Multiple studies suggested using different miRNAs as biomarkers for prognosis of hepatocellular carcinoma (HCC). We aimed to assemble a miRNA expression database from independent datasets to enable an independent validation of previously published prognostic biomarkers of HCC. A miRNA expression database was established by searching the TCGA (RNA-seq) and GEO (microarray) repositories to identify miRNA datasets with available expression and clinical data. A PubMed search was performed to identify prognostic miRNAs for HCC. We performed a uni- and multivariate Cox regression analysis to validate the prognostic significance of these miRNAs. The Limma R package was applied to compare the expression of miRNAs between tumor and normal tissues. We uncovered 214 publications containing 223 miRNAs identified as potential prognostic biomarkers for HCC. In the survival analysis, the expression levels of 55 and 84 miRNAs were significantly correlated with overall survival in RNA-seq and gene chip datasets, respectively. The most significant miRNAs were hsa-miR-149, hsa-miR-139, and hsa-miR-3677 in the RNA-seq and hsa-miR-146b-3p, hsa-miR-584, and hsa-miR-31 in the microarray dataset. Of the 223 miRNAs studied, the expression was significantly altered in 102 miRNAs in tumors compared to normal liver tissues. In summary, we set up an integrated miRNA expression database and validated prognostic miRNAs in HCC.
Background: Potential prognostic biomarker candidates for hepatocellular carcinoma (HCC) are abundant, but their generalizability is unexplored. We cross-validated markers of overall survival (OS) and vascular invasion in independent datasets. Methods: The literature search yielded 318 genes related to survival and 52 related to vascular invasion. Validation was performed in three datasets (RNA-seq, n = 371; Affymetrix arrays, n = 91; Illumina gene chips, n = 135) by uni- and multivariate Cox regression and Mann–Whitney U-test, separately for Asian and Caucasian patients. Results: One hundred and eighty biomarkers remained significant in Asian and 128 in Caucasian subjects at p < 0.05. After multiple testing correction BIRC5 (p = 1.9 × 10−10), CDC20 (p = 2.5 × 10−9) and PLK1 (p = 3 × 10−9) endured as best performing genes in Asian patients; however, none remained significant in the Caucasian cohort. In a multivariate analysis, significance was reached by stage (p = 0.0018) and expression of CENPH (p = 0.0038) and CDK4 (p = 0.038). KIF18A was the only gene predicting vascular invasion in the Affymetrix and Illumina cohorts (p = 0.003 and p = 0.025, respectively). Conclusion: Overall, about half of biomarker candidates failed to retain prognostic value and none were better than stage predicting OS. Impact: Our results help to eliminate biomarkers with limited capability to predict OS and/or vascular invasion.
The hallmarks of cancer capture the most essential phenotypic characteristics of malignant transformation and progression. Although numerous factors involved in this multi-step process are still unknown to date, an ever-increasing number of mutated/altered candidate genes are being identified within large-scale cancer genomic projects. Therefore, investigators need to be aware of available and appropriate techniques capable of determining characteristic features of each hallmark. We review the methods tailored to experimental cancer researchers to evaluate cell proliferation, programmed cell death, replicative immortality, induction of angiogenesis, invasion and metastasis, genome instability, and reprogramming of energy metabolism. Selecting the ideal method is based on the investigator's goals, available equipment and also on financial constraints. Multiplexing strategies enable a more in-depth data collection from a single experiment - obtaining several results from a single procedure reduces variability and saves time and relative cost, leading to more robust conclusions compared to a single end point measurement. Each hallmark possesses characteristics that can be analyzed by immunoblot, RT-PCR, immunocytochemistry, immunoprecipitation, RNA microarray or RNA-seq. In general, flow cytometry, fluorescence microscopy, and multiwell readers are extremely versatile tools and, with proper sample preparation, allow the detection of a vast number of hallmark features. Finally, we also provide a list of hallmark-specific genes to be measured in transcriptome-level studies. Although our list is not exhaustive, we provide a snapshot of the most widely used methods, with an emphasis on methods enabling the simultaneous evaluation of multiple hallmark features.
