It has been known for years that the same genetic defects drive breast cancer formation, yet, the onset of breast cancer in different individuals among the same population differs greatly in their ...life spans with unknown mechanisms.
We used a MMTV-PyMT mouse model with different genetic backgrounds (FVB/NJ vs. C57BL/6J) to generate different cancer onset phenotypes, then profiled and analyzed the gene expression of three tumor stages in both Fvb.B6 and Fvb mice to explore the underlying mechanisms.
We found that in contrast with the FVB/N-Tg (MMTV-PyMT) 634Mul mice (Fvb mice), mammary tumor initiation was significantly delayed and tumor progression was significantly suppressed in the Fvb.B6 mice (generated by crossing FVB/NJ with C57BL/6J mice). Transcriptome sequencing and analysis revealed that the differentially expressed genes were enriched in immune-related pathways. Flow cytometry analysis showed a higher proportion of matured dendritic cells in the Fvb.B6 mice. The plasma levels of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) were significantly reduced in the Fvb.B6 mice. IL-6 also impaired the maturation of bone marrow dendritic cells (BMDCs) of the Fvb mice in vitro.
All these findings suggest that immunity levels (characterized by a reduced IL-6 level and intact DC maturation in Fvb.B6 mice) are the key factors affecting tumor onset in a murine mammary cancer model.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose: This retrospective study aimed to examine the expression and localization of SAM68 (Src-associated in mitosis, 68
kDa) in a larger cohort of surgical specimens of renal cell carcinoma and ...their correlation with the progression of human
renal cell carcinoma.
Experimental Design: The protein and mRNA expression levels of SAM68 in normal renal tubular epithelial cells, renal cell
carcinoma cell lines, as well as nine pairs of renal cell carcinoma and matched tumor-adjacent renal tissues were examined
using reverse transcription-PCR and Western blot. Moreover, SAM68 protein expression and localization in 241 clinicopathologically
characterized renal cell carcinoma samples were examined by immunohistochemistry. Prognostic and diagnostic associations were
examined by statistical analyses.
Results: SAM68 was markedly overexpressed in renal cell carcinoma cell lines and renal cell carcinoma tissues at both the
transcriptional and translational levels. Immunohistochemical analysis revealed high SAM68 protein expression in 129 of the
241 (53.5%) paraffin-embedded archival renal cell carcinoma specimens. Moreover, there was a significant correlation between
SAM68 expression and pathologic stage ( P < 0.001), T classification ( P = 0.003), N classification ( P = 0.001), M classification ( P = 0.006), and Fuhrman grade ( P < 0.001). Patients with higher SAM68 expression had shorter overall survival time than patients with lower SAM68 expression,
and the cytoplasmic localization of SAM68 significantly correlated with clinicopathologic grade and outcome. Multivariate
analysis indicated that SAM68 protein overexpression and cytoplasmic localization were independent predictors for poor survival
of renal cell carcinoma patients.
Conclusions: Our results suggest that SAM68 could represent a novel and useful prognostic marker for renal cell carcinoma.
High SAM68 expression and cytoplasmic localization are associated with poor overall survival in renal cell carcinoma patients.
(Cancer Epidemiol Biomarkers Prev 2009;18(10):2685–93)
The aim of this study was to identify a biomarker useful in the diagnosis and therapy of ovarian malignant germ cell tumor (OMGCT).
The karyopherin 2 (KPNA2) expression in OMGCT and normal ovarian ...tissue was determined by standard gene microarray assays, and further validated by a quantitative RT-PCR and immunohistochemistry. The correlation between KPNA2 expression in OMGCT and certain clinicopathological features were analyzed. Expression of SALL4, a stem cell marker, was also examined in comparison with KPNA2.
