A case of lung carcinoma with a unique biphasic feature: Implications for histogenesis of "fake mucoepidermoid carcinoma" developing in the peripheral lung.

We present a case of lung carcinoma with a unique biphasic feature. The patient was a 67-year-old male smoker with idiopathic pulmonary fibrosis (IPF). A subpleural tumor in the left lower lobe, embedded in fibrotic tissue, was resected. Histologically, the tumor consisted of major and minor components of mucoepidermoid carcinoma (MEC) and surrounding conventional lepidic adenocarcinoma, respectively. Both components had the same TP53 somatic mutation (p.V157F) but not Mastermind-like 2 (MAML2) gene rearrangement. The two components may have developed from an identical origin. The tumor could be trans-differentiating from lepidic adenocarcinoma to MEC, possibly promoted by IPF-induced tissue damage. The final diagnosis was "adenosquamous carcinoma with mucoepidermoid-like features (that may originate from lepidic adenocarcinoma)." This case has implications for the potential histogenesis of peripheral lung MEC. Over time, the MEC would expand and outgrow the lepidic adenocarcinoma, making it impossible to distinguish between fake and true MEC. The present case suggests that peripheral MEC could differ from proximal MEC in its histogenesis and molecular genetics. Thus, careful examination is necessary to diagnose peripheral lung MEC, particularly in patients with interstitial lung diseases.

Frequency of subclinical interstitial lung disease in COVID-19 autopsy cases: potential risk factors of severe pneumonia.

Risk factors of severe coronavirus disease 2019 (COVID-19) have been previously reported; however, histological risk factors have not been defined thus far. The aim of this study was to clarify subclinical hidden interstitial lung disease (ILD) as a risk factor of severe pneumonia associated with COVID-19. We carefully examined autopsied lungs and chest computed tomography scanning (CT) images from patients with COVID-19 for interstitial lesions and then analyzed their relationship with disease severity. Among the autopsy series, subclinical ILD was found in 13/27 cases (48%) in the COVID-19 group, and in contrast, 8/65 (12%) in the control autopsy group (p = 0.0006; Fisher's exact test). We reviewed CT images from the COVID-19 autopsy cases and verified that subclinical ILD was histologically detectable in the CT images. Then, we retrospectively examined CT images from another series of COVID-19 cases in the Yokohama, Japan area between February-August 2020 for interstitial lesions and analyzed the relationship to the severity of COVID-19 pneumonia. Interstitial lesion was more frequently found in the group with the moderate II/severe disease than in the moderate I/mild disease (severity was evaluated according to the COVID-19 severity classification system of the Ministry of Health, Labor, and Welfare [Japan]) (moderate II/severe, 11/15, 73.3% versus moderate I/mild, 108/245, 44.1%; Fisher exact test, p = 0.0333). In conclusion, it was suggested that subclinical ILD could be an important risk factor for severe COVID-19 pneumonia. A benefit of these findings could be the development of a risk assessment system using high resolution CT images for fatal COVID-19 pneumonia.

A method to obtain reproducible Ki-67 indices in lung adenocarcinoma.

AIMS: Proliferative activity, evaluated from the Ki-67 index, is a strong prognostic factor in lung adenocarcinoma (LADC). Here, we optimised a procedure to measure the Ki-67 index and establish the best cut-off value. METHODS AND RESULTS: We examined 342 stage I LADCs for the immunohistochemical expression of Ki-67 using different antibodies, MIB1 and SP6. The results revealed the superior specificity of SP6; therefore, SP6 was used in subsequent analyses. Slides were scanned with a virtual slide system. Using software, tumour cells were counted in a whole tumour. Thereafter, the tumour was evenly subdivided into 0.25-mm2 tiles. The frequency of positive cells was counted in each tile of an invasive area or the whole tumour. We calculated the number of tumour cells required to produce a 95% confidence interval (CI) <0.05. Additionally, we calculated coverage probabilities (CP) using two different methods, counting any number or 200 cells per tile. The results showed that we could meet our goal by counting 2000 cells from 10 random tiles (200 cells each) in invasive areas. CONCLUSIONS: We successfully developed an optimal procedure for determination of the Ki-67 labelling index using an SP6 antibody, which provided CP > 70% and CI of <0.05 in more than 90% of cases. Furthermore, we identified an optimal cut-off value of 0.12 with an alternative of 0.15, based on disease recurrence. This procedure and the cut-off values may be used in the routine pathological diagnosis of LADC.

