Interaction with SP1, but not binding to the E-box motifs, is responsible for BHLHE40/DEC1-induced transcriptional suppression of CLDN1 and cell invasion in MCF-7 cells.

Basic helix-loop-helix family member e40 (BHLHE40) is located in 3p26.1 and acts as a transcriptional repressor of the circadian rhythm by suppressing the expression of the clock genes and clock-controlled genes. Recent research indicated that BHLHE40 may be involved in regulating tumor cell progression. However the mechanism by which BHLHE40 regulates the invasion and metastasis of tumor cells is unclear. Our in vitro assays showed that BHLHE40 promoted tumor cell invasion while BHLHE40 silencing by siRNA suppressed tumor cell invasion of MCF-7 cells. BHLHE40 suppressed the mRNA and protein expression of CLDN1 CLDN4 and CDH1 and promoted the expression of SNAI1 and SNAI2. Reporter assays demonstrated that BHLHE40 suppressed CLDN1 transcription but not through direct binding to the E-box motifs in the CLDN1 promoter. Further studies demonstrated BHLHE40 suppressed CLDN1 transcription by preventing the interaction between SP1 and a specific motif within the promoter region of CLDN1. BHLHE40 could not further suppress CLDN1 transactivation after SP1 siRNA transfection that is, BHLHE40-induced suppression of CLDN1 relied on SP1. Furthermore our data indicated that SP1 was a major regulator of CLDN1 transcription by binding to a specific motif that was located at -233 to -61 bp upstream of the transcription start site. Immunoprecipitation and co-localization data revealed an interaction between BHLHE40 and SP1. By constructing deletion mutants we found that the BHLH and Orange regions are both essential for the BHLHE40-SP1 interaction. BHLHE40 probably acts as an inhibitory nuclear cofactor or perhaps recruits other inhibitory cofactors to inhibit the SP1-mediated CLDN1 transactivation. These results suggest that BHLHE40 facilitates cell invasion and may be used as a novel target for breast cancer prevention and treatment.

Tumor-to-tumor metastasis: lung adenocarcinoma metastasizing to intracranial benign meningioma as a first clinical manifestation, with literature review.

We report a case of lung adenocarcinoma metastasizing to intracranial meningioma as a first clinical manifestation. Surgeons should be aware of this rare lesion. A 70-year-old Chinese woman was admitted to our hospital with a complaint of progressive left hemiparesis, predominantly of the upper extremity, for 20 days. Computed tomography (CT) revealed a mass on the right side of the right occipital cerebral falx. The subsequent magnetic resonance imaging (MRI) showed an oval mass with equal intensity on T1 weighted imaging (WI) and heterogeneous equal intensity on T2 WI. Within the tumor, a low T1 signal lesion was moderately enhanced after enhanced scanning with a relative boundary. Neuroimaging indicated a meningioma and the patient underwent a total mass resection. Formalin-embedded sections demonstrated two histologically distinct tumors (meningioma and adenocarcinoma) simultaneously in the same lesion without an intermediate transitional zone. Meanwhile, immunohistochemical (IHC) staining showed two distinctly different immunophenotypes in these two tumors and indicated that the component of adenocarcinoma might be a metastasis from a primary lung cancer. Therefore, a subsequent pulmonary CT scan was performed and found a mass at the tip of the upper lobe of the right lung. Fine-needle aspiration biopsy demonstrated an adenocarcinoma. The primary lung adenocarcinoma shared similar histologic morphology with that of the intracranial metastatic site. The final diagnosis waslung adenocarcinoma metastasizing to intracranial benign meningioma. The patient died of heart failure 2 weeks after surgery.

Primary mucinous carcinoma of thyroid gland with prominent signet-ring-cell differentiation: a case report and review of the literature.

PURPOSE: This study reports a case of primary mucinous carcinoma of the thyroid gland with signet-ring-cell differentiation, and reviews the literature to evaluate its real incidence and the prognosis of these patients. PATIENTS AND METHODS: A 74-year-old Chinese woman, presenting with a mass in the right lobe of thyroid gland, came to the hospital. Computed tomography revealed a mass in the right lobe of the thyroid gland, accompanied with right neck lymphadenectasis and airway deviation caused by tumor compression. Thyroid imaging suggested a thyroid malignant tumor and suspicious lymph node metastasis. Histologically, the tumor was characterized by the tumor cells arranged in small nests or trabeculae with an abundant extracellular mucoid matrix. The tumor cells formed diffuse invasion among thyroid follicles. In the peripheral regions, prominent signet-ring-cells formed a sheet-like structure and extended into the extrathyroidal fat tissue. The tumor cells were diffusely positive for thyroid transcription factor-1 (TTF-1) and PAX8, while they were focally positive for pan-cytokeratin (AE1/AE3) and weakly expressed thyroglobulin. RESULTS: Based on the histological features and immunohistochemical profile, a diagnosis of primary mucinous carcinoma of the thyroid gland with signet-ring-cell differentiation was rendered. CONCLUSION: Using a panel of immunohistochemical markers may be helpful for differential diagnosis and for determining whether the tumor is primary or not.