it is demonstrated that many miRNAs are engaged in the resistance of cancer therapies with their complex underlying regulatory mechanisms, whose comprehensive cognition can help clinicians and improve patient prognosis. With the belief that studies about miRNAs in human cancer would have great clinical implications, we attempt to summarize the current situation and potential development prospects in this review.

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miRNA-based biomarkers, therapies, and resistance in Cancer.

Up-regulation of miR-383-5p suppresses proliferation and enhances chemosensitivity in ovarian cancer cells by targeting TRIM27.

Fibrosis is one of the largest groups of diseases for which there is no therapy but is believed to occur because of a persistent tissue repair program. During connective tissue repair, “activated” fibroblasts migrate into the wound area, where they synthesize and remodel newly created extracellular matrix. The specialized type of fibroblast responsible for this action is the α-smooth muscle actin (α-SMA)–expressing myofibroblast. Abnormal persistence of the myofibroblast is a hallmark of fibrotic diseases. Proteins such as transforming growth factor (TGF)β, endothelin-1, angiotensin II (Ang II), connective tissue growth factor (CCN2/CTGF), and platelet-derived growth factor (PDGF) appear to act in a network that contributes to myofibroblast differentiation and persistence. Drugs targeting these proteins are currently under consideration as antifibrotic treatments. This review summarizes recent observations concerning the contribution of TGFβ, endothelin-1, Ang II, CCN2, and PDGF and to fibroblas...

Potential Therapeutic Targets for Cardiac Fibrosis

The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted

https://www.mdpi.com/1422-0067/22/7/3464/pdf

PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects.

As the standard treatments for cancer, chemotherapy and radiotherapy have been widely applied to clinical practice worldwide. However, the resistance to cancer therapies is a major challenge in clinics and scientific research, resulting in tumor recurrence and metastasis. The mechanisms of therapy resistance are complicated and result from multiple factors. Among them, non-coding RNAs (ncRNAs), along with their modifiers, have been investigated to play key roles in regulating tumor development and mediating therapy resistance within various cancers, such as hepatocellular carcinoma, breast cancer, lung cancer, gastric cancer, etc. In this review, we attempt to elucidate the mechanisms underlying ncRNA/modifier-modulated resistance to chemotherapy and radiotherapy, providing some therapeutic potential points for future cancer treatment.

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Role of non-coding RNAs and RNA modifiers in cancer therapy resistance

Cardiac fibrosis is the most important mechanism contributing to cardiac remodeling after myocardial infarction (MI). VPO1 is a heme enzyme that uses hydrogen peroxide (H2O2) to produce hypochlorous acid (HOCl). Our previous study has demonstrated that VPO1 regulates myocardial ischemic reperfusion and renal fibrosis. We investigated the role of VPO1 in cardiac fibrosis after MI. The results showed that VPO1 expression was robustly upregulated in the failing human heart with ischemic cardiomyopathy and in a murine model of MI accompanied by severe cardiac fibrosis. Most importantly, knockdown of VPO1 by tail vein injection of VPO1 siRNA significantly reduced cardiac fibrosis and improved cardiac function and survival rate. In VPO1 knockdown mouse model and cardiac fibroblasts cultured with TGF-β1, VPO1 contributes to cardiac fibroblasts differentiation, migration, collagen I synthesis and proliferation. Mechanistically, the fibrotic effects following MI of VPO1 manifested partially through HOCl formation to activate Smad2/3 and ERK1/2. Thus, we conclude that VPO1 is a crucial regulator of cardiac fibrosis after MI by mediating HOCl/Smad2/3 and ERK1/2 signaling pathways, implying a promising therapeutic target in ischemic cardiomyopathy.

Vascular peroxidase 1 is a novel regulator of cardiac fibrosis after myocardial infarction.

