A new synthetic matrix metalloproteinase inhibitor reduces human mesenchymal stem cell adipogenesis.

Development of adipose tissue requires the differentiation of less specialized cells, such as human mesenchymal stem cells (hMSCs), into adipocytes. Since matrix metalloproteinases (MMPs) play critical roles in the cell differentiation process, we conducted investigations to determine if a novel mercaptosulfonamide-based MMP inhibitor (MMPI), YHJ-7-52, could affect hMSC adipogenic differentiation and lipid accumulation. Enzyme inhibition assays, adipogenic differentiation experiments, and quantitative PCR methods were employed to characterize this inhibitor and determine its effect upon adipogenesis. YHJ-7-52 reduced lipid accumulation in differentiated cells by comparable amounts as a potent hydroxamate MMPI, GM6001. However, YHJ-7-82, a non-inhibitory structural analog of YHJ-7-52, in which the zinc-binding thiol group is replaced by a hydroxyl group, had no effect on adipogenesis. The two MMPIs (YHJ-7-52 and GM6001) were also as effective in reducing lipid accumulation in differentiated cells as T0070907, an antagonist of peroxisome-proliferator activated receptor gamma (PPAR-gamma), at a similar concentration. PPAR-gamma is a typical adipogenic marker and a key regulatory protein for the transition of preadiopocyte to adipocyte. Moreover, MMP inhibition was able to suppress lipid accumulation in cells co-treated with Troglitazone, a PPAR-gamma agonist. Our results indicate that MMP inhibitors may be used as molecular tools for adipogenesis and obesity treatment research.

Differentially expressed transcripts and dysregulated signaling pathways and networks in African American breast cancer.

African Americans (AAs) have higher mortality rate from breast cancer than that of Caucasian Americans (CAs) even when socioeconomic factors are accounted for. To better understand the driving biological factors of this health disparity, we performed a comprehensive differential gene expression analysis, including subtype- and stage-specific analysis, using the breast cancer data in the Cancer Genome Atlas (TCGA). In total, 674 unique genes and other transcripts were found differentially expressed between these two populations. The numbers of differentially expressed genes between AA and CA patients increased in each stage of tumor progression: there were 26 in stage I, 161 in stage II, and 223 in stage III. Resistin, a gene that is linked to obesity, insulin resistance, and breast cancer, was expressed more than four times higher in AA tumors. An uncharacterized, long, non-coding RNA, LOC90784, was down-regulated in AA tumors, and its expression was inversely related to cancer stage and was the lowest in triple negative AA breast tumors. Network analysis showed increased expression of a majority of components in p53 and BRCA1 subnetworks in AA breast tumor samples, and members of the aurora B and polo-like kinase signaling pathways were also highly expressed. Higher gene expression diversity was observed in more advanced stage breast tumors suggesting increased genomic instability during tumor progression. Amplified resistin expression may indicate insulin-resistant type II diabetes and obesity are associated with AA breast cancer. Expression of LOC90784 may have a protective effect on breast cancer patients, and its loss, particularly in triple negative breast cancer, could be having detrimental effects. This work helps elucidate molecular mechanisms of breast cancer health disparity and identifies putative biomarkers and therapeutic targets such as resistin, and the aurora B and polo-like kinase signaling pathways for treating AA breast cancer patients.

The impact of baseline serum C-reactive protein and C-reactive protein kinetics on the prognosis of metastatic nasopharyngeal carcinoma patients treated with palliative chemotherapy.

