Global Trends in Research of NF-κB in Melanoma from 2000 to 2021: A Study of Bibliometric Analysis

In the pathogenesis of melanoma, NF-κB is a key signaling pathway. Appling bibliometric analysis, we identify the frontiers and hotspots about NF-κB in melanoma, as well as distinguishing features of scientific research and output all over the world during the past 22 years. 2226 publications published from 2000 to 2021 and related information were retrieved based on Science Citation Index Expanded (SCI-expanded) of Web of Science Core Collection (WoSCC). VOSviewer and Citespace were used to analyze bibliometric indicators and visualize the hotspots and research trend of studies on NF-κB in melanoma. The results indicated that despite fluctuations, the number of publications (Np) related to the research of NF-κB in melanoma per year increased over the past 22 years. The USA had the most publications. H-index and the number of citations (Nc) of the USA were also in the first place. PloS One was the most productive journal, and League of European Research Universities (LERU) was the most productive affiliation. Recently, the keywords “NF-kappa-b,” “melanoma,” “apoptosis,” “expression,” “activation,” “cancer,” and “metastasis” appeared most frequently. Our study suggested that articles associated with NF-κB in melanoma tend to increase. In this field, the USA was an influential country and a big producer. Most publications focused on clinical and basic research in the past 22 years, and keywords “tumor necrosis factor” and “trail induced apoptosis” had the highest burst strength.


Introduction
Melanoma refers to a tumor derived from melanocytes with a high degree of malignancy. Abnormal and excessive proliferation of melanocytes in neural crest is the main cause of its pathogenesis [1]. e incidence rate of melanoma is increasing worldwide. 95% of melanoma patients died of brain metastasis at the end of the disease [2]. e annual mortality of patients with melanoma is higher than 3.5%, and the 5-year survival rate of patients with metastatic melanoma is about 15%∼20% [3]. About 10% of melanoma cases are diagnosed as advanced, which has metastasized and cannot be removed [4]. Inhibiting the invasion and migration of melanoma is critical to ameliorate the survival rate of melanoma patients, and it is urgent to further explore the molecular mechanism of melanoma and seek a treatment scheme with good curative effect to improve the prognosis of patients. Epidemiological studies show that the incidence rate of melanoma is increasing worldwide. It may be due to the early diagnosis and improvement of health cognition obtained by skin biopsy, thus diagnosing a large number of cases with very thin and marginal cutaneous melanoma [5]. Studies have shown that the joint action of internal factors (such as genetic factors) and external factors (such as ultraviolet light) leads to the pathogenesis of melanoma [4]. Multiple signaling pathways play an important role in the pathogenesis of melanoma [6][7][8].
As an excellent transcription factor, nuclear factorkappa B (NF-κB) is a significant role in the invasion and metastasis of many cancers [9]. It also plays a variety of roles in cell survival, differentiation, and proliferation [10]. e NF-κB transcription factor family consists of five different proteins: rela, RelB, c-Rel, P100, and P150 [11]. It is one of the targets of tumor therapy [12]. e activation of NF-κB has been proposed as an event that promotes melanoma tumor progression [13]. Constitutively activated NF-κB signaling pathway plays an important role in melanoma initiation, progression, invasion, metastasis, and resistance to chemotherapy and immunotherapy, and it is the convergence point of dysregulated cellular signaling pathways in melanoma [14]. Shomali et al.'s study suggested that HSP90 may act as a potential therapeutic target in melanoma. However, more studies are needed to determine the exact role of HSP90 and its association with HMG genes [15]. At present, there are mainly immunotherapy, braf/mek inhibitors, and other methods for the treatment of melanoma. In recent years, there are more and more studies on NF-κb in melanoma [16][17][18]. Professors and scholars continue to make breakthroughs in the field. e emergence of new concepts and the introduction of new technologies are also great challenges for researchers. erefore, it is necessary to summarize the research progress in this field. Bibliometrics is defined by Pritchard as "the application of mathematical and statistical methods to books and other media." Historical bibliometrists recognize that adding time and space dimensions to bibliometric analysis can bring new insights into knowledge development and academic records [19]. Bibliometric methods are majorly composed of citation analysis, which is the source of influencing factors. e number of citations of the research center is considered to be high. erefore, the top ranked and highly cited papers provide evidence and information for research trends and scientific progress in specific fields [20]. Bibliometrics and visual analysis can effectively support information integration to improve the understanding of research activities [21]. Over the recent years, bibliometric indicators are increasingly used to evaluate and manage research activities [22]. Bibliometrics is a method of quantifying the research object, which is often used to determine the law of literature. Unlike the traditional narrative review, which depends on the experience and knowledge of researchers, bibliometric analysis takes science as a knowledge generation system [23]. Nowadays, there are many bibliometric research results, such as metformin [21], tourism [24], artemisinin [25], diabetic foot ulcers [26], and macrophages associated with acute lung injury [27]. Nevertheless, bibliometric research on NF-κB in melanoma is still a blank. erefore, the purpose of this study is to systematically analyze study of NF-κB in melanoma to make a scientific and comprehensive evaluation of the hotspots and research status in the field.

