Cancer Translational Medicine

Review | Open Access

Vol.7 (2021) | Issue-1 | Page No: 1-12

DOI: https://doi-ds.org/doilink/01.2022-42537425/CTM/01.2022-11557263/2021.V7/I1/A1

TRAF Proteins In NSCLC: Analysis Of Data From The Public Database And Literature Review

Xuebing Li1, Yaguang Fan1, Hongli Pan1, Yang Li1, Limin Cao1, Zhenhua Pan1, Lingling Zu1, Fanrong Meng2, Mengjie Li3, Qinghua Zhou1, Xuexia Zhou4*

 

Affiliations  

1 Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China;

2 Tianjin Prenatal Diagnostic Center, Obstetrics and Gynecology Department, Tianjin Medical University General Hospital, Tianjin, China;

3 Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China;

4 Department of Neuropathology, Tianjin Key Laboratory of Injuries, Variations and Regeneration of the Nervous System, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System of Education Ministry, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China

*Corresponding Author

Address for correspondence: Dr. Xuexia Zhou, Department of Neuropathology, Tianjin Key Laboratory of Injuries, Variations and Regeneration of the Nervous System, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System of Education Ministry, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China. E-mail: xxzhou@tmu.edu.cn


Important Dates  

Date of Submission:   26-Oct-2021

Date of Acceptance:   05-Nov-2021

Date of Publication:   29-Dec-2021

ABSTRACT

Currently, lung cancer is one of the malignant tumors with a high morbidity and mortality all over the world. However, the exact mechanisms underlying lung cancer progression remain unclear. The TNF receptor associated factor (TRAF) family members are cytoplasmic adaptor proteins, which function as both adaptor proteins and E3 ubiquitin ligases to regulate diverse receptor signaling, leading to the activation of NF-κB, MAPK and IRF signaling. In this article, we analyzed the mRNA expressions, protein expressions and prognostic significance of TRAFs in NSCLC using the data from public online databases. Moreover, we also summarized the abnormal expressions and complex biological functions of TRAFs in NSCLC from published reports. Taken together, the conclusion presented in this article provides a promising therapeutic strategy for NSCLC, which is manipulating TRAF proteins or TRAF-dependent signaling pathways.

Keywords: TNF, TNFR, TRAF, NSCLC, tumor progression

 


INTRODUCTION

Lung cancer is the second common primary malignant tumor around the world. It has the highest morbidity and mortality in men among all malignancies, whereas, in women, it ranks third for incidence and second for mortality.[1] There are nearly 787,000 new cases and more than 631,000 deaths of lung cancer in China every year. According to the latest statistics from Chinese Academy of Medical Sciences, lung cancer has become the first cause of tumor death in China.[2],[3],[4] Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer, which accounts for about 80% of all lung cancer cases. NSCLC comprises of lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC) and large cell lung carcinoma (LCLC). Although medical personnel have made great effort in early screening, diagnosis, surgical resection, radiotherapy, chemotherapy, molecular targeted treatment and immunotherapy for lung cancer during the past 50 years, it is still a major threat to human health due to its increasing morbidity, mortality and poor prognosis.[5] At present, the research on the mechanism of malignant progression of lung cancer is in full swing, and omics studies based on big data have successively found multiple drivers genes.[6] Further research will provide important clues for target selection and strategy optimization on molecular targeted therapy of lung cancer, which is the key to break the existing bottleneck of lung cancer treatment, and has important guiding significance and hopeful application prospects.

The tumor necrosis factor (TNF) superfamily consists of a group of secreted or membrane bound ligands; whereas the tumor necrosis factor receptor (TNFR) superfamily consists of their receptors. These receptors contribute to multiple and widespread physiological functions, including development, differentiation, apoptosis and immune system regulation.[7] Currently there are 19 members in TNF family and 29 members in TNFR family in humans.[8] The existence of more TNFRs than TNFs indicates that some members of TNF family can interact with more than one TNFR.7,8 Various TNFRs involved in important biological processes interact with their adaptor proteins.[9] The TNF receptor associated factor (TRAF) proteins are cytoplasmic adaptor proteins. They function as both adaptor proteins and E3 ubiquitin ligases to regulate TNFR, Toll-like receptor (TLR), NOD-like receptor (NLR), RIG-I-like receptor (RLR) and other cytokine receptor signaling, leading to the activation of NF-κB, MAPKs (ERK, JNK and p38) and IRF signaling.[10] To date, seven different TRAF proteins (TRAF1-7) have been identified in mammals. Moreover, the diverse signaling pathways that TRAF proteins participate to regulate important biological processes includes cell proliferation, differentiation, survival and stress responses.[10],[11] Many of the TRAF-dependent signaling pathways are implicated in cancer pathogenesis. Thus, TRAF members are key regulators in cancer, especially NSCLC progression.


Tumor Necrosis Factor (TNF) & Tumor Necrosis Factor Receptor (TNFR)

Tumor Necrosis Factor (TNF)

In the past 60 years, one of the most well-known concepts in the life science is that the cytokines or molecules that can selectively kill tumor cells can be used as potential drugs for cancer treatment.[7] In 1968, scholars at the University of California found a cytotoxic lymphotoxin (LT) secreted by lymphocytes.[12] Meanwhile, in 1975, Carswell et al. found macrophages could produce cytotoxic substances, and named it as Tumor Necrosis Factor (TNF).[13] In 1984 and 1985, LT and TNF were isolated, purified, cloned and renamed as TNF-β.[14],[15] and TNF-α [16],[17] Nearly 30 years later, 19 different members of the TNF superfamily (TNFSF) have been identified based on gene sequences.[8],[18] The 19 TNFSFs are summarized in Table 1.

Table 1
Table 1. The summary of various members of the TNF superfamily and TNFR superfamily.