A Japanese case of COVID-19: An autopsy report.

A 93-year-old woman was admitted with a 10-day history of cough and prostration. Thoracic computed tomography revealed extensive ground-glass opacities in both the lungs. The polymerase chain reaction test of sputum for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) was positive. She was treated with antiviral agents and steroid pulse therapy. However, her oxygen saturation gradually declined, and she died 10 days after hospitalization. The most important autopsy finding was fuzzily segmented diffuse alveolar damage (DAD) that expanded from the subpleural to the medial area. No remarkable changes were observed in organs other than the lungs. Therefore, pneumocytes were suggested as the primary target for SARS-CoV-2, which might explain why coronavirus infectious disease-19 is a serious condition. Thus, early treatment is essential to prevent viral replication from reaching a level that triggers DAD.

Pulmonary melanocytic nevus - A case report with a mutation analysis of common driver oncogenes.

Nevi are benign melanocytic tumors, and some nevi are considered to develop into malignant melanomas. Most nevi arise in the skin, but nevi occasionally occur in the conjunctiva, esophageal mucosa, or at other sites. Pulmonary melanocytic nevi are extremely rare, and only one case has been reported in the literature. Here, we present a case of pulmonary melanocytic nevus, involving a BRAF gene mutation (V600E), and we discuss the potential significance of this condition as a precursor to pulmonary malignant melanoma.

A molecular pathological study of four cases of ciliated muconodular papillary tumors of the lung.

Ciliated muconodular papillary tumors (CMPTs) are a recently categorized benign or low-grade malignant neoplasm that develops in the peripheral lung. Only about 40 cases have been reported to date, and the clinicopathological characteristics have yet to be defined in detail. Here, we present four cases of CMPTs with a focus on their immunohistochemical profiles and driver gene mutations. These tumors were a papillary proliferation of a mixture of ciliated, mucous, and basal cells located in the peripheral lung. Ciliated, mucous and basal cells were positive for TTF-1 when using the clone SPT24, but negative for HNF-4α. Basal cells were positive for p40. Mucous cells in some tumors were positive for MUC5AC and MUC6. The Ki-67 index was less than 5%, and strong expression of p53 was not detected. Three of the four tumors had a BRAF (V600E) driver mutation, an EGFR (del E746-T751/S752V) driver mutation, or driver mutations in both EGFR (E709G) and KRAS (G12V). These mutation types are rare for any histological type of lung cancer. The present results confirmed that CMPT is a neoplasm with immunohistochemical features and driver gene mutations that are distinct from those of common lung tumors.

The pathological features of idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas.

AIMS: To investigate the pathological features of idiopathic interstitial pneumonia (IIP)-associated pulmonary adenocarcinoma. METHODS AND RESULTS: Surgically resected adenocarcinomas associated with IIP (the IIP group) and adenocarcinomas without IIP (the non-IIP group) were subjected to analysis. Adenocarcinomas in the IIP group were subdivided into two groups: one group included tumours connected to bronchiolar metaplasia in honeycomb lesions (the H-IIP group), and the other included tumours unrelated to honeycomb lesions (the NH-IIP group). Histomorphological appearance and immunohistochemical expression were compared among the H-IIP group, the NH-IIP group, and the non-IIP group. Most of the tumour cells in the H-IIP group had a tall, columnar shape that showed similar features to proximal bronchial epithelium, whereas tumour cells in the NH-IIP group and the non-IIP group had a club-like shape that showed similar features to respiratory bronchiolar/alveolar epithelium. Adenocarcinomas in the H-IIP group tended to be negative for thyroid transcription factor-1 (TTF-1) and positive for hepatocyte nuclear factor-4α (HNF-4α). The frequency of EGFR mutations was significantly lower in adenocarcinomas in the H-IIP group, although the frequencies of KRAS and ALK mutations did not differ among the three groups. CONCLUSIONS: Idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas, especially those arising from honeycomb lesions, have distinct pathological features.