Data Source and Search Strategy.
e publications related to NF-κB in melanoma from 2000 to 2021 were obtained based on the Science Citation Index Expanded (SCI-E) of the Web of Science Core Collection (WOSCC) on April 22, 2022. e retrieval topic was "(TS � (Melanoma)) AND (TS � (NF-kappa B) OR TS � (NF-kB) OR TS � (nuclear transcription factor-κB))," and only the "review" and "article" written in English were included in this study. 2226 publications meeting the search criteria in total were selected to carry out further analysis.

Analytical
Methods. With CiteSpace 5.8.R3 and VOSviewer 1.6.16, data visualization and analysis were carried out. CiteSpace, developed by Professor Chaomei Chen, is a piece of software which can visualize networks among research hotspots and documents as well as citation collaboration [28]. As a software focusing on bibliometrics network, VOSviewer can well analyze literature information, such as keyword cooccurrence, cocitation, and coauthorship. In conclusion, these analytical tools provide an objective and different view of development. e number of publications (Np), the number of citations without selfcitations (Nc), and the academic contribution of researchers are evaluated by the H-index, affiliation, country, or journal [27]. In 2005, Hirsch first introduced the H-index. As a comprehensive scoring, it can well assess the importance and wide-ranging impact for cumulative research contributions of scientists [29].

General Statistics.
ere were 2,226 publications about NF-κB in melanoma from the SCIE of WoSCC during 2000-2021. We found that 75 countries/regions participated in the research field, and these publications were from 623 journals, 2,326 institutions, and 12,830 authors. ere were 8,894 keywords included in all publications. Publishing types were divided into two categories: there were 1,827 research articles accounting for 82.08% and 399 reviews. e total Nc of all publications was 118,172, and the Nc per publication was 55.05. e H-index for all retrieved publications was 148. Figure 1 Table 1 and the number of documents issued by these countries each year is shown in Figure 2 (c). e United States produced the most NF-κB in melanoma-related articles, which was 847 publications in the studied period. China, Germany, and Japan were the following countries in terms of Np. e United States also showed the highest Nc of 66218 and H-index of 117. Even though China is the second productive country, its Nc was lower than Japan. Visualized timeline of countries is shown in Figure 2(d). ere were six clusters including melanoma, IL-6, ROS, oxidative stress, sulforaphane, and thieleanin.

Affiliation and Author Contributions.
A total of 2,326 affiliations and 12,830 authors have contributed to the field of NF-κB in melanoma. Table 2 shows the top 10 affiliations with the highest number of publications. League of European Research Universities (LERU) occupied the first place in Np, and University of Texas System ranked first in Nc and H-index. Although UT MD Anderson Cancer Center ranked 4th in Nc, its H-index was higher than University of California System. To find the most influential researchers in the NF-κB in melanoma field in the last 22 years, according to the H-index and publication number, we ranked the top 10 authors. As the most productive author, Richmond A from Vanderbilt Univ of the United States was with Np of 29 and an H-index of 26. Kuttan G from Amala Canc Res Ctr and Ivanov VN from Columbia University had an H-index of 16 and 14, respectively (Table 3) (Table 4). PloS One ranked first in Np (62). CANCER RESEARCH had the highest H-index (39) and IF (12.701), and ONCOGENE had the highest Nc (5962). 8 journals were from the United States, 1 journal was from England, and 1 journal was from the Netherlands. Impact factor (IF) is a recognized sign to determine the influence of journals based on the frequency of journal articles cited by other scientific publications. Except that PLoS One has a low impact factor or Oncotarget has been removed from science, other journals have high IF (IF > 5).  (123). Keyword clustering and visualization can be carried out through VOSviewer. Due to occurrence >25, 143 keywords reached the specifications and 4 clusters emerged. As shown in Figure 5(a), each word in the 143 keywords is represented by a circle, and the frequency of occurrence of keywords is represented by the size of the circle. A connection line is generated when at least one of the two keywords connected to a keyword coexists. e different colors represented the 4 clusters: cluster 1 (in red) and cluster 2 (in green) mainly concentrated in mechanism research; cluster 3 (in yellow) focused on inflammation research; cluster 4 (in blue) focused on basic and clinical researches. As shown in Figure 5 , the research of anti-inflammation for alleviating melanoma was relatively the latest. As shown in Figure 5(c), the top 7 clusters of keywords were "growth," "transcription factor," "rig i," "metastatic melanoma," "trail," "cyclooxygenase 2," and "reduced glutathione." We found that "tumor necrosis factor" and "trail induced apoptosis" were with the highest burst strength ( Figure 5(d)). Studies have shown that TNF-α treatment of melanoma can induce consistent dedifferentiation [30]. Furthermore, the latest keywords "therapy," "inflammation," "proliferation," and "resistance" emerged in the last 6 years.

