Shigeaki Umeda

Allelic Imbalance in the miR-31 Host Gene Locus in Lung Cancer - Its Potential Role in Carcinogenesis

Small non-protein coding RNA, microRNA (miR), which regulate messenger RNA levels, have recently been identified, and may play important roles in the pathogenesis of various diseases. The present study focused on miR-31 and investigated its potential involvement in lung carcinogenesis. The expression of miR-31 was altered in lung cancer cells through either the amplification or loss of the host gene locus. The strong expression of miR-31 in large cell carcinomas was attributed to the gene amplification. Meanwhile, the loss of miR-31 expression was more frequently observed in aggressive adenocarcinomas. Thus, miR-31 may play a pleiotropic role in the development of lung cancers among different histological types. To the best of our knowledge, this is the first study to show the potential causative mechanism of the altered expression of miR-31 and suggest its potentially diverse significance in the different histological types of lung cancers.

Proteome Analysis for Downstream Targets of Oncogenic KRAS - the Potential Participation of CLIC4 in Carcinogenesis in the Lung

This study investigated the proteome modulated by oncogenic KRAS in immortalized airway epithelial cells. Chloride intracellular channel protein 4 (CLIC4), S100 proteins (S100A2 and S100A11), tropomyosin 2, cathepsin L1, integrinsα3, eukaryotic elongation factor 1, vimentin, and others were discriminated. We here focused on CLIC4 to investigate its potential involvement in carcinogenesis in the lung because previous studies suggested that some chloride channels and chloride channel regulators could function as tumor suppressors. CILC4 protein levels were reduced in some lung cancer cell lines. The restoration of CLIC4 in lung cancer cell lines in which CLIC4 expression was reduced attenuated their growth activity. The immunohistochemical expression of the CLIC4 protein was weaker in primary lung cancer cells than in non-tumorous airway epithelial cells and was occasionally undetectable in some tumors. CLIC4 protein levels were significantly lower in a subtype of mucinous ADC than in others, and were also significantly lower in KRAS-mutated ADC than in EGFR-mutated ADC. These results suggest that the alteration in CLIC4 could be involved in restrictedly the development of a specific fraction of lung adenocarcinomas. The potential benefit of the proteome modulated by oncogenic KRAS to lung cancer research has been demonstrated.

Hepatocyte nuclear factor-1 α inactivated hepatocellular adenomas in patient with congenital absence of the portal vein: a case report.

Hepatocellular adenomas (HCAs) have been recognized recently as a heterogeneous group, and are subclassified according to genotype as well as morphological characteristics. We report a case of a 35‐year‐old Japanese woman who exhibited hepatocyte nuclear factor (HNF)‐1α‐inactivated HCA in the background of the congenital absence of the portal vein (CAPV). On a dynamic contrast computed tomography (CT) scan, the hypovascular tumor enlarged from 1 cm to 3 cm and another tumor emerged in the course of 7 years. Because the possibility of hepatocellular carcinoma (HCC) with multiple metastases was not excluded, partial hepatectomy was performed. On a cut section, two well‐demarcated tumors were observed and one tumor had a central fibrous scar. The histological features of these tumors were similar to those of focal nodular hyperplasia (FNH) with a central scar and HCA; however, these tumors were diagnosed as HNF‐1α‐inactivated HCA by immunohistochemistry according to the criteria of the current World Health Organization (WHO) classification. In non‐tumorous liver tissue, an abnormal architecture of the vessels and a vague nodular appearance of lobuli were observed, which were likely to be those of nodular regenerated hyperplasia (NRH). We discuss its pathogenesis and relationship with CAPV.

A comprehensive search for microRNAs with expression profiles modulated by oncogenic KRAS: potential involvement of miR-31 in lung carcinogenesis.

Small non-protein coding RNAs that regulate messenger RNA levels, namely microRNAs (miRNAs), have been implicated in the pathogenesis of various diseases. The purpose of the present study was to identify essential miRNAs involved in lung carcinogenesis. Previous studies demonstrated that an investigation into the downstream targets of oncogenic KRAS could be used as a strategy to elucidate the molecular mechanisms involved in lung cancer; therefore, we examined the expression profiles of mRNAs modulated by oncogenic KRAS in the present study. We focused on miR-31 from the miRNAs that were differentially expressed, and evaluated its potential role in the development of lung cancer. miR-31 was upregulated not only by oncogenic KRAS, but also by oncogenic EGFR. The expression of miR-31 was markedly attenuated in some lung cancer cell lines by deleting its host gene locus. The restoration of miR-31 in lung cancer cell lines that lost its expression attenuated their growth activities. The knockdown of miR-31 expression in lung cancer cell lines retaining its expression enhanced anchorage-independent growth activity. These results suggest that miR-31 may be a suppressor that regulates an essential oncogenic pathway, the loss of which may promote lung carcinogenesis.

