TRIM63 is a sensitive and specific biomarker for MiT family aberration-associated renal cell carcinoma.

Microphthalmia-associated transcription factor (MiT) family aberration-associated renal cell carcinoma (MiTF-RCC) is a subtype of renal cell carcinoma harboring recurrent chromosomal rearrangements involving TFE3 or TFEB genes. MiTF-RCC is morphologically diverse, can histologically resemble common RCC subtypes like clear cell RCC and papillary RCC, and often poses a diagnostic challenge in genitourinary clinical and pathology practice. To characterize the MiTF-RCC at the molecular level and identify biomarker signatures associated with MiTF-RCC, we analyzed RNAseq data from MiTF-RCC, other RCC subtypes and benign kidney. Upon identifying TRIM63 as a cancer-specific biomarker in MiTF-RCC, we evaluated its expression independently by RNA in situ hybridization (RNA-ISH) in whole tissue sections from 177 RCC cases. We specifically included 31 cytogenetically confirmed MiTF-RCC cases and 70 RCC cases suspicious for MiTF-RCC in terms of clinical and morphological features, to evaluate and compare TRIM63 RNA-ISH results with the results from TFE3/TFEB fluorescence in situ hybridization (FISH), which is the current clinical standard. We confirmed that TRIM63 mRNA was highly expressed in all classes of MiTF-RCC compared to other renal tumor categories, where it was mostly absent to low. While the TRIM63 RNA-ISH and TFE3/TFEB FISH results were largely concordant, importantly, TRIM63 RNA-ISH was strongly positive in TFE3 FISH false-negative cases with RBM10-TFE3 inversion. In conclusion, TRIM63 can serve as a diagnostic marker to distinguish MiTF-RCC from other renal tumor subtypes with overlapping morphology. We suggest a combination of TFE3/TFEB FISH and TRIM63 RNA-ISH assays to improve the accuracy and efficiency of MiTF-RCC diagnosis. Accurate diagnosis of MiTF-RCC and other RCC subtypes would enable effective targeted therapy and avoid poor therapeutic response due to tumor misclassification.

Combined A20 and tripartite motif-containing 44 as poor prognostic factors for breast cancer patients of the Japanese population.

We previously reported that a strong immunoreactivity of tripartite motif-containing 44 (TRIM44) predicts the poor prognosis of patients with invasive breast cancer, and proposed that TRIM44 activates nuclear factor-κB (NF-κB) signaling as a causative mechanism. In the present study, we examined the clinicopathological roles of A20, which is known to be an NF-κB responsive gene, with TRIM44, in an updated cohort. Tissue samples of invasive breast cancer were obtained from 140 Japanese female breast cancer patients who underwent surgical treatment. Immunoreactivities of A20 and TRIM44 were analyzed using specific antibodies for each protein. A positive A20 immunoreactivity was significantly associated with a shorter disease-free survival (P = 0.043) and was positively correlated with TRIM44 immunoreactivity (P = 0.039). Combined use of the immunoreactivities for two proteins revealed that double-positive status for both A20 and TRIM44 immunoreactivities was associated with a shorter disease-free survival (P = 0.012) and was an independent factor for poor prognosis. These results indicate that a combined A20 and TRIM44 immunoreactivity predicted the prognosis of patients with invasive breast cancer. Moreover, the positive correlation between A20 and TRIM44 immunoreactivities suggested that the activation of NF-κB signaling by TRIM44 could occur in clinical breast cancer tissues.

Disease biomarker identification from gene network modules for metastasized breast cancer.

Advancement in science has tended to improve treatment of fatal diseases such as cancer. A major concern in the area is the spread of cancerous cells, technically refered to as metastasis into other organs beyond the primary organ. Treatment in such a stage of cancer is extremely difficult and usually palliative only. In this study, we focus on finding gene-gene network modules which are functionally similar in nature in the case of breast cancer. These modules extracted during the disease progression stages are analyzed using p-value and their associated pathways. We also explore interesting patterns associated with the causal genes, viz., SCGB1D2, MET, CYP1B1 and MMP9 in terms of expression similarity and pathway contexts. We analyze the genes involved in both the stages- non metastasis and metastatsis and change in their expression values, their associated pathways and roles as the disease progresses from one stage to another. We discover three additional pathways viz., Glycerophospholipid metablism, h-Efp pathway and CARM1 and Regulation of Estrogen Receptor, which can be related to the metastasis phase of breast cancer. These new pathways can be further explored to identify their relevance during the progression of the disease.

High expression of TRIM11 correlates with poor prognosis in patients with hepatocellular carcinoma.

