Abstract
Long non-coding RNAs (lncRNAs) play an important role in various biological processes of lung adenocarcinoma (LUAD), such as immune response regulation, tumor microenvironment remodeling and genomic alteration. Nevertheless, immune-related lncRNAs and their immune and genomic alterations characteristics in LUAD samples still remain unreported. Here, using various public databases, statistic and software tools, we constructed two immune-related lncRNA clusters with different immune and genomic alterations characteristics. Notably, cluster 1 had a stronger immunosuppressive tumor microenvironment (TME) and a higher mutation frequency than cluster 2, especially the mutant genes, such as Kelch-like ECH-associated protein 1 (KEAP1) and toll like receptor 4 (TLR4). In cluster 1, both the amplified and deleted portions of copy number variation (CNV) segments were enriched and cyclin dependent kinase inhibitor 2A (CDKN2A) was significantly deleted. GSVA analysis revealed that these immune-related lncRNAs may be involved in stem cell and EMT functions. Furthermore, cluster 1 was related to worse prognosis of LUAD patients. Therefore, we constructed two immune-related and prognostic lncRNA clusters and identified their immune and genomic alterations characteristics in LUAD samples, which could well divide LUAD patients into different immune phenotypes and help to understand immune molecular mechanisms of LUAD.
Introduction
Lung adenocarcinoma (LUAD) is the most prevalent pathological subtype of non small cell lung cancer (NSCLC), which accounts for approximately 40% of lung cancer worldwide [1, 2]. The average 5-year survival rate of patients with LUAD is only 18%, although comprehensive treatments such as surgery and targeted therapies have improved clinical therapies [3]. Recently, immunotherapy strategies have exhibited an unexpected antitumor effect in LUAD [4, 5]. However, fewer patients respond to this therapy, and there is no clearly molecular stratification of the patients [6, 7]. Thus, deeply understanding of immune molecular mechanisms and underlying subtypes of LUAD is of great significance for more effective treatment options.
Long non-coding RNAs (lncRNAs) are non-coding RNAs without protein-coding capacity and are >200 nucleotides (nt) long [8]. LncRNA functions have been discovered in chromatin interactions, transcriptional regulation, RNA processing, mRNA stability or translation, and signal cascade regulation [9–14]. Increasing evidence shows that lncRNAs can regulate not only the innate immune response but also the more sophisticated adaptive immune response as well as immune cell development [15–18]. Moreover, lncRNAs may be pivotal regulators in remodeling the tumor microenvironment (TME) [17, 19, 20], which forms complex and heterogeneous environments consisting of multiple cells, such as infiltrating immune cells and stromal cells [21]. For instance, lnc-EGFR also acts as an immune-suppressor by promoting regulatory T cells differentiation in hepatocellular carcinoma [22]. NF-κB interacting NKILA (an lncRNA) enhances T cell sensitivity to activation-induced cell death by mechanically inhibiting NF-κB signaling [23]. Lymph node metastasis associated transcript 1 (LNMAT1), also a new lncRNA, is involved in the regulation of C-C motif chemokine ligand 2 (CCL2) recruiting macrophages into the tumor [24]. The involvement of lncRNAs in immune regulation is complicated, and many key immune regulatory lncRNAs have not yet been identified. Hence, it is urgent needed to identify new immune-related lncRNAs and elucidate their interactions with immune system in TME. https://www.aging-us.com/article/103251/text
oncotarget acceptance rate
When public mention today’s medicine, accuracy plays one of the most important roles and human lives are literally dependent on it. Hereby, any researches related to medicine are required to comply with the top standards. The challenge today is that any results of researches can be posted online and used as a reference without being adequately verified and approved. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this challenge and attempted to generate an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been founded back in 2010. The major principle of this journal is based on Altmetric scores that are used as a quality measure. That assists both readers and authors to quality-check publications with Altmetric Article Reports that create “real-time feedback containing data summary related to a particular publication.” Oncotarget website demonstrates a full publications list with corresponding scores higher than 100 as well as reports discussed above. Mikhail (Misha) Blagosklonny proud to share his new approach and hopes it creates the required help to anyone, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This study was released back in 2018 by Oncotarget and written by diversified experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study mentions that “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and provides an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The paper has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that majority of readers are aiming to comprehend the very meaning of it. Based on the Altmetric website, the score indicates “how many people have been exposed to and engaged with a scholarly output.” Hereby, the article about melanoma, was utilized for citations in different news articles 69 times. Besides that, it was referred to in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their report on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study
Another Oncotarget’s research with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This study has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have come across a brief overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do receive useful scientific facts. Oncotarget is glad to have the ability to share with online readers this highly appreciated and top-quality information, that is trustworthy and reliable.
