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      Heterogeneous nuclear ribonucleoprotein A/B: an emerging group of cancer biomarkers and therapeutic targets

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          Abstract

          Heterogeneous nuclear ribonucleoprotein A/B (hnRNPA/B) is one of the core members of the RNA binding protein (RBP) hnRNPs family, including four main subtypes, A0, A1, A2/B1 and A3, which share the similar structure and functions. With the advance in understanding the molecular biology of hnRNPA/B, it has been gradually revealed that hnRNPA/B plays a critical role in almost the entire steps of RNA life cycle and its aberrant expression and mutation have important effects on the occurrence and progression of various cancers. This review focuses on the clinical significance of hnRNPA/B in various cancers and systematically summarizes its biological function and molecular mechanisms.

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          CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer

          Background Ferroptosis is a novel mode of non-apoptotic cell death induced by build-up of toxic lipid peroxides (lipid-ROS) in an iron dependent manner. Cancer-associated fibroblasts (CAFs) support tumor progression and drug resistance by secreting various bioactive substances, including exosomes. Yet, the role of CAFs in regulating lipid metabolism as well as ferroptosis of cancer cells is still unexplored and remains enigmatic. Methods Ferroptosis-related genes in gastric cancer (GC) were screened by using mass spectrum; exosomes were isolated by ultra-centrifugation and CAF secreted miRNAs were determined by RT-qPCR. Erastin was used to induce ferroptosis, and ferroptosis levels were evaluated by measuring lipid-ROS, cell viability and mitochondrial membrane potential. Results Here, we provide clinical evidence to show that arachidonate lipoxygenase 15 (ALOX15) is closely related with lipid-ROS production in gastric cancer, and that exosome-miR-522 serves as a potential inhibitor of ALOX15. By using primary stromal cells and cancer cells, we prove that exosome-miR-522 is mainly derived from CAFs in tumor microenvironment. Moreover, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was found to mediate miR-522 packing into exosomes, and ubiquitin-specific protease 7 (USP7) stabilizes hnRNPA1 through de-ubiquitination. Importantly, cisplatin and paclitaxel promote miR-522 secretion from CAFs by activating USP7/hnRNPA1 axis, leading to ALOX15 suppression and decreased lipid-ROS accumulation in cancer cells, and ultimately result in decreased chemo-sensitivity. Conclusions The present study demonstrates that CAFs secrete exosomal miR-522 to inhibit ferroptosis in cancer cells by targeting ALOX15 and blocking lipid-ROS accumulation. The intercellular pathway, comprising USP7, hnRNPA1, exo-miR-522 and ALOX15, reveals new mechanism of acquired chemo-resistance in GC. Graphical abstract
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            The hnRNP family: insights into their role in health and disease

            Heterogeneous nuclear ribonucleoproteins (hnRNPs) represent a large family of RNA-binding proteins (RBPs) that contribute to multiple aspects of nucleic acid metabolism including alternative splicing, mRNA stabilization, and transcriptional and translational regulation. Many hnRNPs share general features, but differ in domain composition and functional properties. This review will discuss the current knowledge about the different hnRNP family members, focusing on their structural and functional divergence. Additionally, we will highlight their involvement in neurodegenerative diseases and cancer, and the potential to develop RNA-based therapies.
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              Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer

              Background Mounting evidence has demonstrated the vital importance of tumor-associated macrophages (TAMs) and exosomes in the formation of the premetastatic niche. However, the molecular mechanisms by which tumor-derived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown. Methods Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify roles of exosomal miR-934. RNA pull-down assay, dual-luciferase reporter assay, etc. were applied to clarify the mechanism of exosomal miR-934 regulated the crosstalk between CRC cells and M2 macrophages. Results In the present study, we first demonstrated the aberrant overexpression of miR-934 in colorectal cancer (CRC), especially in CRLM, and its correlation with the poor prognosis of CRC patients. Then, we verified that CRC cell-derived exosomal miR-934 induced M2 macrophage polarization by downregulating PTEN expression and activating the PI3K/AKT signaling pathway. Moreover, we revealed that hnRNPA2B1 mediated miR-934 packaging into exosomes of CRC cells and then transferred exosomal miR-934 into macrophages. Interestingly, polarized M2 macrophages could induce premetastatic niche formation and promote CRLM by secreting CXCL13, which activated a CXCL13/CXCR5/NFκB/p65/miR-934 positive feedback loop in CRC cells. Conclusions These findings indicate that tumor-derived exosomal miR-934 can promote CRLM by regulating the crosstalk between CRC cells and TAMs. These findings reveal a tumor and TAM interaction in the metastatic microenvironment mediated by tumor-derived exosomes that affects CRLM. The present study also provides a theoretical basis for secondary liver cancer.
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                Author and article information

                Contributors
                fjif@jszlyy.com.cn
                Journal
                Cell Death Discov
                Cell Death Discov
                Cell Death Discovery
                Nature Publishing Group UK (London )
                2058-7716
                25 July 2022
                25 July 2022
                2022
                : 8
                : 337
                Affiliations
                GRID grid.452509.f, ISNI 0000 0004 1764 4566, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, ; Nanjing, China
                Author information
                http://orcid.org/0000-0001-6182-1142
                Article
                1129
                10.1038/s41420-022-01129-8
                9314375
                35879279
                4c4534ad-f034-4665-89a1-d2e71ba2d50a
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 May 2022
                : 11 July 2022
                : 13 July 2022
                Funding
                Funded by: This work was supported by the Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant No. KYCX21_1568).
                Funded by: This work was supported by the Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant No. KYCX21_1568).
                Funded by: This work was supported by the Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant No. KYCX21_1568).
                Funded by: This work was supported by the Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant No. KYCX21_1568).
                Funded by: This work was supported by the Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant No. KYCX21_1568).
                Funded by: This work was supported by the Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant No. KYCX21_1568).
                Funded by: This work was supported by the Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant No. KYCX21_1568).
                Categories
                Review Article
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                © The Author(s) 2022

                tumour biomarkers,targeted therapies
                tumour biomarkers, targeted therapies

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