 

Tumor Necrosis Factor Receptor (TNFR)Structurally, most members of TNFSF belong to Type II transmembrane proteins. The conserved TNF domain in C-terminal can be cleaved by metalloproteinase, which produce soluble cytokines.[19] Partially processed, as well as matured protein can be secreted out of the cell.[20] Functionally, as cytokines, most TNFs are both beneficial and harmful to cells.[18] This double-edged sword plays important roles on morphogenesis, proliferation and apoptosis of the cells.[8]

As ligands, the TNFs need to interact with cell surface receptors to transduct signal. ‘TNF’ often stands for ‘TNF-α’, while ‘TNFR’ also stands for the receptor binding with TNF-α, which is CD120. After the identification of TNFR1 and TNFR2 in 1985,[21] 29 different members of the tumor necrosis factor receptor superfamily (TNFRSF) have been identified.[8],[18] The 29 TNFRSFs are summarized in Table 1.

The expression of TNFR proteins vary according to cell and tissue types.[7],[8] The fact that 19 TNFSFs interacting with 29 TNFRSFs implies that at least some of the ligands must interact with more than one receptor. Indeed, one TNF interacts with different TNFRs, while one TNFR can also be activated by more than one TNF.[22]

Structurally, all members of TNFRSF belong to Type I transmembrane proteins with conserved cysteine-rich repeat domains and a partly conserved extracellular domain. A subgroup of TNFRSF members transducing apoptosis signals also contains a conserved ‘death domain’ in the cytoplasmic region.[23] Functionally, TNFRSF are oligomerized as a consequence of interaction with TNFSF, which is required to deliver functional signals leading to proliferation, survival or apoptosis of the cells. The altered function option deciding either cell death or cell survival depends on the cell type and functional status.[23]

TNFR is also called ‘death receptor’. Self-aggregation and non-covalent trimerization are needed for its activation.[24] Besides, TNFR proteins function in cooperation with adaptor proteins such as tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD), receptor interacting protein (RIP) and TNF receptor associated factor (TRAF), to analyze the extracellular signals and respond differently.


TNF receptor associated factors (TRAFs)

Domain Organization of the Seven TRAF Proteins

The tumor necrosis factor receptor associated factors (TRAFs) constitute a family of adapter proteins mediating signal transduction by cytokines. These genetically conserved adapter proteins have been found in mammals and other species such as Drosophila, Caenorhabditis elegans and Dictyostelium discoideum.[25]

To date, a total of seven members of the TRAF family have been identified in mammals. In 1994, Rothe et al. identified two proteins binding the cytoplasmic tail domain of TNFR2, which were named as TRAF1 and TRAF2.[26] Since then, other members of the TRAF family have been discovered (Fig 1).[27]

Figure 1
Figure 1. Schematic representation of the structures of TRAF proteins.

Structural evidence suggests that TRAF proteins have a relatively conserved domain. They function as adapter proteins for a wide variety of cell-surface receptors and regulate diverse cellular responses.[28] Except for TRAF7, TRAF proteins exhibit the conserved TRAF domain at their C-terminal. The TRAF domain is further divided into two sections: TRAF-N (coiled-coil) domain and TRAF-C domain. The TRAF-N region facilitates the oligomerization of TRAF proteins. The TRAF-C region not only mediates oligomerization, but also mediates interactions with TNFR proteins and other cytoplasmic factors.[29] All TRAF proteins contain a conserved RING finger domain and several adjacent zinc finger domains in N-terminal, except for TRAF1.[30] The N-terminal structure of TRAF proteins is necessary to activate downstream signaling.[29],[31]

The Expression Distributions of TRAFs in vivo

 The TRAF proteins show different expression distribution in vivo. In mice, TRAF1 is selectively expressed in spleen, lungs and testicles; whereas TRAF2, TRAF3, TRAF5 and TRAF6 are widely expressed in all tissues and organs. TRAF4 is expressed in thymic epithelial cells and lymph node dendritic cells in adults.[32] The sequence of TRAF4 contains potential nuclear localization signal, thus TRAF4 predominantly localizes in the nucleus,[33] which is totally different with the cytoplasmic localization of other members of TRAF family. Moreover, TRAF4 is the only member that was not shown to regulate signaling through cell surface receptors, indicating a possible function in the nucleus.[34] The RING finger domains of TRAF2, TRAF3, TRAF6 and TRAF7 are confirmed to be able to promote ubiquitination of substrate proteins, and this necessary process activates the downstream signaling.[35],[36],[37],[38] The TRAF proteins activate downstream signaling through the interaction of cytokine receptors, kinases, regulatory proteins and adaptor proteins containing TRAFs.[39]

TRAF-regulated Signaling and Phenotypes in TRAF-deficient Mice

TRAF proteins possess biological functions mainly through the activation of NF-κB or AP-1 transcription factor. NF-κB signaling is activated by the upstream IKK, and the downstream genes play immune, inflammatory and anti-apoptotic roles; AP-1 signaling is activated by the upstream MAPK, which promotes cell survival or induces cell death.[25] The different TRAF-regulated signaling and multiple phenotypes in TRAF-deficient mice are summarized in Table 2.[25],[27],[40]

Table 2
Table 2. The summary of the TRAF-regulated signaling and phenotypes in TRAF-deficient mice.


Expressions And Functions of TRAFS in NSCLC

MRNA Levels of TRAFs in Multiple Human Cancers

To overview the expression status of TRAF proteins in human cancers, we firstly analyzed their mRNA levels across different types of human cancers by using the TCGA resources from TIMER database (https://cistrome.shinyapps.io/timer/). As shown in Figure 2, TRAF1-7 exhibited overexpression in a majority of the human cancers compared with corresponding controls. The members of TRAFs were simultaneously upregulated in certain types of human cancer, including bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cholangio carcinoma (CHOL), colon adenocarcinoma (COAD), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), stomach adenocarcinoma (STAD) and uterine corpus endometrial Carcinoma (UCEC). All TRAFs except TRAF1 and TRAF6 displayed an obvious upregulation in both LUAD and LUSC with P values < 0.001, suggesting their potential oncogenic functions in NSCLC.