Reduction and fragmentation of elastic fibers in the skin of obese mice is associated with altered mRNA expression levels of fibrillin-1 and neprilysin.

AIM OF THE STUDY: Our previous research suggested that obesity induces structural fragility in the skin. Elastic fibers impart strength and elasticity. In this study, we determined whether elastic fibers decrease in the skin of obese mice. MATERIALS AND METHODS: To confirm alterations in elastic fiber content due to obesity, we used spontaneously obese model mice (TSOD) and control mice (TSNO). Furthermore, to evaluate the elastin structure and gene expression dependent on the severity of obesity, an obesity-enhanced mouse model was developed by feeding a high fat diet to TSOD (TSOD-HF). Back skin samples were stained with hematoxylin and eosin and Elastica van Gieson for microscopic examination, and the samples were stained for immunohistochemical analysis of neprilysin. Gene expression levels were determined using a real-time PCR system. RESULTS: The abundance of elastic fibers beneath the epidermis was remarkably reduced and fragmented in TSOD as compared with TSNO. Fibrillin-1 mRNA levels in TSOD were significantly suppressed compared with those in TSNO, whereas neprilysin mRNA levels and immunohistochemical expression in TSOD were significantly increased, as compared with those in TSNO. The reduction of elastic fibers was enhanced and the expression levels of elastic fiber formed factors were significantly suppressed in TSOD-HF, as compared with those in the TSOD. CONCLUSIONS: The abundance of elastic fibers was reduced and fragmented in obesity, suggesting that the reduction in elastic fibers is initially caused by increased neprilysin and decreased fibrillin-1 expression, which may inhibit formation and stabilization of elastic fibers, resulting in skin fragility in obesity.

The potential significance of alpha-enolase (ENO1) in lung adenocarcinomas - A utility of the immunohistochemical expression in pathologic diagnosis.

We herein analyzed the relationships among the immunohistochemical expression of alpha-enolase (ENO1) and clinicopathological factors in order to define the significance of ENO1 in lung adenocarcinomas (ADCs). ENO1 expression was detected in most of the ADCs examined (95.8%), but not in bronchial and alveolar epithelia. ENO1 expression was typically observed in the cytoplasm among most ADCs (95.8%), but was also detected in the nucleus (56.3%). The levels were significantly higher in terminal respiratory unit (TRU) cytological subtype ADCs. Neither cytoplasmic nor nuclear expression was associated with any other clinicopathological factors including post-operative survival and growth activity. These results suggest that ENO1 is a crucial factor promoting neoplastic transformation exclusively in TRU subtype ADCs. We also investigated the potential utility of the immunohistochemical expression of ENO1 to differentiate TRU-type ADC cells from the reactive hyperplasia of pneumocytes and bronchiolar epithelial cells because difficulties are associated with discriminating these lesions in small biopsy specimens. The sensitivity and specificity of ENO1 (cytoplasmic/nuclear) were 87.5%/37.5% and 88.9%/100%, respectively, which are superior to those of p53 (18.8% and 100%). ENO1 has potential as a biomarker to assist in the histopathological detection of TRU subtype ADC cells.

Alterations in cathepsin L expression in lung cancers.