Cocitation Analysis.
A cocitation relationship was constituted when two or more articles are simultaneously cited by more than one subsequent publication. e higher the cocitation number, the stronger the cocitation relationship, indicating that these articles have high similarity and will produce a common theme. We performed cluster analysis from the cocitation relationship analysis to further delineate the research frontier and obtain the publications with critical citations from a chronological perspective with Among the 103304 references which were cited by these publications, we selected 181 references for further analysis (Figure 6(a)). ere were 96 references in cluster 1 (in red), which mainly paid attention to drug therapy and mechanism of melanin. Cluster 2 (in green) mainly paid attention to study on various signaling pathways in cancer. Cluster 3 (in blue) focused on study of TNF-related apoptosis inducing ligand (TRAIL) and NF-κB in melanoma. e subject of cluster 4 (in yellow) was therapeutic effect and mechanism of betulinic acid on tumor. Furthermore, a visualized timeline of clusters was carried out (Figure 6(b)). We found that "NFkappa B" and "EGF" are early fields in the study of NF-κB in melanoma. However, the current hotspots of NF-κB in melanoma are on "EMT," "apoptosis," and "duck." Finally, a reference burst was conducted. e latest reference was the paper written by Hoesel B; in his article, he provided an overview that during cancer and inflammation, NF-kappa B and other signaling molecules had the most relevant modes of cooperativity and crosstalk. e top 10 cocited journals are shown in Table 5, and the most frequently cited journal is Cancer Res.   847  66218  117  2  China  507  14104  58  3  Germany  171  11693  50  4  Japan  164  14219  46  5  South Korea  135  4902  39  6  Italy  131  6006  42  7  India  97  3331  33  8  Australia  76  4153  37  9  England  75  6830  33  10 France 75 3372 32   Figure 7 shows the bibliographic coupling analysis.