Figure 2
Figure 2. The expressions of TRAF1-7 mRNA in a majority of human cancers (including NSCLC: LUAD and LUSC) compared to the corresponding normal tissues according to the data from TIMER database (https://cistrome.shinyapps.io/timer/). The full names of the cancers are: ACC, adrenocortical carcinoma; BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, cholangio carcinoma; COAD, colon adenocarcinoma; DLBC, lymphoid neoplasm diffuse large B-cell lymphoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LAML, acute myeloid leukemia; LGG, brain lower grade glioma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; MESO, mesothelioma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PRAD, prostate adenocarcinoma; READ, rectum adenocarcinoma; SARC, sarcoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; TGCT, testicular germ cell tumors; THCA, thyroid carcinoma; THYM, thymoma; UCEC, uterine corpus endometrial carcinoma; UCS, uterine carcinosarcoma; UVM, uveal melanoma.

Protein Expression of TRAFs in NSCLC

When referring to gene expression, the protein level and mRNA level are often inconsistent in organisms. We next analyzed the TRAF protein levels in NSCLC (LUAD and LUSC) by using the Human Protein Atlas (https://www.proteinatlas.org/). As shown in Figure 3, immunohistochemistry analyses validated the upregulation of TRAF proteins in NSCLC tissues. Except for TRAF3 and TRAF5, other TRAF proteins displayed an obviously deeper staining in LUAD and LUSC tissues comparing with normal controls. Stronger staining observed in TRAF1, TRAF2, TRAF4 and TRAF6 suggested their overexpression in NSCLC tissues. Of note, the upregulation of TRAF6 protein was inconsistent with the downregulation of TRAF6 mRNA, suggesting its post-transcription modification. Collectively, the overexpression of TRAFs at both mRNA and protein levels fully supported that TRAFs are critical for guiding NSCLC progression.

Figure 3
Figure 3. Immunohistochemistry analyses from the online Human Protein Atlas database (https://www.proteinatlas.org/) validated the protein expressions of TRAF1-7 in normal lung tissues and NSCLC (LUAD and LUSC) tissues. The antibodies used in IHC are: TRAF1, HPA001852; TRAF2, HPA009972; TRAF3, HPA002933; TRAF4, HPA052377; TRAF5, HPA008052; TRAF6, CAB004605; TRAF7, HPA041229.

Significance of TRAFs in Lung Cancer Prognosis

After preliminarily confirming the association of TRAF upregulation with NSCLC diagnosis, we wonder whether TRAF upregulation was associated with NSCLC prognosis. Kaplan-Meier survival analysis was performed by log-rank test using original data from Kaplan-Meier Plotter (http://www.kmplot.com/lung/). As shown in Figure 4, patients with higher levels of TRAF1, TRAF2, TRAF4 and TRAF7 had shorter overall survival than the patients with their lower expression (P<0.05); while higher levels of TRAF3, TRAF5 and TRAF6 had significantly longer overall survival than that with their lower expression (P<0.01). These results supported that the patients with high TRAF1, TRAF2, TRAF4 and TRAF7 levels tended to have worse prognosis; while the higher expression TRAF3, TRAF5 and TRAF6 might predict better outcomes, which were inconsistent with their upregulation in NSCLC tissues.

Figure 4
Figure 4. The prognosis significance of TRAF1-7 in NSCLC patients. (A) Kaplan-Merier survival analysis of overall survival using the data from Kaplan-Meier Plotter (http://www.kmplot.com/lung/). (B) The parameters and P values in survival analysis. OS: overall survival; HR: hazard ratio.


The Altered Expressions and Complex Functions of TRAFs in NSCLC

a) TRAF1 in NSCLC

In 2018, Wen et al. showed that TRAF1 was significantly upregulated in NSCLC patients and negatively associated with overall survival, which promoted cell proliferation.[41] Meanwhile, Dong’s team also observed the overexpression of TRAF1 in NSCLC cell lines and tissues, which correlated with poor prognosis. Moreover, they reported the oncogenic function of TRAF1 in cell growth, invasion, differentiation and induction of cell death.[42] Collectively, they all identify TRAF1 as a new target for NSCLC therapy and offer a candidate molecular target for NSCLC diagnosis.

b) TRAF2 in NSCLC

Zheng et al. and Zhang et al. reported the upregulation of TRAF2 in NSCLC tissues and cell lines, respectively.[43],[44] Functional studies suggested that TRAF2 played oncogenic roles not only in terms of cell proliferation,[43],[44],[45] but also in other malignancy properties. For instance, in 2014, Marivin et al. found that TRAF2 promoted TNF-mediated filopodia formation in lung cancer cells.[46] Besides, one year later, Cai et al. observed a positive correlation between TRAF2 and other signaling molecules regulating cell migration, metastasis and adhesion in metastatic A549L6 cells.[47] The findings of these two teams demonstrated the positive contribution of TRAF2 in metastasis. In 2018, Li et al. found that TRIM37 could induce angiogenesis of NSCLC cells in vitro and in vivo, through binding to TRAF2, promoting K63-linked ubiquitination of TRAF2, and sustaining the eventual activation of the NF-κB pathway.[45] Moreover, TRAF2 was reported to enhance radioresistance in NSCLC cells through activation of NF-κB signaling pathway and subsequently downregulation of cell cycle and cell survival responsible proteins.[43],[48] These studies suggested that TRAF2 was an attractive drug target for NSCLC therapy. Lai et al. and Zhang et al. found the elevated expression level of TRAF2 in cisplatin treated leptin-silenced A549 cells and CSTMP treated A549 cells, respectively, suggesting the ER stress-promoting function of TRAF2.[49],[50] In addition, TRAF2 had also been reported to facilitate the processes of inflammation, autophagy, survival and anti-apopotsis in NSCLC cells.[47],[51],[52],[53] Taken together, the upregulated expression and oncogenic roles of TRAF2 suggested that it might be a potential target for NSCLC therapy.

