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For a long time, cancer has been an important factor in global morbidity and mortality. Especially in recent years, with the rising trend of global aging, the global incidence and mortality of cancer have increased rapidly. In the future, the global medical burden brought by cancer will still increase.[1] Although with the improvement of medical level and the popularization of medical screening, the survival time, quality of life, and prognosis of patients with malignant tumors have been improved to some extent, the treatment of various cancers is still a difficult problem in clinical practice. Active research on the mechanism of cancer progression and new methods of treatment to enhance the efficacy and improve the quality of survival of patients are major challenges that modern medicine and related disciplines need to face together.
In recent years, it has been continuously found that lipid metabolism is involved in the process of tumor growth, proliferation, invasion and migration, and the reprogramming of lipid metabolism becomes an important marker of malignancy.[2,3] Increased lipogenesis in the tumor microenvironment and the storage and mobilization of intracellular lipid droplets are important components that constitute cancer-related lipid changes[4] and show a strong correlation in cancer progression.
The liver X receptor (LXR) was first identified as acting in a mechanism involved in the transport and elimination of cholesterol.[5] As the relationship between lipid metabolism and cancer progression has been revealed, the maintenance of active signaling in cancer cells is dependent on high-intensity endogenous cholesterol biosynthesis and lipid particle uptake. This metabolic mechanism is tightly regulated by a cholesterol homeostatic network that includes the LXR, low-density lipoprotein particle receptor (LDLR) and sterol response element binding protein (SREBP),[6] the mechanism of LXR in cancer cell cholesterol metabolism is expected to be a new target for many types of cancer. There is also an increasing number of studies showing that LXR is also involved in regulating multiple signaling pathways[7–9] as well as participating in tumor immunity[10,11] and other ways involved in tumor progression. Therefore, it is of great significance to systematically review the relevant research and key areas of LXR in cancer progression and discuss the possible future research trends.
Bibliometrics is an interdisciplinary science that uses mathematics and statistics to comprehensively evaluate and analyze certain knowledge carriers in order to summarize the research status of a certain field. The use of bibliometric methods in the evaluation of medical papers and the construction of quantitative evaluation systems through objective indicators is a widely used scientific research method[12] that helps to quickly and objectively establish a scientific understanding of a subject area and to visually analyze its development. This research aims to establish an understanding of the current status and hotspots of the research on the mechanism of LXR and cancer by analyzing the bibliometric method, and to make a judgment on the possible future development trend, with a view to making a useful exploration of new strategies for cancer research.
2. Materials and methods 2.1. Data sourceThe original data of this study were extracted from the Web of Science Core Collection (WoSCC), one of the most commonly used databases for bibliometric analysis studies at present, which can provide information on authors, journals, affiliations, countries/regions, annual publication amount, research areas of papers.
2.2. Search strategyIn order to retrieve and collect the literature information needed for the study more accurately, the retrieval strategy used in this study was an all-field search. Retrieval formula: (ALL = (LXR OR “Liver X receptor” OR “Liver X-activated receptor” OR “Hepatic X receptor” OR Nr1h3 OR Nr1h2) AND ALL = (Cancer OR Neoplasms OR Carcinoma OR Tumor OR Tumor malignant OR malignancies)). A total of 1173 publications were retrieved by the strategy. A total of 1173 articles were retrieved, and those that did not fit the purpose of the study were excluded by the researchers. The search and screening work was carried out independently by 2 researchers, and the results were cross-checked, with a third researcher joining in to make a judgment on the disputed part of the results.
2.3. Screening conditionsPublication time: Based on the publication time of WoSCC, documents published since the establishment of the library until December 2022 are included. Type: publications classified as Articles are included, and other types of publications are excluded. Language: publications in English are included and non-English publications are excluded. Content: Exclude literature whose titles and abstracts are not relevant to the topic of this study, or literature whose content is not related to LXR and cancer.
2.4. Data collectionThe original data were exported from selected publications on the filtered WoSCC database in the form of “plain text file - full record and cited references” as the data source of CiteSpace6.1.6, and in the form of “TAB delimited file - full record and cited references” as the data source of Vosviewer.
