[A Case of Advanced Malignant Melanoma of the Esophagus with Distant Metastases].

A 65-year-old woman with dysphagia visited our outpatient clinic. Esophagogastric endoscopy revealed a number of black-brown, irregularly elevated lesions covering the mucosal layer of nearly the entire esophagus. Following a series of examinations including histological examinations of the biopsies and whole body FDG-PET/CT, the patient was diagnosed with malignant melanoma primarily of the esophagus with metastasis to the distant lymph nodes, duodenum, pancreas head, and left brachial bone [cT3N3M1, StageIVb]. Since surgicalresection was not indicated, dacarbazine (DTIC: 1,000mg/m² body surface area)was intravenously administered 7 times every 3 weeks on an outpatient basis. However, the disease was progressive and metastasized to the stomach, duodenum, and small intestine, and finally to the brain. The patient died 8 months after the diagnosis was made. Malignant melanoma of the esophagus is a relatively rare pathology, and no reliable therapeutic modalities have been established yet. Based on the present case, the effectiveness of DTIC in an advanced case is proposed to be limited. In addition, whole body FDG-PET/CT is very useful for detecting metastatic lesions that could be missed otherwise.

Anti-tumor activity of ESX1 on cancer cells harboring oncogenic K-ras mutation.

Human ESX1 is a 65-kilodalton (kDa) paired-like homeoprotein that is proteolytically processed into N-terminal 45-kDa and C-terminal 20-kDa fragments. The N-terminal ESX1 fragment, which contains the homeodomain, localizes to the nucleus and represses mRNA transcription from the K-ras gene. When we inoculated human colorectal carcinoma HCT116 constitutive expressing N-terminal region of ESX1 (N-ESX1) into nude mice, transfectant cells uniformly showed decreased tumor-forming activity compared with that of the parental cells. Furthermore, pretreatment of HCT116 carcinoma cells with a fusion protein consisting of N-ESX1 and the protein-transduction domain derived from the human immunodeficiency virus type-1 TAT protein gave rise to a dramatic reduction in the tumorigenicity of HCT116 cells in nude mice. Our results provide first in vivo evidence for the molecular targeting therapeutic application of the K-ras repressor ESX1, especially TAT-mediated transduction of N-ESX1, in the treatment of human cancers having oncogenic K-ras mutations.

Paired-like homeoprotein ESXR1 acts as a sequence-specific transcriptional repressor of the human K-ras gene.

Gain-of-function mutation of the K-ras gene is one of the most common genetic changes in human tumors. In tumors carrying K-ras mutation, the presence of oncogenic K-Ras is necessary for maintenance of the transformed phenotype. ESXR1 is a human paired-like homeodomain-containing protein expressed primarily in the testis. In cells, the 65-kDa full-length ESXR1 protein is proteolytically processed into an N-terminal 45-kDa fragment containing the homeodomain, which localizes exclusively within the nucleus, and a C-terminal 20-kDa fragment consisting of a proline-rich repeat region, which is located in the cytoplasm. In this work, we demonstrated that the N-terminal ESXR1 fragment specifically recognizes the TAATNNNATTA P3 consensus sequence for the paired-like homeodomain and functions as a sequence-specific transcriptional repressor. We also showed that the N-terminal ESXR1 fragment binds to the TAATGTTATTA sequence present within the first intron of the human K-ras gene and inhibits its expression at both mRNA and protein levels. Ectopic expression of the N-terminal ESXR1 fragment in human carcinoma cells that carry mutated K-ras reduces the level of K-Ras and thereby inhibits the tumor cell proliferation. Identification of ESXR1 as a transcriptional repressor of K-ras has an important implication for the development of cancer therapy that inhibits oncogenic K-Ras expression.

Paired-like homeodomain protein ESXR1 possesses a cleavable C-terminal region that inhibits cyclin degradation.

The eukaryotic cell cycle is regulated by sequential activation and inactivation of cyclin-cyclin-dependent kinase (Cdk) complexes. In this work, we screened human cDNAs that can rescue yeast Saccharomyces cerevisiae from lethality caused by ectopic expression of human cyclin E and isolated a cDNA encoding ESXR1, a paired-like homeodomain-containing protein with a unique C-terminal proline-rich repeat region. In adult tissues, ESXR1 is primarily expressed in the testis. We demonstrate that ESXR1 prevents degradation of ubiquitinated cyclins in human cells. Accordingly, elevation of ESXR1 level results in accumulation of cyclin A and cyclin B1 and thereby provokes M-phase arrest. In human cells, the 65-kDa full-length ESXR1 protein is capable of proteolytically processing into N-terminal 45-kDa and C-terminal 20-kDa fragments. The C-terminal fragment, containing a proline-rich repeat region, is localized to the cytoplasm and displays the ability to inhibit cyclin degradation. In contrast, the N-terminal fragment, containing a paired-like homeodomain, is localized exclusively in the nucleus, suggesting that it plays a role in transcription. Our results indicate that proteolytic processing of ESXR1 plays a role in concerted regulation of the cell cycle and transcription in human cells.

[Effectiveness of prolonged oral administration of low-dose etoposide in a case of malignant lymphoma in the mesenterium].

Malignant lymphoma in the mesenterium is rare and carries a poor prognosis, although curative resection cases have been reported. A 39-year-old woman with non-resectable mesenteric malignant lymphoma obtained a better QOL and outcome from prolonged oral administration of low-dose etoposide as a maintenance therapy after CHOP therapy.