KPNA2 was found to be over-expressed by approximately eight-fold in yolk sac tumors and immature teratomas compared to normal ovarian tissue by microarray assays. Overexpression was detected in yolk sac tumors, immature teratomas, dysgerminomas, embryonal carcinomas, mature teratomas with malignant transformation and mixed ovarian germ cell tumors at both the transcription and translation levels. A positive correlation between KPNA2 and SALL4 expression at both the transcription level (R = 0.5120, P = 0.0125), and the translation level (R = 0.6636, P<0.0001), was presented. Extensive expression of KPNA2 was positively associated with pathologic type, recurrence and uncontrolled, ascitic fluid presence, suboptimal cytoreductive surgery necessity, resistance/refraction to initial chemotherapy, HCG level and SALL4 level in OMGCT patients. KPNA2 was found to be an independent factor for 5-year disease-free survival (DFS) of OMGCT (P = 0.02). The 5-year overall survival (OS) and DFS rate for KPNA2-low expression patients (88% and 79%, n = 48) were significantly higher than the OS and DFS rate for KPNA2-high expression patients (69% and 57.1%, n = 42)(P = 0.0151, P = 0.0109, respectively). The 5-year OS and DFS rate for SALL4-low expression patients (84% and 74%, n = 62) was marginally significantly higher than the high expression patients (78.6% and 71.4%, n = 28)(P = 0.0519, P = 0.0647, respectively).
KPNA2 is a potential candidate molecular marker and important prognostic marker in OMGCT patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Famitinib is a tyrosine kinase inhibitor against multiple targets, including vascular endothelial growth factor receptor 2/3, platelet‐derived growth factor receptor, and stem cell factor ...receptor (c‐kit). Previous studies have demonstrated anti‐tumour activities of famitinib against a wide variety of advanced‐stage solid cancers. We aimed to determine the safety and efficacy of famitinib with concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We also evaluated the feasibility of contrast‐enhanced ultrasound (D‐CEUS) as a predictor of early tumour response to famitinib and to correlate functional parameters with clinical efficacy.
Methods
The trial was conducted in subjects with stage III or IVa‐b NPC using a 3 + 3 design of escalating famitinib doses. Briefly, subjects received 2 weeks of famitinib monotherapy followed by 7 weeks of famitinib plus CCRT. D‐CEUS of the neck lymph nodes was performed at day 0, 8 and 15 after famitinib was administered before starting concurrent chemoradiotherapy. End points included safety, tolerability and anti‐tumour activity.
Results
Twenty patients were enrolled (six each for 12.5, 16.5 and 20 mg and two for 25 mg). Two patients in the 25 mg cohort developed dose‐limiting toxicities, including grade 4 thrombocytopenia and grade 3 hypertension. The most common grade 3/4 adverse events were leukopenia, neutropenia and radiation mucositis. D‐CEUS tests showed that more than 60% of patients achieved a perfusion parameter response after 2 weeks taking famitinib alone, and the parameter response was associated with disease improvement. In the famitinib monotherapy stage, three patients (15%) showed partial responses. The complete response rate was 65% at the completion of treatment and 95% 3 months after the treatment ended. After a median follow‐up of 44 months, the 3‐year progression‐free survival (PFS) and distant metastasis‐free survival were 70% and 75%, respectively. Subjects with a decrease of perfusion parameter response, such as peak intensity decreased at least 30% after 1 week of famitinib treatment, had higher 3‐year PFS (90.9% vs. 44.4%, 95% CI 73.7%–100% vs. 11.9%–76.9%, P < 0.001) than those with an increase or a reduction of less than 30%.
Conclusions
The recommended famitinib dose for phase II trial is 20 mg with CCRT for patients with local advanced NPC. D‐CEUS is a reliable and early measure of efficacy for famitinib therapies. Further investigation is required to confirm the effects of famitinib plus chemoradiotherapy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
NF-κB is a critical link between inflammation and cancer, but whether long non-coding RNAs (lncRNAs) regulate its activation remains unknown. Here, we identify an NF-KappaB Interacting LncRNA ...(NKILA), which is upregulated by NF-κB, binds to NF-κB/IκB, and directly masks phosphorylation motifs of IκB, thereby inhibiting IKK-induced IκB phosphorylation and NF-κB activation. Unlike DNA that is dissociated from NF-κB by IκB, NKILA interacts with NF-κB/IκB to form a stable complex. Importantly, NKILA is essential to prevent over-activation of NF-κB pathway in inflammation-stimulated breast epithelial cells. Furthermore, low NKILA expression is associated with breast cancer metastasis and poor patient prognosis. Therefore, lncRNAs can directly interact with functional domains of signaling proteins, serving as a class of NF-κB modulators to suppress cancer metastasis.