c) TRAF3 & TRAF4 in NSCLC

The controversy regarding roles of TRAF3 is unlikely to be resolved in the near future. In 2017, Newman et al. proved its oncogenic roles through autophagy regulation in A549 cells.[54] On the contrary, both Yang’s team and Qin’s team reported that the downregulation of TRAF3 increased the proliferation, invasion and migration of NSCLC cells,[55],[56] which are in accordance with our survival analysis, depicted in Figure 4. These conflicting results from various teams could be due to the involvement of TRAF3 in numerous signaling pathways involved in different processes. The overexpression of TRAF4 in NSCLC had been widely recognized by several research teams from 2007 to 2020.[57],[58],[59],[60],[61] It consistently expressed oncogenic roles in terms of cell proliferation, invasion, EMT, radioresistance and stemness through activation of PI3K/Akt and/or NF-κB signaling pathways.[58],[59],[60],[61],[62]58-62 These reports suggested that TRAF4 might be a promising target for NSCLC therapy.

d) TRAF6 in NSCLC

TRAF6 is a hot spot in cancer research. Three independent teams have reported its upregulation in NSCLC.[63],[64],[65] Besides, TRAF6 was shown to be positively correlated with tumor size, TNM stage and lymph node metastasis in NSCLC.[65] Specifically, several findings showed that TRAF6 could promote cell growth and tumorigenesis through the activating NF-κB and transcription of its downstream cyclin D1 gene.[63],[66],[67],[68] Meanwhile, TRAF4 could activate the expression of cytokines such as CCL2, CCL20, CD24 and CXCR4; matrix metallopeptidase such as MMP9, MMP2; EMT markers such as E-cadherin. By means of these molecules, TRAF6 participated in the invasion and migration processes in NSCLC cells, acting as an oncogene.[LinkRef 66-173,67-174,68-175,69-176,70-177] Moreover, TRAF6 knockdown could inhibit survival and promote apoptosis in NSCLC cells through the upregulation of caspase3 via NF-κB activation.[LinkRef 66-173,67-174,70-177,71-178] In addition, in 2017 and 2018, Jiang et al. and Han et al. found the novel functions of TRAF6 in DDP-resistance and autophagy in NSCLC, both of which could be explained by the old mechanism – NF-κB activation.[72],[73] Surprisingly, in 2020, Liu et al. reported the downregulation of TRAF6 and its tumor suppressing roles on proliferation, migration and apoptosis of NSCLC cells.[74] They did not provide any explanation on the mechanisms, but the apoptosis-promoting role of TRAF6 was consistent with the previous report in 2015.[75] Most reports supporting the oncogenic functions of TRAF6 suggested that it may be a promising target for the therapy of NSCLC.

In order to verify the consistency of TRAF expressions between online database and reported research results, as well as to clarify the functions of TRAF proteins in NSCLC, we summarized the published reports in Table 3.

Table 3
Table 3. The expressions and functions of TRAFs in NSCLC. ((+): positive regulation; (−): negative regulation; None: no reports.)

According to the findings summarized in Table 3, TRAF proteins contribute to the development, progression and metastasis of NSCLC by affecting cell survival, proliferation, invasion, migration, inflammation, radioresistance and drug-resistance. The dysregulation of TRAF proteins in NSCLC suggests an important area needing further attention. In fact, each TRAF protein could function either positively or negatively in particular signaling pathway. Thus, the nuanced role of TRAF proteins in NSCLC need to be strictly evaluated before their application in clinics.


CONCLUSION

TRAF proteins exert biological functions mainly through the activation of NF-κB and MAPK signaling by interaction of cytokine receptors, kinases, regulatory proteins and adaptor proteins containing TRAFs. Most TRAF proteins exhibited upregulation at both mRNA and protein level in NSCLC when analyzing the data from public online databases [Figure 2 and Figure 3]. However, only high expressions of TRAF1, TRAF2, TRAF4 and TRAF7 tended to have worse prognosis [Figure 4]. Scholars from various teams had reported the upregulation and oncogenic functions of TRAF1, TRAF2, TRAF4 and TRAF6, whereas a few teams demonstrated the downregulation and tumor suppressing roles of TRAF3 and TRAF6 in NSCLC [Table 3]. Notably, no studies regarding the roles of TRAF5 and TRAF7 in NSCLC have been done yet, which could become interesting topics and need further investigation in future. Although the exact mechanisms of TRAF proteins regulating malignant progression of lung cancer are complex and not entirely clear, they indeed provide new means and potential therapeutic targets for malignant tumor, especially NSCLC.

 

FINANCIAL SUPPORT AND SPONSORSHIP

This study was supported by grants from the National Natural Science Foundation of China (No. 81302002, to Xuebing Li; No. 81502166, No. 81972354 & No. 82172901 to Xuexia Zhou), the Tianjin Natural Science Foundation (No. 14JCQNJC12300, No. 18JCYBJC92100, to Xuebing Li; No. 17JCYBJC27100, to Xuexia Zhou; No. 17JCYBJC25400, to Yaguang Fan; No. 17JCQNJC11700, to Hongli Pan), The Key Project of Cancer Foundation of China (No. CFC2020kyxm003, to Xuebing Li; No. CFC2020kyxm002, to Yaguang Fan), the Natural Science Research Program of Tianjin Municipal Education Commission (No. 2020KJ150, to Limin Cao; No. 2020KJ157, to Zhenhua Pan), the Foundation of Tianjin Medical University General Hospital (No. ZYYFY2019022, to Fanrong Meng), the Introduction of Talents and Doctoral Initiation Fund of Tianjin Medical University Cancer Institute and Hospital (No. B1917, to Mengjie Li), and the Tianjin Key Medical Discipline (Specialty) Construction Project - General Project of Tianjin Lung Cancer Institute (No. TJLCMS2021-03, to Xuebing Li).

 

CONFLICTS OF INTEREST

There are no conflicts of interest.