Mikhail (Misha) V. Blagosklonny graduated with an MD and PhD from First Pavlov State Medical University of St. Petersburg, Russia. Dr. Mikhail V. Blagosklonny has then immigrated to the United States, where he received the prestigious Fogarty Fellowship from the National Institutes of Health. During his fellowship in Leonard Neckers’ lab at the National Cancer Institute (NCI), he was a co-author of 18 publications on various biomedical themes, including targeting HSP90, p53, Bcl2, Erb2, and Raf-1. He also was the last author for a clinical phase I/II trial article.
After authoring seven papers during a brief yet productive senior research fellowship in the El-Deiry Cancer Research Lab at the University of Pennsylvania, Dr. Blagosklonny returned to NCI to work with Tito Fojo. Together, they published 26 papers. Moreover, Dr. Blagosklonny published many of experimental research papers and theoretical papers as sole author. The abovementioned sole-author articles discussed two crucial topics. The first of these discussed selectively killing cancer cells with deregulated cell cycle or drug resistance via verifying their resistance. The outcomes and underlying notion were so revolutionary that they were incorrectly cited by other scientists as “reversal of resistance,” even though the publication was titled, “Exploiting of drug resistance instead of its reversal.” One big supporter of this concept was the world-famous scientist Arthur Pardee, with whom Dr. Blagosklonny co-authored a joint publication in 2001.
The second theme throughout Dr. Blagosklonny’s sole-author articles is a research method to develop knowledge by bringing several facts together from seemingly irrelevant areas. This results in new notions with testable forecasts, which in turn can be “tested” via analyzing the literature further. Likewise, the concept was co-authored by Arthur Pardee in a 2002 article in Nature. The first success of the new research methodology was the description of the feedback regulation of p53, as confirmed by the discovery of mdm2/p53 loop; and the explanation why mutant p53 is always overexpressed, published in 1997. The most important result revealed by Dr. Blagosklonny’s research methodology is the hyperfunction (or quasi-programmed) theory of aging and the revelation of rapamycin as an exclusively well-tolerated anti-aging drug, published in 2006. As mentioned in Scientific American, Michael Hall, who discovered mTOR in 1991, gives Dr. Blagosklonny credit for “connecting dots that others can’t even see.”
In 2002, Dr. Blagosklonny became associate professor of medicine at New York Medical College. He agreed to accept responsibilities as a senior scientist at Ordway Research Institute in Albany, New York, in 2005, before receiving another position at Roswell Park Cancer Institute as professor of oncology in 2009.
Since coming to Roswell Park Comprehensive Cancer Center in 2009, Dr. Blagosklonny has studied the prevention of cancer (an age-related disease) via stopping organism aging - in other words, “preventing cancer via staying young.” His laboratory closely worked together with Andrei Gudkov’s and conducted research on the suppression of cellular senescence, namely suppression of cellular conversion from healthy quiescence to permanent senescence. This led to the discovery of additional anti-aging medicines beyond rapamycin. The cell culture studies were complemented by studies in mice, including several models like normal and aging mice, p53-deficient mice, and mice on a high-fat diet.
Dr. Blagosklonny has also published extensively on the stoppage of cellular senescence via rapamycin and other mTOR inhibitors, life extension and cancer stoppage in mice, and combinations of anti-aging medicines to be taken by humans. A rapamycin-based combination of seven clinically available medications has been named the “Koschei Formula” and is now used for the treatment of aging in patients at the Alan Green Clinic in Little Neck, New York.
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