Expression of Five Target Proteins Related to Human Cytomegalovirus Infection in Brain Metastases of Lung Cancer

Abstract Background: The links between brain metastases of lung cancer and human cytomegalovirus (HCMV) infection have been controversial for a long time. This study aims to explore the links between brain metastases of lung cancer and HCMV infection from the perspective of expression and detection of HCMV immediate early gene (IE), guanine nucleotide-binding protein 4 (GBP4), CXC chemokine receptor 4 (CXCR4), thyroid transcription factor 1 (TTF1) and epidermal growth factor receptor (EGFR) proteins. Methods: We collected brain metastases specimens and lung primary tumor specimens of a series of patients that have not undergone any treatment. Conventional hematoxylin and eosin staining and immunohistochemical staining of target molecules was performed. We used the ImageJ software to process the average optical density value of immune complexes and GraphPad Prism 8.0.1 to perform image analysis, and the SPSS 22.0 statistics package (t test) to analyze the expression differences of target molecules.Results: Based on five cases of brain metastases and two cases of lung primary tumors, a total of seven samples were investigated. Conventional pathology diagnosis reported four cases of brain metastases of lung adenocarcinoma and one case of brain metastases of mixed small cell lung cancer with adenocarcinoma. Among the 19 molecular immunopathological test samples, only GBP4, related to HCMV infection, and TTF1, related to metastases, were highly expressed in all seven samples. A comparison of the AOD values of the primary lung cancer to the AOD values of brain metastases, yielded statistically significant differences as follows: in Case No.1, GBP4 (p=0.016), EGRF (p<0.001); in Case No. 2, IE (p<0.001), CXCR4 (p=0.005), EGFR (p=0.023), TTF1 (p=0.004). Conclusions: Although TTF1 is known to be a kinesin for brain metastases of lung cancer cells and it is associated with poor survival prognosis, the role of GBP4, which is closely related to HCMV infection and a key protein of brain metastases of lung cancer, remains unknown. The findings provide new knowledge into the role of GBP4 and could provide clues for devising novel strategies for target molecular therapy research in brain metastases of lung cancer in the context of HCMV infection.

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EPID-04. THE SINGLE CENTER STUDY FOR BRAIN METASTASES OF UNDIAGNOSED PRIMARY TUMOR AND THE ROLE OF SURGICAL REMOVAL

Neuro-Oncology ◽

10.1093/neuonc/noaa215.322 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii79-ii79

Author(s):

Yuzaburo Shimizu ◽

Mario Suzuki ◽

Osamu Akiyama ◽

Akihide Kondo

Keyword(s):

Lung Cancer ◽

Brain Metastases ◽

Cell Carcinoma ◽

Small Cell Carcinoma ◽

Primary Tumor ◽

Surgical Intervention ◽

Small Cell ◽

Surgical Removal ◽

Primary Tumors

Abstract BACKGROUND The diagnosis of a brain metastases is generally made during the follow up examinations of patients with primary known cancer. However, there are some patients presenting brain metastases as the first manifestation of a previously undiagnosed primary tumor (UDP) pathological confirmation of the diagnosis. The timing of a subsequent neurosurgical intervention is influenced by the distribution of primary tumors in UDP patients. The purpose of this study was to investigate the optimal diagnostic approach and the role of surgery for UDP patients. METHODS In a retrospective study, 35 patients admitted to our institution and underwent brain tumor removal from 2017 to 2019 with the diagnosis of cerebral metastases and diagnosed lung cancer as primary tumor subsequently, or previously diagnosed lung cancer. RESULTS UDP patients represented 46% of the whole group. Primary tumor subtype was the adenocarcinoma (n=13, 81%), small cell carcinoma (n=2, 13%), and neuroendocrine carcinoma (n=1, 6%). They did not have bronchoscopy nor excision of lung cancer. On the other hand, the patients previously diagnosed lung cancer represented 54% and subtype was adenocarcinoma (n=14, 74%) and small cell carcinoma (n=5, 26%). EGFR mutation was detected from 7 patients (44%) in UDP group and treated by EGFR tyrosine kinase inhibitor. CONCLUSION The significance of surgical intervention in metastatic brain tumors has been limited. However, active surgical intervention in UDP patients could identify not only histological diagnosis but also molecular biological characteristics. Our study suggests the possibility to avoid whole brain radiation in UDP patient by the active surgery.

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Treatment of brain metastases from primary lung cancer

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/0360-3016(93)e0073-f ◽

1995 ◽

Vol 31 (2) ◽

pp. 273-278 ◽

Cited By ~ 46

Author(s):

Gail F. Ryan ◽

David L. Ball ◽

Jennifer G. Smith

Keyword(s):

Lung Cancer ◽

Brain Metastases ◽

Primary Lung Cancer

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Role of iterativ surgical therapy for primary lung cancer

Lung Cancer ◽

10.1016/s0169-5002(86)80383-x ◽

1986 ◽

Vol 2 (1-2) ◽

pp. 95

Keyword(s):

Lung Cancer ◽

Surgical Therapy ◽

Primary Lung Cancer

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Extracellular Vesicles in Human Preterm Colostrum Inhibit Infection by Human Cytomegalovirus In Vitro

Microorganisms ◽

10.3390/microorganisms8071087 ◽

2020 ◽

Vol 8 (7) ◽

pp. 1087

Author(s):

Manuela Donalisio ◽

Simona Cirrincione ◽

Massimo Rittà ◽

Cristina Lamberti ◽

Andrea Civra ◽

...