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Yi‑Zhou Jiang1, Demeng Chen2


Mutation Detection with a Liquid Biopsy 96 Mutation Assay in Cancer Patients and Healthy Donors

Aaron Yun Chen, Glenn D. Braunstein, Megan S. Anselmo, Jair A. Jaboni, Fernando Troy Viloria, Julie A. Neidich, Xiang Li, Anja Kammesheidt


The Application of Estrogen Receptor‑1 Mutations’ Detection through Circulating Tumor DNA in Breast Cancer

Binliang Liu, Yalan Yang, Zongbi Yi, Xiuwen Guan, Fei Ma


Circulating MicroRNAs and Long Noncoding RNAs: Liquid Biomarkers in Thoracic Cancers

Pablo Reclusa1, Anna Valentino1, Rafael Sirera1,2, Martin Frederik Dietrich3, Luis Estuardo Raez3, Christian Rolfo1


Exosomes Biology: Function and Clinical Implications in Lung Cancer

Martin Frederik Dietrich1, Christian Rolfo2, Pablo Reclusa2, Marco Giallombardo2, Anna Valentino2, Luis E. Raez1


Circulating Tumor DNA: A Potential Biomarker from Solid Tumors’ Monitor to Anticancer Therapies

Ting Chen1,2, Rongzhang He1,3, Xinglin Hu1,3,4, Weihao Luo1, Zheng Hu1,3, Jia Li1, Lili Duan1, Yali Xie1,2, Wenna Luo1,2, Tan Tan1,2, Di‑Xian Luo1,2


Novel Molecular Multilevel Targeted Antitumor Agents

Poonam Sonawane1, Young A. Choi1, Hetal Pandya2, Denise M. Herpai1, Izabela Fokt3,
Waldemar Priebe3, Waldemar Debinski1


Fish Oil and Prostate Cancer: Effects and Clinical Relevance

Pei Liang, Michael Gao Jr.


Stemness‑related Markers in Cancer

Wenxiu Zhao1, Yvonne Li2, Xun Zhang1


Autophagy Regulated by miRNAs in Colorectal Cancer Progression and Resistance

Andrew Fesler1, Hua Liu1, Ning Wu1,2, Fei Liu3, Peixue Ling3, Jingfang Ju1,3


Gastric Metastases Mimicking Primary Gastric Cancer: A Brief Literature Review

Simona Gurzu1,2,3, Marius Alexandru Beleaua1, Laura Banias2, Ioan Jung1


Possibility of Specific Expression of the Protein Toxins at the Tumor Site with Tumor‑specialized Promoter

Liyuan Zhou1,2, Yujun Li1,2, Changchen Hu3, Binquan Wang1,2


SKI‑178: A Multitargeted Inhibitor of Sphingosine Kinase and Microtubule Dynamics Demonstrating Therapeutic Efficacy in Acute Myeloid Leukemia Models

Jeremy A. Hengst1,2, Taryn E. Dick1,2, Arati Sharma1, Kenichiro Doi3, Shailaja Hegde4, Su‑Fern Tan5, Laura M. Geffert1,2, Todd E. Fox5, Arun K. Sharma1, Dhimant Desai1, Shantu Amin1, Mark Kester5, Thomas P. Loughran5, Robert F. Paulson4, David F. Claxton6, Hong‑Gang Wang3, Jong K. Yun1,2


A T‑cell Engager‑armed Oncolytic Vaccinia Virus to Target the Tumor Stroma

Feng Yu1, Bangxing Hong1, Xiao‑Tong Song1,2,3


Real‑world Experience with Abiraterone in Metastatic Castration‑resistant Prostate Cancer

Yasar Ahmed1, Nemer Osman1, Rizwan Sheikh2, Sarah Picardo1, Geoffrey Watson1


Combination of Interleukin‑11Rα Chimeric Antigen Receptor T‑cells and Programmed Death‑1 Blockade as an Approach to Targeting Osteosarcoma Cells In vitro

Hatel Rana Moonat, Gangxiong Huang, Pooja Dhupkar, Keri Schadler, Nancy Gordon,
Eugenie Kleinerman


Efficacy and Safety of Paclitaxel‑based Therapy and Nonpaclitaxel‑based Therapy in Advanced Gastric Cancer

Tongwei Wu, Xiao Yang, Min An, Wenqin Luo, Danxian Cai, Xiaolong Qi


Motion Estimation of the Liver Based on Deformable Image Registration: A Comparison Between Four‑Dimensional‑Computed Tomography and Four‑Dimensional-Magnetic Resonance Imaging

Xiao Liang1, Fang‑Fang Yin1,2, Yilin Liu1, Brian Czito2, Manisha Palta2, Mustafa Bashir3, Jing Cai1,2


A Feasibility Study of Applying Thermal Imaging to Assist Quality Assurance of High‑Dose Rate Brachytherapy

Xiaofeng Zhu1, Yu Lei1, Dandan Zheng1, Sicong Li1, Vivek Verma1, Mutian Zhang1, Qinghui Zhang1, Xiaoli Tang2, Jun Lian2, Sha X. Chang2, Haijun Song3, Sumin Zhou1, Charles A. Enke1


Role of Exosome microRNA in Breast Cancer

Wang Qu, Ma Fei, Binghe Xu


Recent Progress in Technological Improvement and Biomedical Applications of the Clustered Regularly Interspaced Short Palindromic Repeats/Cas System

Yanlan Li1,2*, Zheng Hu1*, Yufang Yin3, Rongzhang He1, Jian Hu1, Weihao Luo1, Jia Li1, Gebo Wen2, Li Xiao1, Kai Li1, Duanfang Liao4, Di-Xian Luo1,5


The Significance of Nuclear Factor‑Kappa B Signaling Pathway in Glioma: A Review

Xiaoshan Xu1, Hongwei Yang2, Xin Wang2, Yanyang Tu1


Markerless Four‑Dimensional‑Cone Beam Computed Tomography Projection‑Phase Sorting Using Prior Knowledge and Patient Motion Modeling: A Feasibility Study

Lei Zhang1,2, Yawei Zhang2, You Zhang1,2,3, Wendy B. Harris1,2, Fang‑Fang Yin1,2,4, Jing Cai1,4,5, Lei Ren1,2


The Producing Capabilities of Interferon‑g and Interleukin‑10 of Spleen Cells in Primary and Metastasized Oral Squamous Cell Carcinoma Cells-implanted Mice