We herein investigated the potential role of cathepsin L in lung carcinogenesis. Lung cancer cell lines and surgically resected tumors were examined for the expression of the cathepsin L protein and copy number alterations in its gene locus. Cathepsin L was stably expressed in bronchiolar epithelial cells. Neoplastic cells expressed cathepsin L at various levels, whereas its expression was completely lost in most of the lung cancer cell lines (63.6%, 7/11) examined. Furthermore, expression levels were lower in a large fraction of lung tumors (69.5%, 139/200) than in bronchiolar epithelia. The expression of cathepsin L was lost in some tumors (16.0%, 32/200). In adenocarcinomas, expression levels were significantly lower in high-grade tumors than in low-grade tumors (one-way ANOVA, P < 0.0500). Copy number alterations were found in 18.0% (36 [32 gain + 4 loss] /200) of lung tumors. No relationship existed between cathepsin L protein expression levels and the copy number of its gene locus (Spearman's rank-order correlation, P = 0.3096). Collectively, these results suggest that the down-regulated expression of cathepsin L, which is caused by an undefined mechanism other than copy number alterations, is involved in the progression of lung adenocarcinomas.

Leptomeningeal melanomatosis associated with neurocutaneous melanosis: an autopsy case report.

An autopsy case of leptomeningeal melanomatosis associated with neurocutaneous melanosis (NCM) involving a 44-year-old male is reported. The autopsy showed that the leptomeningeal surface of the brain and the spinal cord were covered with a diffuse black lesion. A histological examination detected diffusely distributed, proliferating, melanin-containing cells and demonstrated that the lesion consisted of three different components; i.e. regions of melanomatosis, melanocytosis, and melanocyte hyperplasia. In the leptomeningeal melanomatosis component, tumor cells with pleomorphic nuclei and prominent nucleoli had infiltrated into the cerebral parenchyma via Virchow-Robin spaces. The Ki-67 labeling index and the nuclear accumulation of p53 and p16 protein were immunohistochemically examined in each component. The Ki-67 labeling indices of the melanomatosis, melanocytosis, and melanocyte hyperplasia components were 8.7%, 0.8%, and 0%, respectively. Immunostaining of nuclear p16 produced a negative result in the melanomatosis component, but positive results in the melanocytosis and melanocyte hyperplasia components, whereas nuclear p53 expression was not detected in any of the components. This case suggests that p16(INK4) /CDKN2 may play a significant role in progression of leptomeningeal melanocytic neoplasms. We also reviewed previously reported cases of leptomeningeal neoplasms associated with NCM and discussed the relationship between the biological behavior and proliferative activity of such lesions.

The potential role of microRNA-31 expression in early colorectal cancer.

The expression of microRNA-31 (miR-31) has been implicated in the progression of some human malignancies including colorectal cancer. However, the clinical significance of the expression of miR-31 in submucosally invasive (T1) colorectal cancer remains unclear. The aim of the present study was to delineate the relationship between clinicopathological features and the oncogenic modulator miR-31 in submucosally invasive colorectal cancer. We investigated the expression of miR-31 in 50 submucosally invasive colorectal cancer specimens, along with the corresponding non-tumoral mucosa specimens, using a real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The relationships between miR-31 expression levels and clinicopathological characteristics were assessed. The miR-31 host gene locus was investigated using fluorescence in situ hybridization. qRT-PCR revealed that the expression of miR-31 was higher in colorectal cancer tissue than in non-tumoral tissue (P = 0.0002). The up-regulated expression of miR-31 may play an oncogenic role in the early stage of carcinogenesis in colorectal cancers.

Oral Intake of Linseed Oil Inhibits Skin Barrier Dysfunction in Obese Mice.