Discussion
Melanoma is a form of skin cancer that occurs in areas where there is little exposure to sunlight. Melanoma is mainly found in the back of men and the legs of women. is type of tumor develops from existing moles and it is usually irregular in shape and uneven at the edges. is type of skin cancer is a disease that can lead to fatal results depending on the stage of diagnosis. e five-year survival rate of patients with metastatic melanoma is less than 15%. Almost all organs are the target of metastasis. However, the liver, bones, and brain are most often affected. Local chemotherapy is becoming a promising strategy to avoid the sequelae of traditional treatment.
erefore, it is necessary to implement newly developed alternative therapies, such as the use of liposomes as drug carriers to prevent a variety of skin diseases [31].
We conducted a bibliometrics analysis according to 2226 articles related to NF-κB in melanoma from the SCIE of WoSCC database during 2000-2021 with computational algorithm and multiple literature analysis software. Our work summed up research trends, hotspots, and frontiers for     NF-κB in melanoma, and a summary of global research on its impact was obtained. Over the past 22 years, the annual number of publications fluctuates, but on the whole, it shows an upward trend, indicating its rapid development and constant research interest of NF-κB in melanoma. As for the top countries/regions, the USA ranked first in Np, indicating that the USA was a highly productive country on NF-κB in melanoma. In the top 10 authors, six authors came from the USA in the research of NF-κB in melanoma, suggesting that the USA has the most professional researchers in the world, and it explained why the USA developed rapidly in this field over the past 22 years. Compared with China, Japan had a moderately high Nc, although Japan's Np is much lower than that of China. is showed that Chinese scholars and institutions should make more efforts on the quality of papers in this field. Notably, eight of the 10 most productive journals had higher IF. is means that publishing studies on NF-κB in melanoma in high-quality journals is not a challenge. Keyword analysis shows that the research of inflammation in melanoma is a research hotspot this year.
ere is increasing evidence that systemic inflammatory response is an important determinant of tumor progression and survival in many malignancies [32]. Several stages occur in the cellular process that transforms normal melanocytes into tumor cells. From benign nevus to mature tumor cells, genetic instability and proinflammatory environment can lead to tumorigenesis and metastasis. In the cellular microenvironment, immune cells and immune-related molecules play a decisive role in the inflammatory environment. Although the typical cell interface studied in tumors is between CTLS and cancer cells, the contribution of other immune cells is now widely recognized. ese immune cells set up complex immune responses in cancer, including promoting tumors and promoting cancer progression. In some unpredictable situations, the clinical evolution of melanoma requires additional prognostic markers to identify patients at early stage and high risk of melanoma, thereby contributing to improved clinical surveillance strategies and treatment management. One of these additional biomarkers includes inflammatory immune cell infiltration that may describe local antitumor responses or may trigger protumor pathways [33]. Recent data suggest that secreted inflammatory cytokines play a paracrine role in the tumor microenvironment and also promote tumor growth.
Proliferation is another research hotspot in this field. Studies have shown that dendritic cells (DCS) are active molecules that indirectly resist the proliferation of melanoma cells. In addition, DC maturation, migration, and cross-initiation, as well as their functional interactions with cytotoxic T cells through immune checkpoint receptor ligands, are impaired. Many signals are transmitted by highly proliferating melanoma cells and helper cells as T cells, natural killer cells (NKs), tumor-associated macrophages (TAMs), T-regulatory cells (T-Regs), and myeloid suppressor cells (MDSCs), and endothelial cells contribute to the immunosuppressive environment. Results Phagocytosis of tolerance factors and interleukins (IL), such as IL-6 and IL-10. To highlight the role of immune infiltration in blocking melanoma progression, the composition, density, and distribution of cytotoxic T cells in the surrounding stroma have been described as predictors of response to immunotherapy [35]. In addition, NF-κB is an important pathway for melanoma to proliferate [36]. Punita Dhawan et al. reported that, through inhibitors of IKK, NF-κB could be suppressed and then inhibit the proliferation of melanoma cells [37]. e research of An'an XU suggested that inflammatory cytokines could activate NF-κB and induce the expression of proinflammatory cytokines, so accelerating the development of melanoma [38]. In recent years, although targeted therapy and immunotherapy have completely changed the treatment of metastatic melanoma, most patients have not been cured. Treatment of drug resistance remains a major clinical challenge. Melanoma includes cell subsets with different phenotypes, showing different genetic characteristics, leading to tumor heterogeneity and conducive to therapeutic resistance. Cellular plasticity in melanoma is called phenotypic transformation. Regardless of their genomic classification, melanoma will change from a proliferative and differentiated phenotype to an invasive, dedifferentiated, and usually treatment-resistant state [39]. Advances in the use of targeted therapy and immunotherapy have revolutionized the clinical management of melanoma    patients, significantly prolonging their overall and progression-free survival. However, due to gene mutation and epigenetic modification, targeted therapy and immunotherapy are limited, which determines the huge heterogeneity and phenotypic plasticity of melanoma cells. Acquired resistance of melanoma patients to BRAF (brafi) and MEK (MEKI) inhibitors that block the mitogenactivated protein kinase (MAPK) pathway limits their long-term use. On the other hand, immune checkpoint inhibitors can only improve the prognosis of some patients, and the molecular mechanism of lack of response is being studied. Activating MAPK pathway through BRAF mutation may be a potential molecular target to overcome melanoma cells escaping immune surveillance.

Conclusion
In our study, a systematic view of the research hotspots, future directions, and evolutionary process of NF-κB in melanoma study was provided through bibliometrics analysis. It will help the younger generation of researchers who have just entered this field and experts who have been doing research in this field for a long time to better understand the current situation, trends, and future development hotspots of global research.
Data Availability e data of this study are available from the corresponding author.

Conflicts of Interest
e authors declare no conflicts of interest.