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Development of drug resistance is a major factor limiting the continued success of cancer chemotherapy. To overcome drug resistance, understanding the underlying mechanism(s) is essential. We found that HOXC10 is over-expressed in primary carcinomas of the breast, and even more significantly in distant metastasis arising after failed chemotherapy. High HOXC10 expression correlates with shorter recurrence-free and overall survival in patients with estrogen receptor (ER)-negative breast cancer undergoing chemotherapy. We found that HOXC10 promotes survival in cells treated with doxorubicin, paclitaxel or carboplatin by suppressing apoptosis and upregulating NF-κB. Overexpressed HOXC10 increases S-phase specific DNA damage repair by homologous recombination (HR) and checkpoint recovery in cells at three important phases. For double strand break repair, HOXC10 recruits HR proteins at sites of DNA damage. It enhances resection and lastly, it resolves stalled replication forks, leading to initiation of DNA replication following DNA damage. We show that HOXC10 facilitates, but is not directly involved in DNA damage repair mediated by HR. HOXC10 achieves integration of these functions by binding to, and activating cyclin dependent kinase, CDK7, which regulates transcription by phosphorylating the carboxy-terminal domain of RNA polymerase II. Consistent with these findings, inhibitors of CDK7 reverse HOXC10-mediated drug resistance in cultured cells. Blocking HOXC10 function, therefore, presents a promising new strategy to overcome chemotherapy resistance in breast cancer.
The introduction of trastuzumab for anti-HER2 therapy dramatically changed the clinical outcome for HER2 (ERBB2, neu) positive breast cancer patients. Today, patients eligible for trastuzumab are selected using HER2 expression/amplification status of the primary tumor. However, acquired and inherent resistance to anti-HER2 therapy in these patients poses a significant challenge, and better patient stratification will be needed to improve clinical response. Here, we provide a wide-ranging overview of potential biomarkers capable of stratifying patients regarding their response to trastuzumab. These include HER2 amplification, impaired access to the binding site (p95HER2, Δ16HER-2, MUC4), augmented signaling through other ERBB family receptors (HER1, HER3, HER4) and their ligands, activation of HER2 targets by alternate heterodimers (EphA2, IGF-1R, GDF15, MUC1*), signaling triggered by downstream members (PIK3CA, PTEN, SRC, mTOR), altered expression of cell cycle and apoptotic regulators (CDKs, p27(kip1), Bcl-2), hormone receptor status, resistance to antibody-dependent cellular cytotoxicity (FcγR), and altered miRNA expression signatures. Multigenic molecular profile analyses have revealed further genes not directly associated with classical oncogenic pathways. Although numerous biomarkers have shown promise in pre-clinical studies, many have delivered controversial results when evaluated in clinical trials. One of the keys for targeting ERBB2 will be to consider the entire ERBB family and downstream associated pathways responsible for the malignant transformation. The heterogeneity of the disease is likely to represent a significant obstacle to accurately predicting the course of resistance. The future most probably involves the incorporation of multiple biomarkers into a unified predictor enabling selection of patients for superior targeted drug administration.
Childhood medulloblastomas (MB) are heterogeneous and are divided into four molecular subgroups. The provisional non-wingless-activated (WNT)/non-sonic hedgehog-activated (SHH) category combining group 3 and group 4 represents over two thirds of all MBs, coupled with the highest rates of metastases and least understood pathology. The molecular era expanded our knowledge about molecular aberrations involved in MB tumorigenesis, and here, we review processes leading to non-WNT/non-SHH MB formations.The heterogeneous group 3 and group 4 MBs frequently harbor rare individual genetic alterations, yet the emerging profiles suggest that infrequent events converge on common, potentially targetable signaling pathways. A mutual theme is the altered epigenetic regulation, and in vitro approaches targeting epigenetic machinery are promising. Growing evidence indicates the presence of an intermediate, mixed signature group along group 3 and group 4, and future clarifications are imperative for concordant classification, as misidentifying patient samples has serious implications for therapy and clinical trials.To subdue the high MB mortality, we need to discern mechanisms of disease spread and recurrence. Current preclinical models do not represent the full scale of group 3 and group 4 heterogeneity: all of existing group 3 cell lines are MYC-amplified and most mouse models resemble MYC-activated MBs. Clinical samples provide a wealth of information about the genetic divergence between primary tumors and metastatic clones, but recurrent MBs are rarely resected. Molecularly stratified treatment options are limited, and targeted therapies are still in preclinical development. Attacking these aggressive tumors at multiple frontiers will be needed to improve stagnant survival rates.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.