Yasuka Azuma1,2, Masako Mizuno‑Kamiya3, Eiji Takayama1, Harumi Kawaki1, Toshihiro Inagaki4, Eiichi Chihara2, Yasunori Muramatsu5, Nobuo Kondoh1


“Eating” Cancer Cells by Blocking CD47 Signaling: Cancer Therapy by Targeting the Innate Immune Checkpoint

Yi‑Rong Xiang, Li Liu


Glycosylation is Involved in Malignant Properties of Cancer Cells

Kazunori Hamamura1, Koichi Furukawa2


Biomarkers in Molecular Epidemiology Study of Oral Squamous Cell Carcinoma in the Era of Precision Medicine

Qing‑Hao Zhu1*, Qing‑Chao Shang1*, Zhi‑Hao Hu1*, Yuan Liu2, Bo Li1, Bo Wang1, An‑Hui Wang1


I‑Kappa‑B Kinase‑epsilon Activates Nuclear Factor‑kappa B and STAT5B and Supports Glioblastoma Growth but Amlexanox Shows Little Therapeutic Potential in These Tumors

Nadège Dubois1, Sharon Berendsen2, Aurélie Henry1,2, Minh Nguyen1, Vincent Bours1,
Pierre Alain Robe1,2


Suppressive Effect of Mesenchymal Stromal Cells on Interferon‑g‑Producing Capability of Spleen Cells was Specifically Enhanced through Humoral Mediator(s) from Mouse Oral Squamous Cell Carcinoma Sq‑1979 Cells In Vitro

Toshihiro Inagaki1,2, Masako Mizuno‑Kamiya3, Eiji Takayama1, Harumi Kawaki1, Eiichi Chihara4, Yasunori Muramatsu5, Shinichiro Sumitomo5, Nobuo Kondoh1


An Interplay Between MicroRNA and SOX4 in the Regulation of Epithelial–Mesenchymal Transition and Cancer Progression

Anjali Geethadevi1, Ansul Sharma2, Manish Kumar Sharma3, Deepak Parashar1


MicroRNAs Differentially Expressed in Prostate Cancer of African‑American and European‑American Men

Ernest K. Amankwah


The Role of Reactive Oxygen Species in Screening Anticancer Agents

Xiaohui Xu1, Zilong Dang2, Taoli Sun3, Shengping Zhang1, Hongyan Zhang1


Panobinostat and Its Combination with 3‑Deazaneplanocin‑A Induce Apoptosis and Inhibit In vitro Tumorigenesis and Metastasis in GOS‑3 Glioblastoma Cell Lines

Javier de la Rosa*, Alejandro Urdiciain*, Juan Jesús Aznar‑Morales, Bárbara Meléndez1,
Juan A. Rey2, Miguel A. Idoate3, Javier S. Castresana


Cancer Stem‑Like Cells Have Cisplatin Resistance and miR‑93 Regulate p21 Expression in Breast Cancer

Akiko Sasaki1, Yuko Tsunoda2, Kanji Furuya3, Hideto Oyamada1, Mayumi Tsuji1, Yuko Udaka1, Masahiro Hosonuma1, Haruna Shirako1, Nana Ichimura1, Yuji Kiuchi1


The Contribution of Hexokinase 2 in Glioma

Hui Liu1, Hongwei Yang2, Xin Wang3, Yanyang Tu1


The Mechanism of BMI1 in Regulating Cancer Stemness Maintenance, Metastasis, Chemo‑ and Radiation Resistance

Xiaoshan Xu, Zhen Wang, Nan Liu, Pengxing Zhang, Hui Liu, Jing Qi, Yanyang Tu


A Multisource Adaptive Magnetic Resonance Image Fusion Technique for Versatile Contrast Magnetic Resonance Imaging

Lei Zhang1,2, Fang‑Fang Yin1,2,3, Brittany Moore1,2, Silu Han1,2, Jing Cai1,2,4


Senescence and Cancer

Sulin Zeng1,2, Wen H. Shen2, Li Liu1


The “Wild”‑type Gastrointestinal Stromal Tumors: Heterogeneity on Molecule Characteristics and Clinical Features

Yanhua Mou1, Quan Wang1, Bin Li1,2


Retreatment with Cabazitaxel in a Long‑Surviving Patient with Castration‑Resistant Prostate Cancer and Visceral Metastasis

Raquel Luque Caro, Carmen Sánchez Toro, Lucia Ochoa Vallejo


Therapy‑Induced Histopathological Changes in Breast Cancers: The Changing Role of Pathology in Breast Cancer Diagnosis and Treatment

Shazima Sheereen1, Flora D. Lobo1, Waseemoddin Patel2, Shamama Sheereen3,
Abhishek Singh Nayyar4, Mubeen Khan5


Glioma Research in the Era of Medical Big Data

Feiyifan Wang1, Christopher J. Pirozzi2, Xuejun Li1


Transarterial Embolization for Hepatocellular Adenomas: Case Report and Literature Review

Jian‑Hong Zhong1,2, Kang Chen1, Bhavesh K. Ahir3, Qi Huang4, Ye Wu4, Cheng‑Cheng Liao1, Rong‑Rong Jia1, Bang‑De Xiang1,2, Le‑Qun Li1,2


Nicotinamide Phosphoribosyltransferase: Biology, Role in Cancer, and Novel Drug Target

Antonio Lucena‑Cacace1,2,3, Amancio Carnero1,2


Enhanced Anticancer Effect by Combination of Proteoglucan and Vitamin K3 on Bladder Cancer Cells

Michael Zhang, Kelvin Zheng, Muhammad Choudhury, John Phillips, Sensuke Konno


Molecular Insights Turning Game for Management of Ependymoma: A Review of Literature

Ajay Sasidharan, Rahul Krishnatry


IDH Gene Mutation in Glioma

Leping Liu1, Xuejun Li1,2


Challenges and Advances in the Management of Pediatric Intracranial Germ Cell Tumors: A Case Report and Literature Review