2.5. Analytical methodCiteSpace software (Chaomei Chen, Drexel University, USA) has the functions of identifying co-cited authors and references, capturing high burst keywords, generating time zone views, and visual presentation of co-occurrence results. Used CiteSpace6.1.6 to import data sources, create a research project after removing duplicates, set the time slice as 1 year, the pruning settings were selected as “pathfinder” and “pruning sliced networks,” then ran the project for analysis.
Vosviewer (the Centre for Science and Technology Studies, Leiden University) generates an intuitive visual network from the co-citation relationships of the literature and the co-occurrence of keywords and generates a visual data map by parameter adjustment. This study also used Pajek software to assist in adjusting the node network generated by Vosviewer for better clustering presentation and node placement.
Some of the relevant data statistics generated by the software will be exported to Excel for further organization and presentation in graphical form.
In the generated node network, each node represents an item, and the size of the node is positively correlated with the strength of the item (e.g., number, citation frequency, etc.); the link between different nodes indicates the existence of a correlation between nodes, and the thickness of the connection line indicates the strength of the association; closely related nodes are often arranged closer together to facilitate the generation of cluster views. A bright purple box around a node indicates that the centrality of the node is greater than 0.1 and is marked as a key node, suggesting that the node may be the central hub node associated with multiple clusters or types.
3. Results and discussionA total of 1173 articles were retrieved in this field by using the search formula, and we finally obtained 631 eligible articles according to the filtering criteria to exclude the results that did not meet the requirements, as shown in Figure 1.
Figure 1.: The flow chart of literature screening.
3.1. Analysis of annual publications and journalsThe results of the analysis of the WoSCC database using Excel software (Fig. 2A) showed that the annual number of articles in the field related to liver X receptors and cancer increased from 7 articles in 2003 to 71 articles in 2019, and although the number of articles decreased from 2019 to 2022, it still maintained a high number level, and the cumulative number of articles showed a more stable growth trend in general. The 631 articles retrieved were cited 20,537 times in total, and the average article was cited 32.5 times. The relatively stable growth trend represents the development space and research heat of this research field.
Figure 2.: (A) The annual number of publications and the cumulative number of publications in this field; (B) A dual-map overlays visualization of the journal created based on CiteSpace software.
In terms of research areas, the top 3 research areas in the literature were biochemistry molecular biology, oncology, and cell biology, which occupied 24.41%, 20.60%, and 16.16% of the research, respectively, and the rest of the top 10 research areas in terms of number are shown in Table 1.
Table 1 - The top 10 research areas in terms of number. Rank Research areas Publication counts Percentage Centrality Degree 1 Biochemistry Molecular Biology 154 24.41 0.54 16 2 Oncology 130 20.60 0.34 12 3 Cell Biology 102 16.16 0.26 13 4 Endocrinology Metabolism 59 9.35 0.07 6 5 Pharmacology Pharmacy 56 8.87 0.29 10 6 Multidisciplinary Sciences 53 8.40 0 1 7 Medicine Research Experimental 48 7.61 0.19 11 8 Immunology 41 6.50 0.29 13 9 Gastroenterology Hepatology 27 4.28 0 2 10 Biophysics 26 4.12 0.03 3From the source of published journals, the publications included in this research were from 297 journals. and the top 5 journals in terms of number of publications and citations (Tables 2 and 3) had the highest number of publications for PLOS ONE (n = 19) and the highest number of citations for CELL (n = 1730). The dual-map overlays visualization of journals was generated based on the CiteSpace software (Fig. 2B), in which the labels represent the research fields included in the journals, the left part is the journals publishing in the research field, the right part is the journals included in the references in the journals, and the curves from left to right are the citation lines. As can be seen from the figure, most of the papers included in this research were published in molecular, biology, immunology and other journals, mainly citing molecular, biology, and genetics journals.