Osteosarcoma is the most common primary malignant bone tumor among adolescents and children, with high level of lung metastasis and poor prognosis. The treatment of metastatic cases remains a challenge in the clinic, leading to the dramatically decreased survival rate. However, the molecular mechanisms are still unclear. A recent article by Kang et al. demonstrated how chromosomal translocations in osteosarcoma facilitated lung metastasis, and shed new light on its therapeutic strategies (Fig. 1). Gene fusions have been identified as driver mutations in neoplasia for more than three decades, and the insights gained from these studies help shape our understanding of multiple tumorigenesis. Previous literatures have pointed out several disease-associated structural chromosomal translocations. For example, the high instability of somatic genome in osteosarcoma, including chromothripsis, chromosomal aneuploidy, and chromosomal rearrangements, could contribute to the production of truncated or fusion proteins, and inhibit many key tumor suppressor genes like TP53 and ATRX, triggering tumor cells migration. Although many fusion proteins have been validated as effective targets for treating several cancer types in the clinic, there are no such therapies for osteosarcoma. To comprehensively explore this novel area, Kang et al. used TopHat-fusion and SQUID algorithms to screen out some related structural variations in metastatic osteosarcoma. Unlike the prevailing algorithms, which normally filter out intron-related structural variations when searching RNA sequences, this method can preserve exon–intron fusion information, which lays a solid foundation for the following experiment. Kang et al. first confirmed that the chromosomal translocationderived aberrant Rab22a was the driver for osteosarcoma lung metastasis in multiple osteosarcoma cell lines and clinical samples. Specially, six fusion transcripts related to RAB22A were identified, designated as RAB22A-NeoF1-6. All of them contain the first two exons of RAB22A, which encode the first 38 amino acids of Rab22a and multiple inverted noncoding regions of chromosome 20. To investigate the role of these transcripts, they were overexpressed in different osteosarcoma cell lines and cell migration and invasion, but not proliferation, were significantly increased. Consistently, authors screened some clinical samples from osteosarcoma patients w/o metastasis and got the same result. Notably, among these six fusions, they revealed that the protein products of RAB22A-NeoF1 were more stable and dominant when compared to others. Therefore, they selected Rab22a-NeoF1 for further study. And by using fluorescence in situ hybridization and immunoprecipitation, the specific presence of endogenous Rab22a-NeoF1 in ZOS/ZOS-M cell lines and tumor tissues was determined. Furthermore, via either knockdown or overexpression of Rab22a-NeoF1 in osteosarcoma cell lines and tumor tissues, they verified that Rab22a-NeoF1 could promote tumor migration and invasion, which might be a potential therapeutic target in patients with metastatic osteosarcoma. The next step of experiment was to investigate how Rab22aNeoF1 drives metastasis. To explore the Rab22a-NeoF1 protein interactome, authors performed tandem affinity purification (TAP) with mass spectrometry (TAP–MS), and determined Rho family members as the key downstream factors in metastasis. Then, through coimmunoprecipitation and other techniques, Rab22aNeoF1 was uncovered to promote osteosarcoma lung metastasis by activating RhoA. The above data indicated that the activation of RhoA by Rab22a-NeoF1 could be a critical determinant to boost the metastasis in osteosarcoma. The authors next sought to how RhoA is activated by Rab22a-NeoF1. From TAP–MS data and cotransfection results, they showed that Rab22a-NeoF1 constitutively bound to a negatively charged region of SmgGDS-607. Interestingly, this region of SmgGDS has been reported to be crucial for its association with RhoA. Based on that, Kang et al. further revealed that the interaction between SmgGDS-607 and RhoA was notably diminished in the presence of Rab22a-NeoF1, indicating that Rab22a-NeoF1 changes the binding of SmgGDS607 to RhoA and transfers RhoA into active form. To further investigate the binding area of Rab22a-NeoF1 and SmgGDS-607, Kang et al. confirmed that amino acids 1–10 of Rab22a-NeoF1 was required for the interaction with SmgGDS-607. Meanwhile, the author team has already reported that the promoting function of Rab22a-NeoF1 is largely dependent on its Lys7 acetylation in osteosarcoma. Based on that, they focused on some positively charged residues and found that Arg4 and Lys7 of Rab22a-NeoF1 were essential for this interaction during lung metastasis. And when using specific targeting peptides of Rab22a, the interaction between Rab22a-NeoF1 and SmgGDS-607 was

/pdf/rab22a-neof1-a-promising-target-for-osteosarcoma-patients-4dkqtls2hv.pdf

Xinyi Zhang

Papers

Role of non-coding RNAs and RNA modifiers in cancer therapy resistance

Vascular peroxidase 1 is a novel regulator of cardiac fibrosis after myocardial infarction.

Rab22a-NeoF1: a promising target for osteosarcoma patients with lung metastasis.