Gerard Cathal Millen1, Karen A. Manias1,2, Andrew C. Peet1,2, Jenny K. Adamski1


Assessing the Feasibility of Using Deformable Registration for Onboard Multimodality‑Based Target Localization in Radiation Therapy

Ge Ren1,2,3, Yawei Zhang1,2, Lei Ren1,2


Research Advancement in the Tumor Biomarker of Hepatocellular Carcinoma

Qing Du1, Xiaoying Ji2, Guangjing Yin3, Dengxian Wei3, Pengcheng Lin1, Yongchang Lu1,
Yugui Li3, Qiaohong Yang4, Shizhu Liu5, Jinliang Ku5, Wenbin Guan6, Yuanzhi Lu7


Novel Insights into the Role of Bacterial Gut Microbiota in Hepatocellular Carcinoma

Lei Zhang1, Guoyu Qiu2, Xiaohui Xu2, Yufeng Zhou3, Ruiming Chang4


Central Odontogenic Fibroma with Unusual Presenting Symptoms

Aanchal Tandon, Bharadwaj Bordoloi, Safia Siddiqui, Rohit Jaiswal


The Prognostic Role of Lactate in Patients Who Achieved Return of Spontaneous Circulation after Cardiac Arrest: A Systematic Review and Meta‑analysis

Dongni Ren1, Xin Wang2, Yanyang Tu1,2


Inhibitory Effect of Hyaluronidase‑4 in a Rat Spinal Cord Hemisection Model

Xipeng Wang1,2, Mitsuteru Yokoyama2, Ping Liu3


Research and Development of Anticancer Agents under the Guidance of Biomarkers

Xiaohui Xu1, Guoyu Qiu1, Lupeng Ji2, Ruiping Ma3, Zilong Dang4, Ruling Jia1, Bo Zhao1


Idiopathic Hypereosinophilic Syndrome and Disseminated Intravascular Coagulation

Mansoor C. Abdulla


Phosphorylation of BRCA1‑Associated Protein 1 as an Important Mechanism in the Evasion of Tumorigenesis: A Perspective

Guru Prasad Sharma1, Anjali Geethadevi2, Jyotsna Mishra3, G. Anupa4, Kapilesh Jadhav5,
K. S. Vikramdeo6, Deepak Parashar2


Progress in Diagnosis and Treatment of Mixed Adenoneuroendocrine Carcinoma of Biliary‑Pancreatic System

Ge Zengzheng1, Huang-Sheng Ling2, Ming-Feng Li2, Xu Xiaoyan1, Yao Kai1, Xu Tongzhen3,
Ge Zengyu4, Li Zhou5


Surface-Enhanced Raman Spectroscopy to Study the Biological Activity of Anticancer Agent

Guoyu Qiu1, Xiaohui Xu1, Lupeng Ji2, Ruiping Ma3, Zilong Dang4, Huan Yang5


Alzheimer’s Disease Susceptibility Genes in Malignant Breast Tumors

Steven Lehrer1, Peter H. Rheinstein2


OSMCC: An Online Survival Analysis Tool for Merkel Cell Carcinoma

Umair Ali Khan Saddozai1, Qiang Wang1, Xiaoxiao Sun1, Yifang Dang1, JiaJia Lv1,2, Junfang Xin1, Wan Zhu3, Yongqiang Li1, Xinying Ji1, Xiangqian Guo1


Protective Activity of Selenium against 5‑Fluorouracil‑Induced Nephrotoxicity in Rats

Elias Adikwu, Nelson Clemente Ebinyo, Beauty Tokoni Amgbare


Advances on the Components of Fibrinolytic System in Malignant Tumors

Zengzheng Ge1, Xiaoyan Xu1, Zengyu Ge2, Shaopeng Zhou3, Xiulin Li1, Kai Yao1, Lan Deng4


A Patient with Persistent Foot Swelling after Ankle Sprain: B‑Cell Lymphoblastic Lymphoma Mimicking Soft‑tissue Sarcoma

Crystal R. Montgomery‑Goecker1, Andrew A. Martin2, Charles F. Timmons3, Dinesh Rakheja3, Veena Rajaram3, Hung S. Luu3


Coenzyme Q10 and Resveratrol Abrogate Paclitaxel‑Induced Hepatotoxicity in Rats

Elias Adikwu, Nelson Clemente Ebinyo, Loritta Wasini Harris


Progress in Clinical Follow‑up Study of Dendritic Cells Combined with Cytokine‑Induced Killer for Stomach Cancer

Ling Wang1,2, Run Wan1,2, Cong Chen1,2, Ruiliang Su1,2, Yumin Li1,2


Supraclavicular Lymphadenopathy as the Initial Manifestation in Carcinoma of Cervix

Priyanka Priyaarshini1, Tapan Kumar Sahoo2


ABO Typing Error Resolution and Transfusion Support in a Case of an Acute Leukemia Patient Showing Loss of Antigen Expression

Debasish Mishra1, Gopal Krushna Ray1, Smita Mahapatra2, Pankaj Parida2


Protein Disulfide Isomerase A3: A Potential Regulatory Factor of Colon Epithelial Cells

Yang Li1, Zhenfan Huang2, Haiping Jiang3


Clinicopathological Association of p16 and its Impact on Outcome of Chemoradiation in Head‑and‑Neck Squamous Cell Cancer Patients in North‑East India

Srigopal Mohanty1, Yumkhaibam Sobita Devi2, Nithin Raj Daniel3, Dulasi Raman Ponna4,
Ph. Madhubala Devi5, Laishram Jaichand Singh2


Potential Inhibitor for 2019‑Novel Coronaviruses in Drug Development

Xiaohui Xu1, Zilong Dang2, Lei Zhang3, Lingxue Zhuang4, Wutang Jing5, Lupeng Ji6, Guoyu Qiu1


