Amplifying hepatic L-aspartate levels suppresses CCl4-induced liver fibrosis by reversing glucocorticoid receptor ß-mediated mitochondrial malfunction.

Liver fibrosis is a determinant-stage process of many chronic liver diseases and affected over 7.9 billion populations worldwide with increasing demands of ideal therapeutic agents. Discovery of active molecules with anti-hepatic fibrosis efficacies presents the most attacking filed. Here, we revealed that hepatic L-aspartate levels were decreased in CCl4-induced fibrotic mice. Instead, supplementation of L-aspartate orally alleviated typical manifestations of liver injury and fibrosis. These therapeutic efficacies were alongside improvements of mitochondrial adaptive oxidation. Notably, treatment with L-aspartate rebalanced hepatic cholesterol-steroid metabolism and reduced the levels of liver-impairing metabolites, including corticosterone (CORT). Mechanistically, L-aspartate treatment efficiently reversed CORT-mediated glucocorticoid receptor ß (GRß) signaling activation and subsequent transcriptional suppression of the mitochondrial genome by directly binding to the mitochondrial genome. Knockout of GRß ameliorated corticosterone-mediated mitochondrial dysfunction and hepatocyte damage which also weakened the improvements of L-aspartate in suppressing GRß signaling. These data suggest that L-aspartate ameliorates hepatic fibrosis by suppressing GRß signaling via rebalancing cholesterol-steroid metabolism, would be an ideal candidate for clinical liver fibrosis treatment.

A Zic2/Runx2/NOLC1 signaling axis mediates tumor growth and metastasis in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies with rapid growth and high metastasis, but lacks effective therapeutic targets. Here, using public sequencing data analyses, quantitative real-time PCR assay, western blotting, and IHC staining, we characterized that runt-related transcription factor 2 (Runx2) was significantly upregulated in ccRCC tissues than that in normal renal tissues, which was associated with the worse survival of ccRCC patients. Overexpression of Runx2 promoted malignant proliferation and migration of ccRCC cells, and inversely, interfering Runx2 with siRNA attenuates its oncogenic ability. RNA sequencing and functional studies revealed that Runx2 enhanced ccRCC cell growth and metastasis via downregulation of tumor suppressor nucleolar and coiled-body phosphoprotein 1 (NOLC1). Moreover, increased Zic family member 2 (Zic2) was responsible for the upregulation of Runx2 and its oncogenic functions in ccRCC. Kaplan-Meier survival analyses indicated that ccRCC patients with high Zic2/Runx2 and low NOLC1 had the worst outcome. Therefore, our study demonstrates that Zic2/Runx2/NOLC1 signaling axis promotes ccRCC progression, providing a set of potential targets and prognostic indicators for patients with ccRCC.

Expression of P63 and its correlation with prognosis in diffuse large B-cell lymphoma: a single center experience.

BACKGROUND: Large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma among adults. In some cases, DLBCL may seem similar to carcinoma cells, presenting a round, oval, or polygonal shape and clear nuclei. We found that the expression of P63 accounted for a considerable proportion of DLBCL cases. Under the circumstances, P63 expression may lead to a misdiagnosis, especially with a small biopsy. We aim to investigate the expression status and prognostic significance of P63 in a cohort of Chinese DLBCL patients. METHODS: P63, ΔNP63(P40), P53 and Ki67 were detected by immunohistochemistry (IHC). A ROC curve was adopted to find the best cut-off value for positive P63/P53 expression and high Ki67 expression. We defined P53 as positive when ≥50% of the tumor cells showed staining. The relationship between P63 and P53/Ki67 expression was examined. Time-to-event endpoints were estimated according to the Kaplan-Meier method. Moreover, multivariate analyses were conducted to evaluate the prognostic factors in DLBCL. RESULTS: Out of all the 159 DLBCL cases, 76 (47.8%) expressed P63 in the nuclei, while 41 (25.8%) were determined to have high expression by using a ROC cut-off value "≥6". Examination of the different P63 isoforms revealed that the ΔNP63(P40) was unclearly and weakly expressed in only 3 cases, showing a fuzzy yellow cytoplasm. P63 expression was not correlated with subtype (GCB or non-GCB) or P53 but was correlated with a high proliferative index (Ki67). Kaplan-Meier analyses revealed that P63 expression was correlated with overall survival, and P63 positive cases showed poor survival outcomes (P<0.05) in our cohort. CONCLUSIONS: ΔNP63(P40) is a useful marker in the differential diagnosis of poorly differentiated squamous cell carcinoma versus DLBCL in small needle biopsy. P63 may be involved in DLBCL tumor progression, and it is an unfavorable prognostic marker in DLBCL. A subgroup of P63 and P53 coexpression DLBCL patients with an extremely poor prognosis should be noted.

