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      WGCNA reveals key gene modules regulated by the combined treatment of colon cancer with PHY906 and CPT11

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          Abstract

          Irinotecan (CPT11) is one of the most effective drugs for treating colon cancer, but its severe side effects limit its application. Recently, a traditional Chinese herbal preparation, named PHY906, has been proved to be effective for improving therapeutic effect and reducing side effects of CPT11. The aim of the present study was to provide novel insight to understand the molecular mechanism underlying PHY906-CPT11 intervention of colon cancer. Based on the GSE25192 dataset, for different three treatments (PHY906, CPT11, and PHY906-CPT11), we screened out differentially expressed genes (DEGs) and constructed a co-expression network by weighted gene co-expression network analysis (WGCNA) to identify hub genes. The key genes of the three treatments were obtained by merging the DEGs and hub genes. For the PHY906-CPT11 treatment, a total of 18 key genes including Eif4e, Prr15, Anxa2, Ddx5, Tardbp, Skint5, Prss12 and Hnrnpa3, were identified. The results of functional enrichment analysis indicated that the key genes associated with PHY906-CPT11 treatment were mainly enriched in ‘superoxide anion generation’ and ‘complement and coagulation cascades’. Finally, we validated the key genes by Gene Expression Profiling Interactive Analysis (GEPIA) and RT-PCR analysis, the results indicated that EIF4E, PRR15, ANXA2, HNRNPA3, NCF1, C3AR1, PFDN2, RGS10, GNG11, and TMSB4X might play an important role in the treatment of colon cancer with PHY906-CPT11. In conclusion, a total of 18 key genes were identified in the present study. These genes showed strong correlation with PHY906-CPT11 treatment in colon cancer, which may help elucidate the underlying molecular mechanism of PHY906-CPT11 treatment in colon cancer.

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          The spliceosome is a therapeutic vulnerability in MYC-driven cancer

          c-MYC (MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its pro-tumorigenic functions have been attributed to its ability to regulate gene expression programs 1–3 . Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts 4–7 . While such increases in RNA and protein production may endow cancer cells with pro-tumor hallmarks, this elevation in synthesis may also generate new or heightened burden on MYC-driven cancer cells to properly process these macromolecules 8 . Herein, we discover the spliceosome as a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (SF3B1, U2AF1, and others) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total pre-mRNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Importantly, genetic or pharmacologic inhibition of the spliceosome in vivo impairs survival, tumorigenicity, and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.
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            Targeting transcription factor STAT3 for cancer prevention and therapy.

            Signal Transducers and Activators of Transcription (STATs) comprise an important class of transcription factors that have been implicated in a wide variety of essential cellular functions related to proliferation, survival, and angiogenesis. Among various STAT members, STAT3 is frequently overexpressed in tumor cells as well as tissue samples, and regulates the expression of numerous oncogenic genes controlling the growth and metastasis of tumor cells. The current review briefly discusses the importance of STAT3 as a potential target for cancer therapy and also provides novel insights into various classes of existing pharmacological inhibitors of this transcription factor that can be potentially developed as anti-cancer drugs.
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              Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer.

              Irinotecan hydrochloride is a camptothecin derivative that exerts antitumor activity against a variety of tumors. SN-38 produced in the body by carboxylesterase is the active metabolite of irinotecan. After irinotecan was introduced for the treatment of metastatic colorectal cancer (CRC) at the end of the last century, survival has improved dramatically. Irinotecan is now combined with 5-fluorouracil, oxaliplatin and several molecularly-targeted anticancer drugs, resulting in the extension of overall survival to longer than 30 mo. Severe, occasionally life-threatening toxicity occurs sporadically, even in patients in relatively good condition who have a low risk of chemotherapy-induced toxicity, often causing the failure of irinotecan-based chemotherapy. Clinical pharmacological studies have revealed that such severe toxicity is related to exposure to SN-38 and genetic polymorphisms in UDP-glucuronosyltransferase 1A1 gene. The large inter- and intra-patient variability in systemic exposure to SN-38 is determined not only by genetic factors but also by physiological and environmental factors. This review first summarizes the roles of irinotecan in chemotherapy for metastatic CRC and then discusses the optimal dosing of irinotecan based on the aforementioned factors affecting systemic exposure to SN-38, with the ultimate goal of achieving personalized irinotecan-based chemotherapy.
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                Author and article information

                Contributors
                Journal
                Biosci Rep
                Biosci. Rep
                bsr
                Bioscience Reports
                Portland Press Ltd.
                0144-8463
                1573-4935
                30 September 2020
                02 September 2020
                : 40
                : 9
                : BSR20200935
                Affiliations
                [1 ]Department of Oncology, Dongfang Hospital of Beijing University of Chinese Medicine, Beijing 100078, China
                [2 ]Department of Orthopaedics, Dongfang Hospital of Beijing University of Chinese Medicine, Beijing 100078, China
                Author notes
                Author information
                http://orcid.org/0000-0002-6627-0826
                Article
                BSR20200935
                10.1042/BSR20200935
                7468096
                32812032
                f15672e3-82f6-4e80-b3b0-54412a687e4e
                © 2020 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                History
                : 08 April 2020
                : 13 August 2020
                : 17 August 2020
                : 18 August 2020
                Page count
                Pages: 20
                Categories
                Bioinformatics
                Cancer
                Genomics
                Research Articles

                Life sciences
                chemotherapy,colon cancer,irinotecan,phy906,traditional chinese medicine
                Life sciences
                chemotherapy, colon cancer, irinotecan, phy906, traditional chinese medicine

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