Abstract Breast cancer is a very complex and heterogeneous disease with variable molecular mechanisms of carcinogenesis and clinical behaviors. The identification of prognostic risk factors may enable effective diagnosis and treatment of breast cancer. In particular, numerous gene-expression-based prognostic signatures were developed and some of them have already been applied into clinical trials and practice. In this study, we summarized several representative gene-expression-based signatures with significant prognostic value and separately assessed their ability of prognosis prediction in their originally targeted populations of breast cancer. Notably, many of the collected signatures were originally designed to predict the outcomes of estrogen receptor positive (ER+) patients or the whole breast cancer cohort; there are no typical signatures used for the prognostic prediction in a specific population of patients with the intrinsic subtype. We thus attempted to identify subtype-specific prognostic signatures via a computational framework for analyzing multi-omics profiles and patient survival. For both the discovery and an independent data set, we confirmed that subtype-specific signature is a strong and significant independent prognostic factor in the corresponding cohort. These results indicate that the subtype-specific prognostic signature has a much higher resolution in the risk stratification, which may lead to improved therapies and precision medicine for patients with breast cancer.
Fibroblast growth factor receptor 2 (FGFR2) has been proved to be a significant prognostic factor and a potential therapeutic target in several types of cancer, including gastric cancer. FGFR2 consists two isoforms: FGFR2-IIIb and FGFR2-IIIc, which can be stimulated by different ligands and trigger different downstream signaling pathways. As a specific ligand to FGFR2-IIIb, fibroblast growth factor 10 (FGF10) is expressed in the gastric mesenchyme cell and is involved in stomach development and morphogenesis, but its expression and clinical significance is not well elucidated in gastric cancer. We analyzed FGF10 expression by immunohistochemistry in 178 samples of gastric adenocarcinoma (134 male and 44 female patients, with the average age of 63.2 years old and the average follow-up of 21.6 months). Using the arbitrarily scoring method based on positive cell percentage and staining intensity, we sub-divided the patients into FGF10 high-expression group (58 patients) and low-expression group (120 patients). We thus found that FGF10 expression is significantly associated with lymph node invasion (P = 0.004) and distant metastasis (P = 0.032). Importantly, FGF10 expression is an independent unfavorable prognostic factor (P = 0.042). Moreover, FGF10 knockdown significantly decreased the migration of cultured gastric adenocarcinoma cells, suggesting that FGF10 could promote the invasion of gastric adenocarcinoma. In conclusion, FGF10 expression was identified as a poor prognostic biomarker in gastric adenocarcinoma, and FGF10 could promote the invasion of gastric cancer cells. We suggest that FGF10 could be a potential and promising drug target in gastric adenocarcinoma.
Abstract Combining lentiviral (LV) delivered shRNA against NANOG (shNG-1) or NANOGP8 (shNp8-1) with BH3 mimetics (ABT-737 and ABT-199) was undertaken to determine whether inhibition of NANOG/NANOGP8 enhances the cytotoxic effect of these BH3 mimetics in Colorectal Cancer (CRC) cells. NANOG is a key transcription factor important for both pluripotency in embryonic stem cells and malignant transformation and progression of colorectal carcinoma (CRC). Inhibition of NANOG or its paralog NANOGP8 reduces the proliferation, stemness and tumorigenicity of CRC cells. The cytotoxic potential of ABT-737 or ABT-199, as single agents, was tested in the CRC cell lines- Clone A, CX-1 and LS174T that have high levels of anti-apoptotic BCL-2 family proteins. Treatment with ABT-737 or ABT-199 showed variable cytotoxicity in the three CRC lines with LS174T being the most resistant. Inhibition of NANOG and NANOGP8 with LVshNG-1 or LVshNp8-1 in these cell lines decreased expression of MCL-1. The combination of LVshNG-1 and/or LVshNp8-1, with ABT-737 produced enhanced killing of the CRC cells by caspase-dependent apoptosis. These results were were confirmed when LV shNG-1 or LV shNp8-1 was used in combination with ABT-199. siRNA targeting MCL-1 reproduced the effects of NANOG/NANOGP8 inhibition. The CRC cells that survived the combination treatment showed lower regrowth potential and reduced clonogenicity when re-plated in fresh media. These results demonstrate that inhibition of NANOGP8 or NANOG enhances the cytotoxicity of BH3 mimetics that target BCL-2 family members through inhibition of MCL-1 expression. Citation Format: Abid R. Mattoo, Jingyu Zhang, Luis A. Espinoza, Snorri S. Thorgeirsson, J. M. Jessup. Inhibition of NANOG/NANOGP8 downregulates MCL-1 in colorectal cancer (CRC) cells, enhances the efficacy of BH3 mimetics and inhibits clonogenicity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 339. doi:10.1158/1538-7445.AM2014-339