Table 2 - The top 5 of journals in terms of publications. Rank Source Counts Total citations Average citation per item Total link strength IF (2022) Quartile in category 1 Plos One 19 487 25.6 65 3.7 Q2 2 Biochemical and Biophysical Research Communications 14 275 19.6 69 3.1 Q3 3 Scientific Reports 13 195 15 51 4.6 Q2 4 Journal of Biological chemistry 12 973 81.1 59 4.8 Q2 5 International Journal of Molecular Sciences 11 154 14 15 5.6 Q1The research on the mechanism of LXR and cancer is concentrated in the field of molecular biology and oncology, which is also evidenced by the types of journals published. In addition to comprehensive journals containing a wide range of genres, other journals with high impact or high publication counts show more advantages in the fields of molecular biology and oncology. For example, Cell, as a top journal covering the field of experimental biology such as molecular biology and oncology, is the main journal found to be high-influence in the present study. In Figure 2B, we found that this study also has a certain amount of publications in the field of medicine and clinical medicine, and partially intersects with the field of molecular biology and oncology. No matter what discipline type of cancer research, it is ultimately to return to the purpose of medical and human health services, so our team believes that such cross-referencing can reflect the application transformation level of scientific research and clinical medicine to a certain extent, although the intensity of such cross-referencing curve is insignificant compared with the self-induction in the fields of molecular biology and oncology. This just shows that the existing experimental research still has a lot of room for development in the process of clinical transformation, which may become one of the research directions worth promoting in the future.
3.2. Countries and institutions situation analysisA global geographic view of countries and regions participating in the study created based on Vosviewer (Fig. 3A) shows that 50 countries have been involved in the publication of relevant studies, some of which were done by researchers from several different countries. The country with the highest number of publications was the United States (n = 217), followed by China (including China and Taiwan, n = 195), Japan (n = 53), France (n = 51), the United Kingdom (n = 39), Italy (n = 36), South Korea (n = 30), Germany (n = 29), Spain (n = 28), and Sweden (n = 26) (Fig. 3B).
Figure 3.: (A) The global geographic view of countries and regions participating created by Vosvierer; (B) Statistics on the number of publications of participating countries; (C) A statistical chart of the number of total citation and average citation; (D) The statistics of the number of publications and citations of the institutions; and (E) A time view of the network of reference relationships between institutions.
In terms of total citations (Fig. 3C), the country with the highest number of total citations is the United States (n = 11,155), which far exceeds the other countries, followed by China (n = 3419), which also reaches more than twice the number of other countries. As to the average number of citations, the United States (n = 51.41), Sweden (n = 45.77), the United Kingdom (n = 41.54), and Italy (n = 40.72) possess a higher average number of citations. The US has the highest number of publications, citations, and citations per article, far ahead of other countries, which reflects the dominant position of the US in this research field. In addition, although China has a huge number of publications and citations after the US, it has the lowest average number of citations among the top 10 countries, which indicates that China’s high citations are based on a high number of publications, but the overall quality of articles still needs to be improved.
The institution analysis is independent of the country-region analysis, which can objectively grasp the strength of the institution in the relevant research progress. A total of 1038 institutions are involved in research related to the mechanisms of LXR and cancer. Institutions with at least 8 publications and at least 100 citations are defined as active institutions in the relevant field, with a total of 23 institutions making significant contributions in the field (Fig. 3D). Karolinska Institute (n = 19), University of California, Los Angeles (n = 16), University of Chicago (n = 13), and Nanjing Medical University (n = 13) had more published papers, while the University of California, Los Angeles, University of Pittsburgh, Mem Sloan Kettering Cancer Center had higher average citations. It indicates literature from these institutions has a higher authority. Using Vosviewer to analyze the citation relationships among these institutions and plotting the citation network time view (Fig. 3E) shows that the average time of publication of literature at institutions such as UCLA, the University of Pittsburgh, and the University of Chicago is mainly concentrated in the early years, and that these institutions provide an important foundation for the study of LXR-related mechanisms.
From the institutional analysis, many of the high-impact institutions in this field were published in the early years, suggesting that there may have been a wave of research related to this field in the early years and established a more influential theoretical foundation. It is worth noting that a significant proportion of the more recent studies with some influence are from China, suggesting that the focus of Chinese research in this field may be on the latest cutting-edge research and promoting the development of the field, which may also partially explain the low average citation in China. We tried to sort out relevant clues from the time node in Figure 3E. The high number of published papers and citations of UCLA was our entry point. According to the mark of 2012 as the time range, we found that a considerable degree of highly cited papers came from this institution during the period from 2008 to 2010. These papers[13,14] provide a solid foundation for LXR as an important regulatory hub for cholesterol metabolism and successfully correlate LXR signaling with immune responses through LXR-dependent sterol metabolism, suggesting that LXR acts primarily through lipid metabolism and modulation of immune pathways. This period of research on the role and properties of LXR set the tone for subsequent scientific progress and provided the theoretical basis for the proposal of LXR as a therapeutic target for tumors, and scholars from the Karolinska Institute and the University of Houston were the key promoters of this new concept.[15] These early important research results were mainly driven by institutions from the United States, while in the subsequent period, many institutions from China, such as Chongqing Medical University, Nanjing Medical University, Sun Yat-sen University, Fudan University, etc., have conducted many studies based on this foundation, and these projects[16–19] focus more on the impact of LXR as an activation target on multiple types of cancer and multiple pathways. According to the time view and our search results, the period was positioned around 2014-2018, which is the most booming period of research on LXR and cancer, with multiple types of cancers being revealed to be affected by the regulation of LXR activation, and China was able to become the second country after the United States in terms of the number of papers published.