OBJECTIVE: Obesity is not only a risk factor for lifestyle-related diseases but also causes skin barrier dysfunction, which leads to a reduced quality of life due to dryness, itching, and scratching, and thus requires appropriate treatment. However, there are no studies on this issue. Therefore, this study aimed to examine whether oral intake of linseed oil is effective for skin barrier function in obesity and to confirm how the effect is demonstrated. METHODS: TSOD mice received either sterile distilled water (Control group) or linseed oil (Omega group), containing a high level of omega-3 fatty acids, including α-linolenic acid, orally for eight weeks. Mice were then irradiated with ultraviolet B (UVB) and three days later, transepidermal water loss (TEWL), which is the primary outcome of skin barrier function, was measured and gross skin appearance was observed. Hematoxylin and eosin (HE) staining and Ki-67 immunostaining were performed on skin samples. mRNA expression levels of the inflammatory markers Tnfα, Cox2, Mcp1, and Hmox1 were measured by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). We also performed fatty acid analysis of skin and erythrocytes by gas chromatography. Statistical analysis was performed using unpaired Student's t-test and Pearson's correlation analysis. RESULTS: Compared with the Control group, the Omega group exhibited lower TEWL values and little skin erythema. Histological analysis revealed thinner epidermis and fewer Ki-67 positive cells. Additionally, in the Omega group, mRNA levels of four inflammation-related genes were lower, α-linolenic acid levels in both skin and erythrocytes were higher, and a lower n-6/n-3 ratio was observed. And α-linolenic acid levels in the skin were negatively correlated with the expression levels of inflammation-related genes. CONCLUSION: Oral intake of linseed oil was found to inhibit skin barrier dysfunction in obesity. This effect was mediated by α-linolenic acid, a major component of linseed oil with anti-inflammatory properties, which was taken up by erythrocytes and supplied to the skin. Therefore, oral intake of linseed oil is expected to be a useful therapeutic method for skin barrier dysfunction in obesity.

Earliest histopathological changes in COVID-19 pneumonia with comprehensive gene expression analyses: A case series study.

AIMS: In COVID-19 pneumonia, early detection and appropriate treatment are essential to prevent severe exacerbation. Therefore, it is important to understand the initiating events of COVID-19 pneumonia. However, at present, the literature about early stage disease has been very limited. Here, we investigated the earliest histopathological changes and gene expression profiles associated with COVID-19 pneumonia. METHODS AND RESULTS: We carefully examined 25 autopsied cases with different clinical courses. Dilation of capillaries and edematous thickening of the alveolar septa were found even in areas that macroscopically looked almost normal. Pneumocytes, histocytes/macrophages, and vascular endothelial cells were immunohistochemically positive for tissue factor, which is an important early responder to tissue injuries. Comprehensive gene expression analyses revealed that those lesions presented differential profiles compared to those of control lungs and were associated with a significant upregulation of the lysosomal pathway. CONCLUSIONS: Alveolar capillary dilation and edematous thickening may be the earliest histopathological change detected in COVID-19 pneumonia. Intensive investigations of such lesions may lead to an understanding of the initiating event of not only COVID-19 pneumonia but also of general diffuse alveolar damage.

Prognostic value of the IASLC/ATS/ERS classification of lung adenocarcinoma in stage I disease of Japanese cases.

A new classification of adenocarcinoma (ADC) was proposed by the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society (IASLC/ATS/ERS) in 2011. The present study evaluates its prognostic value in stage I disease of Japanese cases. One-hundred-and-seventy-nine cases with pathological stage I ADC were classified according to the new classification system and their association with disease recurrence was analyzed. Eighteen (10.1%) and 24 (13.4%) cases were adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), respectively. One-hundred-and-thirty-seven cases (76.5%) were invasive adenocarcinoma (IVA), in which 43 (24.0%) were lepidic (LEP), 59 (33.0%) were acinar (ACN), 16 (8.9%) were papillary (PAP), 1 (0.6%) was micropapillary (MPAP), 12 (6.7%) were solid predominant subtypes (SOL), and 6 (3.4%) were invasive mucinous adenocarcinoma (MUC). The5-year disease-free survivals (DFS) of patients with AIS and MIA were 100%. Those of LEP, ACN, PAP, SOL and MUC were 93.5%, 83.7%, 75.0%, 44.4% and 62.5%, respectively. Multivariate analysis showed that high-histological grade (SOL, MPAP, MUC) had an independent prognostic value to predict post-operative recurrence (HR 3.661, 95% CI 1.421-9.437, P = 0.007). In conclusion, the present study demonstrates a prognostic value of the 2011 IASLC/ATS/ERS classification of ADC in Japanese cases.