Abstract Triple-negative breast cancer (TNBC) has an aggressive clinical course and paclitaxel (PTX)-based chemotherapy is still its main therapeutic drug. Metadherin (MTDH) acts as an oncogene by regulating cellular transformation, proliferation, invasion, metastasis, chemoresistance, and angiogenesis. This study aimed to investigate whether TNBC chemosensitivity to PTX was related to the MTDH/AKT/GSK-3β pathway. We found that higher expression of MTDH or AKT showed poorer DFS and lower Miller–Payne grad. MTDH promoted cell proliferation and increased p-AKT and pGSK3β expression in TNBC cells. Notably, suppression of AKT terminated MTDH overexpression-induced cell proliferation and apoptosis. MTDH knockdown or AKT inhibitor MK2206 could reduce the p-AKT and pGSK3β ratio, reduced cell viability and proliferation, increased cell apoptosis, and increased chemosensitivity to PTX. In vivo , xenograft tumor of an MTDH knockdown + MK2206 group treated with PTX was the smallest compared to other groups. These results showed that MTDH inhibits TNBC chemosensitivity to PTX via activating AKT/GSK-3β signaling pathway, while inhibiting both MTDH and AKT can significantly increase the sensitivity.
Y-box-binding protein-1 (YB-1) is aberrantly expressed in a variety of cancers. However, the biological functional role of YB-1 in glioma is not yet clear.The expression of MDM2 and YB-1 was analyzed by real time PCR. Overexpression and knockdown of YB-1 in glioma cells were created by transfection of pcDNA-YB-1 and siRNA against YB-1, respectively. Cell viability was performed by CCK8 assay.Our findings showed that glioma tissues had higher expressions of YB-1 than that in cancer-free tissues in 54 glioma patients, which were also positively correlated with Murine MDM2 expression. Overexpression of YB-1 or MDM2 renders a drug resistance feature in glioma cell exposed to temozolomide (TMZ), by directly targeting p53. Genetic or chemical inhibition of MDM2 significantly blocked YB-1-modulated response of glioma cells to TMZ. Moreover, inhibition of YB-1 or MDM2 reduced glioma cells metastasis and mortality in mice.YB-1 facilitates the resistance of glioma cells to TMZ by direct activation of MDM2/p53 signaling and represents a promising molecular target for glioma treatment.
All results were analyzed using the Statistical Package for the Social Sciences version 20.0 (IBM Corporation, Armonk, NY, USA). The results of Schoenfeld residuals method were analyzed using the R 4.2.2 software and survminer package.
Objective: This study explores the potential causal association between proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors and tumor development using Mendelian randomization (MR) based on drug targets. Methods: Instrumental variables within ±100 kb of the PCSK9 gene locus, impacting low-density lipoprotein cholesterol (LDL-C), were utilized for MR analysis. Coronary heart disease (CHD) served as a positive control to validate the causal relationship between PCSK9 inhibitors and various cancers. We employed reverse MR to address the reverse causation concerns. Data from positive controls and tumors were sourced from OpenGWAS. Results: MR analysis suggested a negative causal relationship between PCSK9 inhibitors and both breast and lung cancers (95%CIBreast cancer 0.81~0.99, p = 2.25 × 10−2; 95%CILung cancer 0.65~0.94, p = 2.55 × 10−3). In contrast, a positive causal link was observed with gastric, hepatic, and oral pharyngeal cancers and cervical intraepithelial neoplasia (95%CIGastric cancer 1.14~1.75, p = 1.88 × 10−2; 95%CIHepatic cancer 1.46~2.53, p = 1.16 × 10−2; 95%CIOral cavity and pharyngeal cancer 4.49~6.33, p = 3.36 × 10−4; 95%CICarcinoma in situ of cervix uteri 4.56~7.12, p = 6.91 × 10−3), without heterogeneity or pleiotropy (p > 0.05). Sensitivity analyses confirmed these findings. The results of MR of drug targets suggested no causal relationship between PCSK9 inhibitors and bladder cancer, thyroid cancer, pancreatic cancer, colorectal cancer, malignant neoplasms of the kidney (except for renal pelvis tumors), malignant neoplasms of the brain, and malignant neoplasms of the esophagus (p > 0.05). Reverse MR helped mitigate reverse causation effects. Conclusions: The study indicates a divergent causal relationship of PCSK9 inhibitors with certain cancers. While negatively associated with breast and lung cancers, a positive causal association was observed with gastric, hepatic, oral cavity, and pharyngeal cancers and cervical carcinoma in situ. No causal links were found with bladder, thyroid, pancreatic, colorectal, certain kidney, brain, and esophageal cancers.