3.3. Author citation analysisA total of 4418 authors participated in the research on the mechanism of LXR and cancer, of which 89.2% published only 1 article (Fig. 4A). Among the top fifteen authors with the number of publications and citations (Tables 4 and 5), Gustafsson, Jan-ake (n = 14) published the most articles, followed by Steffensen, Knut r. (n = 11), Xie, Wen (n = 9), Nelson, Erik r. (n = 8), and the most cited author was Tontonoz, P (n = 1222), followed by Xie, Wen (n = 977), Pei, Lm (n = 961), Lee, Jung hoon (n = 797). The author collaboration network created based on Vosviewer (Fig. 4B and C) shows that some of the more active or high-impact authors tend to have close collaborative ties and form stable research teams, such as the team of Xie, Wen, Lee, Jung hoon and Wada, Taira, the team of Tontonoz, P, Pei, Lm, Castrillo, A, Joseph, Sb, the partnership between Gustafsson, Jan-ake and Steffensen, Knut r., the partnership between Nelson, Erik r. and Ma, Liqian.
Table 4 - The top 15 authors with the number of publications. Rank Author Publication counts Total citations Average citation per item H-Index Total link strength 1 gustafsson, jan-ake 14 758 54.14 10 79 2 steffensen, knut r. 11 609 55.36 10 121 3 xie, wen 9 977 108.56 8 60 4 nelson, erik r. 8 640 80 6 76 5 poirot, marc 7 118 16.86 5 49 6 russo, vincenzo 7 313 44.71 5 53 7 silvente-poirot, sandrine 7 118 16.86 6 49 8 baron, silvere 6 164 27.33 6 32 9 cao, haixia 6 62 10.33 6 53 10 chuu, chih-pin 6 322 53.67 6 9 11 feng, jifeng 6 50 8.33 6 46 12 ma, liqian 6 65 10.83 4 73 13 maggioni, daniela 6 288 48 6 52 14 moschetta, antonio 6 460 76.67 6 39 15 wu, jianzhong 6 62 10.33 6 53
Figure 4.: (A) The statistics of the number of authors and the number of publications; (B and C) The author citation network and time view respectively.
In the author citation analysis, several stable collaborative teams or close collaborative relationships were formed among high-impact or high-activity scholars. Among them, Xie, Wen’s team and Tontonoz’s team had an important influence on early studies. Xie, Wen et al focused on the mechanism of the role of nuclear receptors including LXR and liver fatty acid transporter protein CD36 in lipid homeostasis[20,21] and early studies on prostate cancer,[22] which may serve as a precursor to studies related to lipid homeostasis in cancer progression. The studies of Tontonoz et al mainly focused on the regulation of the mechanism of action between LXR and macrophages,[10,23] which may become an important basis for the research of LXR and tumor immune response. The research by Gustafsson, Jan-ake et al involved LXR-mediated processes of cell metabolism, proliferation, immune response and inflammatory response[15,24] and revealed the mechanism by which its regulation of lipid and cholesterol metabolism affects the proliferation of breast cancer cell lines.[25] The studies by Nelson, Erik r et al are on average newly published and focus on the mechanism of action of LXR and its ligand (endogenous cholesterol derivative) 27-hydroxycholesterol (27-HC) in selected cancers such as ovarian and breast cancer[26,27] and reveal the relationship between cholesterol homeostasis and the pathological progression of these cancers. The high-quality research results formed by these stable groups can also be summarized into 2 major directions: cholesterol metabolism and tu
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