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

To investigate the pathological features of idiopathic interstitial pneumonia (IIP)‐associated pulmonary adenocarcinoma.

A case of pulmonary hamartoma with distinctive histopathological features: a discussion of its differential diagnosis and histogenesis.

We herein describe a case of a benign pulmonary tumor with distinctive histopathological features. A 55‐year‐old Japanese male presented with a well‐demarcated tumor in the left upper lobe of his lung, which gradually increased in size from 18 to 21 mm over 24 months. The resected tumor consisted of an epithelial component of compact irregular glands and mesenchymal component of fascicles between the glands. The differentiation of pneumocytes and smooth muscle cells was immunohistochemically detected in the epithelial component and the mesenchymal component, respectively. No mitosis, necrosis, bleeding, or invasion was observed. A histopathologic diagnosis of fibroleiomyomatous hamartoma was made. We also review previously reported tumors with similar histopathological features and discuss their differential diagnosis and histogenesis.

A Histopathological Feature of EGFR-Mutated Lung Adenocarcinomas with Highly Malignant Potential – An Implication of Micropapillary Element -

The purpose of this study was to define histological features determining the malignant potential of EGFR-mutated lung adenocarcinoma (LADC). Surgically resected tumors (EGFR-mutated LADCs with (21) and without (79) lymph node metastasis and EGFR wild-type LADCs with (26) and without (108) lymph node metastasis) and biopsy samples from inoperably advanced tumors (EGFR-mutated LADCs (78) and EGFR wild-type LADCs (99)) were examined. In surgically resected tumors, the EGFR-mutated LADCs with lymph node metastasis had the micropapillary element in a significantly greater proportion than others (Mann-Whitney tests P ≤0.026). The proportion of micropapillary element was higher in the EGFR-mutated LADC at the advanced stage (stage II, III, or IV) than in the tumor at the early stage (stage I) (Mann-Whitney test, P<0.0001). In the biopsy samples from inoperably advanced LADCs (177), EGFR-mutated tumors also had micropapillary element at a higher frequency than EGFR-wild type tumors (53/78 (68%), versus 30/99 (30%), Pearson x2 test, P<0.0001). In stage I EGFR-mutated LADCs (84), the tumors with the micropapillary element (34) exhibited a significantly higher recurrence rate than tumors without micropapillary element (50) (5-year Recurrence-free survival 64.4% versus 93.3%, log-rank test P = 0.028). The micropapillary element may be an exclusive determinant of malignant potential in EGFR-mutated LADC. It is suggested that EGFR-mutated LADC may develop through a distinct histogenesis, in which the micropapillary element is important for promoting progression.

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.

The Spontaneous Regression of Grade 3 Methotrexate-related Lymphomatoid Granulomatosis: A Case Report and Literature Review

Lymphomatoid granulomatosis (LYG) is a rare lung disorder diagnosed by radiological imaging of multiple pulmonary nodules and occasionally induced by methotrexate (MTX) use. To date, the treatment of LYG has not been standardized. We herein report the case of a patient with grade 3 MTX-related LYG who presented a bulky lung mass. Importantly, the disease condition only improved after the discontinuation of MTX and remained stable for more than 1 year. Chest physicians should be aware that LYG can develop as a single lung mass and spontaneously regress, even without aggressive chemotherapy, following the cessation of MTX.

Two surgical cases of thymic MALT lymphoma associated with multiple lung cysts: possible association with Sjögren’s syndrome

Thymic mucosa-associated lymphoid tissue (MALT) lymphoma is rare. Sjögren’s syndrome (SjS) has strong association with thymic MALT lymphoma but the exact etiology is unknown. On the other hand, SjS is characterized by the complication of various lung manifestations, including lung cysts. The mechanism for these lesions is also unknown. But the underlying SjS could result in MALT lymphoma with lung cysts. Herein, we demonstrate two surgical cases of thymic MALT lymphoma associated with multiple lung cysts and the characterization of this rare tumor. During surgery, the tumors were found to be well capsuled and had no adhesion or invasion to the surrounding tissues consistent with its characteristics of low grade malignancy. When thymic MALT lymphoma is suspected clinically, video-assisted thoracoscopic surgery might be the best approach for diagnosis. We propose that radiological findings of a thymic tumor along with lung cysts are an indication of thymic MALT lymphoma.