Keyword(s):

Breast Milk ◽

Extracellular Vesicles ◽

Human Cytomegalovirus ◽

Hcmv Infection ◽

Protective Role ◽

Surface Proteins ◽

Human Colostrum ◽

Clinical Illness

Breast milk is a complex biofluid that nourishes infants, supports their growth and protects them from diseases. However, at the same time, breastfeeding is a transmission route for human cytomegalovirus (HCMV), with preterm infants being at a great risk of congenital disease. The discrepancy between high HCMV transmission rates and the few reported cases of infants with severe clinical illness is likely due to the protective effect of breast milk. The aim of this study was to investigate the anti-HCMV activity of human preterm colostrum and clarify the role of colostrum-derived extracellular vesicles (EVs). Preterm colostrum samples were collected and the EVs were purified and characterized. The in vitro anti-HCMV activity of both colostrum and EVs was tested against HCMV, and the viral replication step inhibited by colostrum-purified EVs was examined. We investigated the putative role EV surface proteins play in impairing HCMV infection using shaving experiments and proteomic analysis. The obtained results confirmed the antiviral action of colostrum against HCMV and demonstrated a remarkable antiviral activity of colostrum-derived EVs. Furthermore, we demonstrated that EVs impair the attachment of HCMV to cells, with EV surface proteins playing a role in mediating this action. These findings contribute to clarifying the mechanisms that underlie the protective role of human colostrum against HCMV infection.

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Immunohistochemical characteristics of brain metastases and corresponding primary lung cancer

Annals of Oncology ◽

10.1093/annonc/mdx094.004 ◽

2017 ◽

Vol 28 ◽

pp. ii53

Author(s):

D. Marinova ◽

Y. Slavova ◽

S. Nachev ◽

D. Dimitrova ◽

E. Mekov ◽

...

Keyword(s):

Lung Cancer ◽

Brain Metastases ◽

Primary Lung Cancer

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Little role of anti-gB antibodies in neutralizing activity of patient's sera with human cytomegalovirus (HCMV) infection

Journal of Korean Medical Science ◽

10.3346/jkms.2000.15.2.133 ◽

2000 ◽

Vol 15 (2) ◽

pp. 133 ◽

Cited By ~ 1

Author(s):

Jae Won Park ◽

Dae Joong Kim ◽

Jinhee Kim ◽

Chung Gyu Park ◽

Eung Soo Hwang ◽

...

Keyword(s):

Human Cytomegalovirus ◽

Hcmv Infection ◽

Neutralizing Activity

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The Human Cytomegalovirus Transmembrane Protein pUL50 Induces Loss of VCP/p97 and Is Regulated by a Small Isoform of pUL50

Journal of Virology ◽

10.1128/jvi.00110-20 ◽

2020 ◽

Vol 94 (13) ◽

Author(s):

Myoung Kyu Lee ◽

Seokhwan Hyeon ◽

Jin-Hyun Ahn

Keyword(s):

Human Cytomegalovirus ◽

Hcmv Infection ◽

Transmembrane Domain ◽

Transmembrane Protein ◽

Amino Acid Position ◽

Mutant Virus ◽

Early Gene ◽

Immediate Early ◽

Nuclear Egress ◽

The Unfolded Protein Response

ABSTRACT The human cytomegalovirus (HCMV) UL50 gene encodes a transmembrane protein, pUL50, which acts as a core component of the nuclear egress complex (NEC) for nucleocapsids. Recently, pUL50 has been shown to have NEC-independent activities: downregulation of IRE1 to repress the unfolded protein response and degradation of UBE1L to inhibit the protein ISG15 modification pathway. Here, we demonstrate that a 26-kDa N-terminal truncated isoform of pUL50 (UL50-p26) is expressed from an internal methionine at amino acid position 199 and regulates the activity of pUL50 to induce the loss of valosin-containing protein (VCP/p97). A UL50(M199V) mutant virus expressing pUL50(M199V) but not UL50-p26 showed delayed growth at a low multiplicity of infection. There was also delayed accumulation of the viral immediate early 2 (IE2) protein in the mutant virus, and this correlated with the reduced expression of VCP/p97, which promotes IE2 expression. Infection with mutant virus did not significantly alter ISGylation levels. In transient expression assays, pUL50 induced VCP/p97 loss posttranscriptionally, and this was dependent on the presence of its transmembrane domain. In contrast, UL50-p26 did not destabilize VCP/p97 but, rather, inhibited pUL50-mediated VCP/p97 loss and the associated major IE gene suppression. Both pUL50 and UL50-p26 interacted with VCP/p97, although UL50-p26 did so more weakly than pUL50. UL50-p26 interacted with pUL50, and this interaction was much stronger than the pUL50 self-interaction. Furthermore, UL50-p26 was able to interfere with the pUL50-VCP/p97 interaction. Our study newly identifies UL50-p26 expression during HCMV infection and suggests a regulatory role for UL50-p26 in blocking pUL50-mediated VCP/p97 loss by associating with pUL50. IMPORTANCE Targeting the endoplasmic reticulum (ER) by viral proteins may affect ER-associated protein homeostasis. During human cytomegalovirus (HCMV) infection, pUL50 targets the ER through its transmembrane domain and moves to the inner nuclear membrane (INM) to form the nuclear egress complex (NEC), which facilitates capsid transport from the nucleus to the cytoplasm. Here, we demonstrate that pUL50 induces the loss of valosin-containing protein (VCP/p97), which promotes the expression of viral major immediate early gene products, in a manner dependent on its membrane targeting but that a small isoform of pUL50 is expressed to negatively regulate this pUL50 activity. This study reports a new NEC-independent function of pUL50 and highlights the fine regulation of pUL50 activity by a smaller isoform for efficient viral growth.

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