Expression of the potential cancer stem cell markers, CD133, CD44, ALDH1, and ß-catenin, in primary lung adenocarcinoma--their prognostic significance.

The present study investigated expression profiles of the potential CSC markers including CD133, CD44, ALDH1, and ß-catenin, and evaluated their prognostic value in lung adenocarcinomas. One-hundred-and-seventy-seven tumors (stage I) were immunohistochemically examined for the expression of these markers, and thresholds to subdivide expression levels were determined using receiver operating characteristics curves. Tumors with high levels of CD133 (adjusted hazard ratio (HR) 4.55 (95% confidence interval (CI) 1.26-16.40, P = 0.021), CD44 (HR 3.73, 95% CI 1.20-11.58, P = 0.023) or ALDH1 (HR 3.61, 95% CI 1.09-12.3, P = 0.036), but not ß-catenin (HR 2.43, 95% CI 0.59-10.8, P = 0.220), showed a significantly higher risk of recurrence than the corresponding low expressers. In conclusion, levels of CD133, CD44, and ALDH1 had independent prognostic value to predict the recurrence of lung adenocarcinoma.

Rapid anticalcification treatment for glutaraldehyde-fixed autologous tissue in cardiovascular surgery.

BACKGROUND: Glutaraldehyde (GA)-fixed autologous tissues, including the pericardium, are widely used as patches and valve substitutes in cardiovascular surgery. However, GA treatment causes tissue calcification. No rapid anticalcification method has been established for use during surgery. Here, we aimed to establish a rapid anticalcification method using ethanol, as has already been demonstrated for bioprosthetic valves. METHODS: Thoracic aorta tissues were first fixed with GA for 3 min and then treated with ethanol for 0 (group 2), 10 (group 3), 20 (group 4), and 30 (group 5) min; untreated tissues (group 1) served as the control. The treated tissues were subdermally implanted into 3-week-old male Wistar rats and kept in place for 28 days. The calcification in each explant was semiquantitatively evaluated by annotating and measuring the area using virtual slides, and the data obtained were statistically analyzed. RESULTS: Semiquantitative analysis revealed that calcification of the implants from the untreated group (group 1; P = 0.0014) and groups 4 (P = 0.0014) and 5 (P = 0.0031) was significantly lower than that of implants from group 2. Moreover, implants from group 3 showed a tendency toward decreased calcification, although it was not significant (P = 0.0503). CONCLUSIONS: A rapid ethanol treatment prevents calcification of GA-fixed tissues in a rat model of subdermal implantation. This method may facilitate effective and rapid anticalcification of autologous tissues for use during cardiovascular surgery.

Implications of thyroid transcription factor-1 gene methylation in carcinogenesis of interstitial pneumonia-related non-terminal respiratory unit lung adenocarcinoma.