Best‑Match Blood Transfusion in Pediatric Patients with Mixed Autoantibodies

Debasish Mishra1, Dibyajyoti Sahoo1, Smita Mahapatra2, Ashutosh Panigrahi3


Characteristics and Outcome of Patients with Pheochromocytoma

Nadeema Rafiq1, Tauseef Nabi2, Sajad Ahmad Dar3, Shahnawaz Rasool4


Comparison of Histopathological Grading and Staging of Breast Cancer with p53‑Positive and Transforming Growth Factor‑Beta Receptor 2‑Negative Immunohistochemical Marker Expression Cases

Palash Kumar Mandal1, Anindya Adhikari2, Subir Biswas3, Amita Giri4, Arnab Gupta5,
Arindam Bhattacharya6


Chemical Compositions and Antiproliferative Effect of Essential Oil of Asafoetida on MCF7 Human Breast Cancer Cell Line and Female Wistar Rats

Seyyed Majid Bagheri1,2, Davood Javidmehr3, Mohammad Ghaffari1, Ehsan Ghoderti‑Shatori4


Cyclooxygenase‑2 Contributes to Mutant Epidermal Growth Factor Receptor Lung Tumorigenesis by Promoting an Immunosuppressive Environment

Mun Kyoung Kim1, Aidin Iravani2, Matthew K. Topham2,3


Potential role of CircMET as A Novel Diagnostic Biomarker of Papillary Thyroid Cancer

Yan Liu1,2,3,4#, Chen Cui1,2,3,4#, Jidong Liu1,2,3,4, Peng Lin1,2,3,4,Kai Liang1,2,3,4, Peng Su5, Xinguo Hou1,2,3,4, Chuan Wang1,2,3,4, Jinbo Liu1,2,3,4, Bo Chen6, Hong Lai1,2,3,4, Yujing Sun1,2,3,4* and Li Chen 1,2,3,4*


Cuproptosis-related Genes in Glioblastoma as Potential Therapeutic Targets

Zhiyu Xia1,2, Haotian Tian1, Lei Shu1,2, Guozhang Tang3, Zhenyu Han4, Yangchun Hu1*, Xingliang Dai1*


Cancer Diagnosis and Treatments by Porous Inorganic Nanocarriers

Jianfeng Xu1,2, Hanwen Zhang1,2, Xiaohui Song1,2, Yangong Zheng3, Qingning Li1,2,4*


Delayed (20 Years) post-surgical Esophageal Metastasis of Breast Cancer - A Case Report

Bowen Hu1#, Lingyu Du2#, Hongya Xie1, Jun Ma1, Yong Yang1*, Jie Tan2*


Subtyping of Undifferentiated Pleomorphic Sarcoma and Its Clinical Meaning

Umair Ali Khan Saddozai, Zhendong Lu, Fengling Wang, Muhammad Usman Akbar, Saadullah Khattak, Muhammad Badar, Nazeer Hussain Khan, Longxiang Xie, Yongqiang Li, Xinying Ji, Xiangqian Guo


Construction of Glioma Prognosis Model and Exploration of Related Regulatory Mechanism of Model Gene

Suxia Hu, Abdusemer Reyimu, Wubi Zhou, Xiang Wang, Ying Zheng, Xia Chen, Weiqiang Li, Jingjing Dai


ESRP2 as a Non-independent Potential Biomarker-Current Progress in Tumors

Yuting Chen, Yuzhen Rao, Zhiyu Zeng, Jiajie Luo, Chengkuan Zhao, Shuyao Zhang


Resection of Bladder Tumors at the Ureteral Orifice Using a Hook Plasma Electrode: A Case Report

Jun Li, Ziyong Wang, Qilin Wang


Structural Characterization and Bioactivity for Lycium Barbarum Polysaccharides

Jinghua Qi1,2,  Hangping Chen3,Huaqing Lin2,4,Hongyuan Chen1,2,5* and Wen Rui2,3,5,6*


The Role of IL-22 in the Prevention of Inflammatory Bowel Disease and Liver Injury

Xingli Qi1,2, Huaqing Lin2,3, Wen Rui2,3,4,5 and Hongyuan Chen1,2,3


RBM15 and YTHDF3 as Positive Prognostic Predictors in ESCC: A Bioinformatic Analysis Based on The Cancer Genome Atlas (TCGA)

Yulou Luo1, Lan Chen2, Ximing Qu3, Na Yi3, Jihua Ran4, Yan Chen3,5*


Mining and Analysis of Adverse Drug Reaction Signals Induced by Anaplastic Lymphoma Kinase-Tyrosine Kinase Inhibitors Based on the FAERS Database

Xiumin Zhang1,2#, Xinyue Lin1,3#, Siman Su1,3#, Wei He3, Yuying Huang4, Chengkuan Zhao3, Xiaoshan Chen3, Jialin Zhong3, Chong Liu3, Wang Chen3, Chengcheng Xu3, Ping Yang5, Man Zhang5, Yanli Lei5*, Shuyao Zhang1,3*


Advancements in Immunotherapy for Advanced Gastric Cancer

Min Jiang1#, Rui Zheng1#, Ling Shao1, Ning Yao2, Zhengmao Lu1*


Tumor Regression after COVID-19 Infection in Metastatic Adrenocortical Carcinoma Treated with Immune Checkpoint Blockade: A Case Report

Qiaoxin Lin1, Bin Liang1, Yangyang Li2, Ling Tian3*, Dianna Gu1*


Mining and Analysis of Adverse Events of BRAF Inhibitors Based on FDA Reporting System

Silan Peng1,2#, Danling Zheng1,3#, Yanli Lei4#, Wang Chen3, Chengkuan Zhao3, Xinyue Lin1, Xiaoshan Chen3, Wei He3, Li Li3, Qiuzhen Zhang5*, Shuyao Zhang1,3*


Malignant Phyllodes Tumor with Fever, Anemia, Hypoproteinemia: A Rare and Strange Case Report and Literature Review

Zhenghang Li1, Yuxian Wei1*


Construction of Cuproptosis-Related LncRNA Signature as a Prognostic Model Associated with Immune Microenvironment for Clear-Cell Renal Cell Carcinoma

Jiyao Yu1#, Shukai Zhang2#, Qingwen Ran3, Xuemei Li4,5,6*


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