Abstract Although anti-angiogenic therapy has emerged as a leading modality in treating human cancer, further improvements in the duration and frequency of clinical response of various human cancers remain important clinical needs. Maturity of the tumor vasculature has been identified as one of the major determinants of response of cancers to anti-angiogenic treatments. We have developed and optimized the application of a quantitative, high throughput, hyper-plexed, fluorescence imaging technology to refine our understanding of the complexity of vascular phenotypes in various human malignancies. The technology was used to quantify tumor blood vessels and expression of thirteen proteins of known roles in blood vessel biology in single sections from archival primary tumor tissues from 64 prostate cancer patients. CD31 was used to segment vascular objects in each image. CD31 and CD34 endothelial cell staining, SMA pericyte staining, and collagen IV basement membrane staining were used to classify detected vessels using K-means cluster analysis. Segmented vessels were clustered into 2-20 cluster sets, and the reproducibility of vessel classification of each cluster set was determined using the consensus clustering algorithm. A six cluster set that reflected biologically relevant tumor vascular subsets with high consensus clustering concordance was selected for further analysis. Clusters consistent with different stages of vessel development were obtained, including clusters with CD34 high/SMA low and CD34 low/SMA high profiles, reflecting immature and mature vascular phenotypes. Additional clusters representing phenotypes consistent with transitional vascular developmental stages were also identified. Nine additional proteins involved in angiogenesis were also quantified in each vessel and expression profiles for each cluster were determined. The enrichment of blood vessel clusters was then analyzed for each patient. This revealed differential patterns of vascular maturity phenotypes in the prostate cancer tissues analyzed. We have demonstrated that high-throughput, quantitative characterization of vascular maturity phenotypes is feasible in human cancer tissue specimens. Such immunofluorescence hyper-plex profiling of vascular-related proteins has the potential to illuminate the complex biology of tumor angiogenesis and to enable novel approaches for patient tailoring in clinical trials of anti-angiogenic therapeutics. Citation Format: Chris Sevinsky, Alberto Santamaria-Pang, Jingyu Zhang, Christina Lowes, Dipen Sangurdekar, Beverly Falcon, Qing Li, Bronek Pytowski, Laura Benjamin, Jeremy Graff, Fiona Ginty, Aejaz Nasir, Mark T. Uhlik. Quantification of biologically relevant vascular phenotypes in human prostate cancer: automated image analysis using hyperplexed immunofluorescence. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1709. doi:10.1158/1538-7445.AM2015-1709
Abstract Cholangiocarcinoma is an aggressive malignancy with rapid invasion, metastasis and poor prognosis, however, the mechanism mediating its cholangiocarcinoma development needs further investigation. Here, we demonstrate that decreased miR‐138 in tumor tissues is related to the poor prognosis in patients, and that miR‐138 mediates sorafenib‐induced cell survival in cholangiocarcinoma cells. Moreover, miR‐138 negatively regulates SOX4 expression by specifically targeting its 3′ untranslated region (3′ UTR). As per our results, overexpression of SOX4 reversed sorafenib‐induced changes in cell viability and apoptosis. Furthermore, the elevated levels of SOX4 in the tumor tissues that correlated with poor prognosis. Overall, the present study reveals that miR‐138/SOX4 is involved in sorafinib‐mediated cell survival in cholangiocarcinoma cells, and is associated with poor prognosis.
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