The present study aimed to elucidate the mechanisms underlying the histogenesis of interstitial pneumonia (IP)-related lung adenocarcinoma (LADC). We focused on the methylation of thyroid transcription factor 1 (TTF-1). The TTF-1 locus was highly methylated in IP-LADCs compared to non-IP-LADCs. Among the IP-LADCs, the non-terminal respiratory unit (TRU) LADCs showed marked hypermethylation in CpG sites in a particular intragenic region. This region was also found to be highly methylated in the IP lungs. The hierarchical dendrogram based on methylation levels divided the IP lungs into three different clusters. One of them showed a methylation profile similar to that of non-TRU LADCs. The non-TRU LADCs developed from this cluster with a significantly higher frequency. Moreover, bronchiolar metaplasia lining honeycomb/cystic lesions in IP lungs, IP-related non-TRU LADCs, and bronchiolar epithelia in healthy lungs were separately collected by microdissection and examined for methylation. Bronchiolar metaplasia showed hypermethylation, but bronchiolar epithelia did not. The methylation patterns in bronchiolar metaplasia were similar to those in non-TRU LADCs. In summary, a particular region of TTF-1 was highly methylated in IP-related non-TRU LADCs and bronchiolar metaplasia, supporting the theory that IP-related non-TRU LADCs may develop from bronchiolar metaplasia lining honeycomb/cystic lesions.

Early growth response-1 induces and enhances vascular endothelial growth factor-A expression in lung cancer cells.

Vascular endothelial growth factor-A (VEGF-A) is crucial for angiogenesis, vascular permeability, and metastasis during tumor development. We demonstrate here that early growth response-1 (EGR-1), which is induced by the extracellular signal-regulated kinase (ERK) pathway activation, activates VEGF-A in lung cancer cells. Increased EGR-1 expression was found in adenocarcinoma cells carrying mutant K-RAS or EGFR genes. Hypoxic culture, siRNA experiment, luciferase assays, chromatin immunoprecipitation, electrophoretic mobility shift assays, and quantitative RT-PCR using EGR-1-inducible lung cancer cells demonstrated that EGR-1 binds to the proximal region of the VEGF-A promoter, activates VEGF-A expression, and enhances hypoxia inducible factor 1alpha (HIF-1alpha)-mediated VEGF-A expression. The EGR-1 modulator, NAB-2, was rapidly induced by increased levels of EGR-1. Pathology samples of human lung adenocarcinomas revealed correlations between EGR-1/HIF-1alpha and VEGF-A expressions and relative elevation of EGR-1 and VEGF-A expression in mutant K-RAS- or EGFR-carrying adenocarcinomas. Both EGR-1 and VEGF-A expression increased as tumors dedifferentiated, whereas HIF-1alpha expression did not. Although weak correlation was found between EGR-1 and NAB-2 expressions on the whole, NAB-2 expression decreased as tumors dedifferentiated, and inhibition of DNA methyltransferase/histone deacetylase increased NAB-2 expression in lung cancer cells despite no epigenetic alteration in the NAB-2 promoter. These findings suggest that EGR-1 plays important roles on VEGF-A expression in lung cancer cells, and epigenetic silencing of transactivator(s) associated with NAB-2 expression might also contribute to upregulate VEGF-A expression.

Frequent DYRK2 gene amplification in micropapillary element of lung adenocarcinoma - an implication in progression in EGFR-mutated lung adenocarcinoma.

The present study aimed to discern the molecular alterations involved in the progression of EGFR-mutated lung adenocarcinoma (LADC). We previously demonstrated that the micropapillary (mPAP) element is the most important histological factor for assessing malignant grades in LADCs. Therefore, mPAP and other elements were separately collected from three cases of EGFR-mutated LADC using laser capture microdissection and subjected to a comprehensive mRNA expression analysis. We focused on DYRK2 in this study because its level showed a substantial increase in EGFR-mutated LADCs with mPAP. We also immunohistochemically examined 130 tumors for the expression of DYRK2. The results confirmed a strong expression of DYRK2 in EGFR-mutated LADC with mPAP. Fluorescent in situ hybridization (FISH) analyses targeting the DYRK2 locus revealed frequent gene amplification in EGFR-mutated LADC, specifically occurring in the high-grade components, like mPAP. In summary, the results of this study suggest that DYRK2 overexpression through gene amplification is one of the molecular mechanisms responsible for promoting the progression of EGFR-mutated LADC.