Clonal Mutations Activate the NF-κB Pathway to Promote Recurrence of Nasopharyngeal Carcinoma.

The genetic events occurring in recurrent nasopharyngeal carcinoma (rNPC) are poorly understood. Here, we performed whole-genome and whole-exome sequencing in 55 patients with rNPC and 44 primarily diagnosed NPC (pNPC), with 7 patients having paired rNPC and pNPC samples. Previously published pNPC exome data were integrated for analysis. rNPC and pNPC tissues had similar mutational burdens, however, the number of clonal mutations was increased in rNPC samples. TP53 and three NF-κB pathway components (TRAF3, CYLD, and NFKBIA) were significantly mutated in both pNPC and rNPC. Notably, mutations in TRAF3, CYLD, and NFKBIA were all clonal in rNPC, however, 55.6% to 57.9% of them were clonal in pNPC. In general, the number of clonal mutations in NF-κB pathway-associated genes was significantly higher in rNPC than in pNPC. The NF-κB mutational clonality was selected and/or enriched during NPC recurrence. The amount of NF-κB translocated to the nucleus in samples with clonal NF-κB mutants was significantly higher than that in samples with subclonal NF-κB mutants. Moreover, the nuclear abundance of NF-κB protein was significantly greater in pNPC samples with locoregional relapse than in those without relapse. Furthermore, high nuclear NF-κB levels were an independent negative prognostic marker for locoregional relapse-free survival in pNPC. Finally, inhibition of NF-κB enhanced both radiosensitivity and chemosensitivity in vitro and in vivo. In conclusion, NF-κB pathway activation by clonal mutations plays an important role in promoting the recurrence of NPC. Moreover, nuclear accumulation of NF-κB is a prominent biomarker for predicting locoregional relapse-free survival. SIGNIFICANCE: This study uncovers genetic events that promote the progression and recurrence of nasopharyngeal carcinoma and has potential prognostic and therapeutic implications.See related commentary by Sehgal and Barbie, p. 5915.

Loss of CD15 expression in clear cell renal cell carcinoma is correlated with worse prognosis in Chinese patients.

PURPOSE: To explore the role of CD15 expression in the prognosis of clear cell renal cell carcinoma (ccRCC) in Chinese patients. METHODS: The study included 301 patients who had undergone surgery for localized ccRCC. All paraffin-embedded tumor sections were collected to make a set of tissue microarrays. CD15 expression was assessed by immunohistochemistry. The relationship between CD15 expression and survival parameters, clinicopathology features was assessed. Kaplan-Meier and Cox proportional hazards model were utilized to determine the correlation between CD15 expression and overall survival (OS). RESULTS: The median follow-up time was 54.6 months (range, 3-121 months). The positive rate of CD15 expression was 81.7% (246/301). The cut-off value of CD15 expression was defined as the maximum for Youden index by plotting the receiver operating characteristic curve for survival status. As the threshold was 0.5, all cases were divided into two groups: positive expression group and negative expression group. In correlation analysis, loss of CD15 expression was correlated with female gender, higher Fuhrman nuclear grade, with sarcomatoid differentiation, with necrosis, and with vascular invasion. Kaplan-Meier analysis indicated that the OS time of patients with loss of CD15 expression was shorter than that of patients with positive CD15 expression (P = 0.013). CONCLUSION: CD15 is a significant prognostic factor in clear cell renal cell carcinoma.