BACKGROUND: Tripartite Motif Containing 11 (TRIM11), a member of TRIM proteins is overexpressed in gliomas and lung cancer. However, the role of TRIM11 in hepatocellular carcinoma (HCC) is unknown. BASIC PROCEDURES: Herein, we aimed to investigate the expression and clinical significance role of TRIM11 in HCC. MAIN FINDING: In this study, our data showed significant higher TRIM11 in HCC tissues (n=117) than in the matched non-tumor liver (NTL) tissues (P<0.01). In consistent with above data, we also found TRIM11 protein expression was significantly increased compared with the matched NTL (P<0.01) by immunohistochemistry analysis. Additionally, our results showed that TRIM11 protein expression in HCC tissues was significantly associated with pathological grade (P<0.01), tumor postoperative metastasis (P=0.031), recurrence (P=0.022), and serum a-fetoprotein (AFP) (P<0.01). Moreover, patients' survival was negatively correlated with TRIM11 protein expression. Furthermore, we found that TRIM11 protein was an independent prognostic factor for disease-free (P<0.01) and overall survival (P<0.01) in HCC patients. PRINCIPAL CONCLUSIONS: Our data showed that TRIM11 expression was significantly elevated in HCC tissues. The overexpression of TRIM11 is closely associated with HCC progression and poor survival of the patients, indicating TRIM11 is a potential therapeutic target for HCC patients.

Disturbed P53-MDM2 Feedback Loop Contributes to Thoracic Aortic Dissection Formation and May be a Result of TRIM25 Overexpression.

BACKGROUND: The development of thoracic aortic dissection (TAD) is attributed to a broad range of degenerative, genetic, structural, oxidative, apoptotic, and acquired disease states. In this study, we examined the role of the disturbed p53-MDM2 (murine double minute 2) feedback loop in the formation of TAD, and one of a potential feedback loop regulator, TRIM25 (tripartite motif protein-25). METHODS: Surgical specimens of the aorta from TAD patients (n = 10) and controls (n = 10) were tested for α-smooth muscle actin (α-SMA), p53, MDM2, and TRIM25 by western blot, immunohistochemical staining, and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), respectively. RESULTS: When compared with controls, western blot shows that the protein levels of p53, MDM2, and TRIM25 were increased significantly in the aortic media of TAD patients. qRT-PCR further verified that the mRNA expression of MDM2 and TRIM25 was also increased 6- and 4-folds, respectively, in the TAD media of the aortic wall. Immunohistochemistry results showed significantly decreased staining of α-SMA, smooth muscle cells, and more collagen deposition in the media of the aortic wall from patients with TAD. CONCLUSION: This study provided a new insight into the disturbed p53-MDM2 feedback loop in the pathogenesis of TAD, and this may be because of the TRIM25 overexpression.

The study on mechanism of the modified Chinese herbal compound, jianpijiedu, on a mouse model of hepatic carcinoma cachexia.

Various studies have investigated hepatic carcinoma cachexia, however, there is little published information regarding the effect of Chinese Medicine carcinoma cachexia. The present study was performed to investigate the effect of modified Chinese herbal compound jianpijiedu (MJPJD) on a mouse model of ascites­induced hepatic carcinoma cachexia. C57BL/6 mice were randomized to five groups: Control (Group A); xenograft tumor (Group B); low concentration of MJPJD (Group C); high concentration of MJPJD (Group D) and medroxyprogesterone (MPA) combined with indometacin (IND; Group E). The mouse model of ascites­induced hepatic carcinoma cachexia was established by abdominal injection of H22 hepatic carcinoma cells. Subsequently, the body weight, food intake and gastrocnemius weight were recorded, and the levels of interleukin (IL)­lα, IL­6, tumor necrosis factor­α (TNF­α) in ascites were detected by enzyme­linked immunosorbent assay. The protein expression levels of muscle RING­finger protein­1 (MU­RF1) and atrogin 1 were detected by western blotting and immunohistochemistry, and the mRNA levels in gastrocnemius were detected by reverse transcription­quantitative polymerase chain reaction. Compared with the xenograft tumor group, the administration of MJPJD inhibited the increase in body weight and the volume of ascites, the consumption of gastrocnemius was reduced, the net weight of ascites was maintained, the food intake was enhanced and the levels of the cytokines IL­lα, IL­6, TNF­α in ascites and the levels of MU­RF1 and atrogin 1 proteins were reduced. These results indicated that MJPJD delays the pathological process of ascites­induced hepatic carcinoma cachexia, and the mechanism of action may be correlated with a reduction in the levels of IL­lα, IL­6, TNF­α and inhibiting the activation of the ubiquitin proteosome pathway.