SIRT7 sustains tumor development and radioresistance by repressing endoplasmic reticulum stress-induced apoptosis in cutaneous melanoma.

Cutaneous melanoma is one of the most malignant human tumors and possesses strong resistance to radiotherapy. However, the mechanisms contribute to such radioresistance of melanoma is unclear. In this study, SIRT7 is identified to be higher-expressed in melanoma and positively correlated with melanoma staging. Under ionizing radiation (IR)-treatment condition, loss of SIRT7 compromised the survivability of melanoma cells showed by decreased proliferation, colony formation, migration, but enhancing apoptosis. Transcriptomic sequencing analysis indicated the apoptosis induced after SIRT7 knockdown is tightly related with the induction of endoplasmic reticulum stress (ER stress) by IR treatment. Loss of SIRT7 enhanced EIF2α acetylation and activated its phosphorylation to induce the expression of ER stress proteins including DDIT3, XBP1 and GRP78, among which DDIT3 is responsible for apoptosis induction. SIRT7 depletion enriched ER stress-activated transcription factor ATF4 at the promoter region of DDIT3 gene to transactivate its expression and induces apoptotic cascade in both mock- and IR-treatment conditions. Consistently, SIRT7 is highly upregulated in radioresistant melanoma cell strain and still modulates the ER-stress responsive genes to maintain the homeostasis of melanoma. Collectively, SIRT7 negatively regulates ER stress-activated apoptosis to enhance the survivability of melanoma cells in both non-IR- and IR-treatment conditions. Our study highlights the role of SIRT7 in repressing ER stress and the following apoptosis to sustain tumor development and mediate radioresistance in melanoma, which may suggest a novel intervention target for melanoma therapy.

Resveratrol rescues cutaneous radiation-induced DNA damage via a novel AMPK/SIRT7/HMGB1 regulatory axis.

Cutaneous radiation injury (CRI) interrupts the scheduled process of radiotherapy and even compromises the life quality of patients. However, the current clinical options for alleviating CRI are relatively limited. Resveratrol (RSV) has been shown to be a promising protective agent against CRI; yet the mechanisms of RSV enhancing radioresistance were not fully elucidated and limited its clinical application. In this study, we demonstrate RSV promotes cutaneous radioresistance mainly through SIRT7. During ionizing radiation (IR) treatment, RSV indirectly phosphorylates and activates SIRT7 through AMPK, which is critical for maintaining the genome stability of keratinocytes. Immunoprecipitation and mass spectrometry identified HMGB1 to be the key interacting partner of SIRT7 to mediate the radioprotective function of RSV. Mechanistic study elucidated that SIRT7 interacts with and deacetylates HMGB1 to redistribute it into nucleus and "switch on" its function for DNA damage repair. Our findings establish a novel AMPK/SIRT7/HMGB1 regulatory axis that mediates the radioprotective function of RSV to alleviate IR-induced cutaneous DNA injury, providing an efficiently-curative option for patients with CRI during radiotherapy.

SALIS transcriptionally represses IGFBP3/Caspase-7-mediated apoptosis by associating with STAT5A to promote hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common subtype of liver cancer and the second most fatal cancer in the world despite the great therapeutic advances in the past two decades, which reminds us of the gap in fully understanding the oncogenic mechanism of HCC. To explore the key factors contributing to the progression of HCC, we identified a LncRNA, termed SALIS (Suppression of Apoptosis by LINC01186 Interacting with STAT5A), functions in promoting the proliferation, colony formation, migration and invasion while suppressing apoptosis in HCC cells. Mechanistic study indicated SALIS physically associates with transcription factor STAT5A and binds to the promoter regions of IGFBP3 and Caspase-7 to transcriptionally repress their expression and further inhibit apoptosis. Our findings identified SALIS as an oncogene to promote HCC by physically binding with STAT5A to inhibit the expression of pro-apoptotic IGFBP3 and Caspase-7, which suggests novel therapeutic targets for HCC treatments.

PURPL represses autophagic cell death to promote cutaneous melanoma by modulating ULK1 phosphorylation.