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•NF-κB interacting long noncoding RNA (NKILA) directly blocks IκB phosphorylation•NKILA interacts with NF-κB/IκB to form a stable ternary complex•NKILA is a negative feedback regulator of NF-κB in both resting and activated cells•Decreased NKILA in invasive breast cancer is associated with poor patient outcome
Liu et al. identify an NF-KappaB Interacting LncRNA (NKILA) that binds to NF-κB/IκB complex and represses NF-κB signaling and cancer-associated inflammation. Low NKILA expression is associated with breast cancer metastasis and poor patient prognosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
It is well recognized that metastasis can occur early in the course of lung adenocarcinoma (LAD) development, and yet the molecular mechanisms driving this capability of rapid metastasis remain ...incompletely understood. Here we reported that a long noncoding RNA, LINC00673, was up-regulated in LAD cells. Of note, we first found that LINC00673-v4 was the most abundant transcript of LINC00673 in LAD cells and its expression was associated with adverse clinical outcome of LAD. In vitro and in vivo experiments demonstrated that LINC00673-v4 enhanced invasiveness, migration, and metastasis of LAD cells. Mechanistically, LINC00673-v4 augmented the interaction between DDX3 and CK1e and thus the phosphorylation of dishevelled, which subsequently activated WNT/β-catenin signaling and consequently caused aggressiveness of LAD. Antagonizing LINC00673-v4 suppressed LAD metastasis in vivo. Together, our data suggest that LINC00673-v4 is a driver molecule for metastasis via constitutively activating WNT/β-catenin signaling in LAD and may represent a potential therapeutic target against the metastasis of LAD.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Tumor-derived extracellular vesicles (TEVs) have emerged as promising sources of diagnostic and prognostic biomarkers for nasopharyngeal carcinoma (NPC). However, the lack of high-sensitivity ...analytic methods for ultratrace membrane proteins on TEVs hamper their clinical application of TEVs. Herein, by combining aptamers that specifically bind to protein targets on TEVs, PCR-based exponential amplification and CRISPR/Cas12a real-time DNA detection, we developed a novel technique, termed the aptamer-CRISPR/Cas12a assay, to detect CD109+ and EGFR+ TEVs from cell lines and complex biofluids. The platform enables highly sensitive detection of CD109+ and EGFR+ TEVs at as low as 100 particles/mL with a linear range spanning 6 orders of magnitude (102-108 particles/mL), which was found to be sufficient to effectively detect TEV proteins directly in low-volume (50 μl) samples. Furthermore, clinical serum sample analysis verified that the combination of serum CD109+ and EGFR+ TEV levels yielded high diagnostic accuracy, with an AUC of 0.934 (95% CI: 0.868–1.000), a sensitivity of 84.1% and a specificity of 85.0%, in discriminating NPC from healthy controls. Moreover, the dramatic decrease in both biomarkers in responders after radiotherapy indicated their potential roles in radiotherapy surveillance. Given that the aptamer-CRISPR/Cas12a assay rapidly and conveniently detects ultralow concentrations of CD109+ and EGFR+ TEVs directly in serum, it could be useful in NPC diagnosis and prognosis.
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•A novel approach, called the aptamer-CRISPR/Cas12a assay, was developed.•A highly sensitive, specific and cost-effective method to measure EV surface protein.•Serum CD109+ and EGFR+ EVs as new biomarkers in NPC.•Provided possibility of CRISPR/Cas12a to detect trace surface proteins on EVs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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