BACKGROUND: The aim of this study was to determine whether baseline C-reactive protein (CRP) levels and CRP kinetics predict the overall survival in metastatic nasopharyngeal carcinoma (mNPC) patients. METHODS: A total of 116 mNPC patients from January 2006 to July 2011 were retrospectively reviewed. Serum CRP level was measured at baseline and thereafter at the start of each palliative chemotherapy cycle for all patients. RESULTS: Patients with higher values of baseline CRP (≥ 3.4 mg/L) had significantly worse survival than those with lower baseline CRP values (< 3.4 mg/L). Patients were divided into four groups according to baseline CRP and CRP kinetics: (1) patients whose CRP < 3.4 mg/L and never elevated during treatment; (2) patients whose CRP < 3.4 mg/L and elevated at least one time during treatment; (3) patients whose CRP ≥ 3.4 mg/L and normalized at least one time during treatment; and (4) patients whose CRP ≥ 3.4 mg/L and never normalized during treatment. The patients were further assigned to non-elevated, elevated, normalized, and non-normalized CRP groups. Overall survival rates were significantly different among the four groups, with three-year survival rates of 68%, 41%, 33%, and 0.03% for non-elevated, elevated, normalized, and non-normalized CRP groups respectively. When compared with the non-elevated group, hazard ratios of death were 1.69, 2.57, and 10.34 in the normalized, elevated, and non-normalized groups (P < 0.001). CONCLUSIONS: Baseline CRP and CRP kinetics may be useful to predict the prognosis of metastatic NPC patients treated with palliative chemotherapy and facilitate individualized treatment. A prospective study to validate this prognostic model is still needed however.

Matrix metalloproteinase inhibitors based on the 3-mercaptopyrrolidine core.

New series of pyrrolidine mercaptosulfide, 2-mercaptocyclopentane arylsulfonamide, and 3-mercapto-4-arylsulfonamidopyrrolidine matrix metalloproteinase inhibitors (MMPIs) were designed, synthesized, and evaluated. Exhibiting unique properties over other MMPIs (e.g., hydroxamates), these newly reported compounds are capable of modulating activities of several MMPs in the low nanomolar range, including MMP-2 (~2 to 50 nM), MMP-13 (~2 to 50 nM), and MMP-14 (~4 to 60 nM). Additionally these compounds are selective to intermediate- and deep-pocket MMPs but not shallow-pocketed MMPs (e.g., MMP-1, ~850 to >50,000 nM; MMP-7, ~4000 to >25,000 nM). Our previous work with the mercaptosulfide functionality attached to both cyclopentane and pyrrolidine frameworks demonstrated that the cis-(3S,4R)-stereochemistry was optimal for all of the MMPs tested. However, in our newest compounds an interesting shift of preference to the trans form of the mercaptosulfonamides was observed with increased oxidative stability and biological compatibility. We also report several kinetic and biological characteristics showing that these compounds may be used to probe the mechanistic activities of MMPs in disease.

Coordinated peak expression of MMP-26 and TIMP-4 in preinvasive human prostate tumor.

The identification of novel biomarkers for early prostate cancer diagnosis is highly important because early detection and treatment are critical for the medical management of patients. Disruption in the continuity of both the basal cell layer and basement membrane is essential for the progression of high-grade prostatic intraepithelial neoplasia (HGPIN) to invasive adenocarcinoma in human prostate. The molecules involved in the conversion to an invasive phenotype are the subject of intense scrutiny. We have previously reported that matrix metalloproteinase-26 (MMP-26) promotes the invasion of human prostate cancer cells via the cleavage of basement membrane proteins and by activating the zymogen form of MMP-9. Furthermore, we have found that tissue inhibitor of metalloproteinases-4 (TIMP-4) is the most potent endogenous inhibitor of MMP-26. Here we demonstrate higher (p<0.0001) MMP-26 and TIMP-4 expression in HGPIN and cancer, compared to non-neoplastic acini. Their expression levels are highest in HGPIN, but decline in invasive cancer (p<0.001 for each) in the same tissues. Immunohistochemical staining of serial prostate cancer tissue sections suggests colocalization of MMP-26 and TIMP-4. The present study indicates that MMP-26 and TIMP-4 may play an integral role during the conversion of HGPIN to invasive cancer and may also serve as markers for early prostate cancer diagnosis.