Uncontrolled overactivation of autophagy may lead to autophagic cell death, suppression of which is a pro-survival strategy for tumors. However, mechanisms involving key regulators in modulating autophagic cell death remain poorly defined. Here, we report a novel long noncoding RNA, p53 upregulated regulator of p53 levels (PURPL), functions as an oncogene to promote cell proliferation, colony formation, migration, invasiveness, and inhibits cell death in melanoma cells. Mechanistic studies showed that PURPL promoted mTOR-mediated ULK1 phosphorylation at Ser757 by physical interacting with mTOR and ULK1 to constrain autophagic response to avoid cell death. Loss of PURPL led to AMPK-mediated phosphorylation of ULK1 at Ser555 and Ser317 to over-activate autophagy and induce autophagic cell death. Our results identify PURPL as a key regulator to modulate the activity of autophagy initiation factor ULK1 to repress autophagic cell death in melanoma and may represent a potential intervention target for melanoma therapy.

Knowledge framework and emerging trends in intracranial aneurysm magnetic resonance angiography: a scientometric analysis from 2004 to 2020.

BACKGROUND: As magnetic resonance angiography (MRA) has been increasingly used in the follow-up of intracranial aneurysms (IAs) as a non-invasive technique, the knowledge framework and areas of research interest in intracranial aneurysms magnetic resonance angiography (IAMRA) change approximately every 10 years. However, few studies have quantitatively analyzed the published literature in this field. In the present study, we used scientometrics to survey the knowledge field, development trends, and research focus of IAMRA with the aim of providing a reference for further study. METHODS: We collected articles on IAMRA published from 2004 (Jan 1, 2004) to 2020 (May 24, 2020). Web of Science Core Collection databases (WoSCCd) including the Science Citation Index Expanded were searched. An experienced staff member from the Department of Radiology at Southern Medical University, assisted in screening articles for relevant articles. We used ArcGIS (a mapping and location analytics platform) to perform geographic visualization. Excel 2016 was used to analyze the literature data, including number of publications, impact factor (IF), and publication year. CiteSpace V was used to conduct a series of literature feature clustering, including author co-citation analysis, reference co-citation analysis (RCA), and burst keywords analysis. RESULTS: A total of 1,272 articles on IAMRA published between 2004 and 2020 were included. Of 257 journals, American Journal of Neuroradiology (IF 2018: 3.256) published the most IAMRA articles (109 publications, 8.57%), followed by Journal of Neurosurgery (IF 2018: 4.131, 51 publications, 4.16%), and Neuroradiology (IF 2018: 2.504, 51 publications, 4.01%). Of 56 countries, the USA published the most, with 347 articles [27.28%, IF: 3.14 (average IF of all journals in the country)], followed by Japan (242 articles, 19.03%, IF: 2.38), Germany (135 articles, 10.61%, IF: 3.21), and China (101 articles, 7.94%, IF: 2.86). A total of 1387 institutions published articles, with the Mayo Clinic publishing the most (33 articles, 2.59%), followed by Shanghai Jiao Tong University (25 article, 1.97%), Seoul National University (23 articles, 1.81%), and University Medical Center Utrecht (19 articles, 1.49%). Of 399 authors, Rinkel ranked first with 19 articles, followed by Li MH (18 articles), Uchino A (15 articles), and Saito N (13 articles). Cluster RCA showed that the first cluster was "#0 growth", followed by "#1 Guglielmi detachable coils". Timeline views showed that the time span of "#0 growth" was the closest to today. The modularity value was 0.6971, and the mean silhouette value was 0.5477. According to the burst keyword analysis, "risk factors associated to rupture" was the topic with the strongest burst since 2017. Studies conducted in several countries suggested that age is inversely related to the risk of rupture, which implies the importance of MRA follow-up for patients of different age. CONCLUSIONS: From 2004 to 2020, the number of published IAMRA-related articles gradually increased. The USA and Western Europe lead in the field, with a concentration of cutting-edge talents and high-level scientific research institutions. A synthesis of the clustering results of RCA and burst keyword analysis indicated that unruptured IA growth, stent-assisted coil embolization, and risk factors associated to rupture were the current hotspots in IAMRA research.