Genes and Cancer最新文献

Hepatocellular carcinoma (HCC) is the most common primary liver cancer whose incidence continues to rise in many parts of the world due to a concomitant rise in many associated risk factors, such as alcohol use and obesity. Although early-stage HCC can be potentially curable through liver resection, liver-directed therapies, or transplantation, patients usually present with intermediate to advanced disease, which continues to be associated with a poor prognosis. This is because HCC is a cancer with significant complexities, including substantial clinical, histopathologic, and genomic heterogeneity. However, the scientific community has made a major effort to better characterize HCC in those aspects via utilizing tissue sampling and histological classification, whole genome sequencing, and developing viable animal models. These efforts ultimately aim to develop clinically relevant biomarkers and discover molecular targets for new therapies. For example, until recently, there was only one approved systemic therapy for advanced or metastatic HCC in the form of sorafenib. Through these efforts, several additional targeted therapies have gained approval in the United States, although much progress remains to be desired. This review will focus on the link between characterizing the pathogenesis of HCC with current and future HCC management.

Ewing sarcoma is an aggressive cancer of bone and soft tissue in children. It is characterized by the chromosomal translocation between EWS and an Ets family transcription factor, most commonly FLI1. We recently reported that Ewing sarcoma depends on the autocrine signaling mediated by a cytokine, NELL2. NELL2 signaling stimulates the transcriptional output of EWS-FLI1 through the BAF chromatin remodeling complexes. While studying the impact of NELL2 silencing on Ewing sarcoma, we found that suppression of NELL2 signaling induces the expression of endogenous retroviruses (ERVs) and LINE-1 retrotransposons, an interferon response, and growth arrest. We determined that a histone methyltransferase, EZH2, is the critical downstream target of NELL2 signaling in suppressing ERVs, LINE-1, an interferon response, and growth arrest. We show that EZH2 inhibitors induce ERVs, LINE-1, and an interferon response in a variety of cancer types. These results uncover the role for NELL2-EZH2 signaling in suppressing endogenous virus-like agents and an antiviral response, and suggest the potential utility of EZH2 inhibitors in enhancing anti-tumor immunity.

Dishevelled-1 (DVL-1) mediates Wnt signals critical for development and cellular homeostasis. DVL-1 is also linked with tumorigenesis, however its association with specific breast cancer (BC) subtypes and how it contributes to tumorigenicity remains poorly studied. Herein, using bioinformatics and genomics analyses, we investigate the role of DVL-1 in different molecular subtypes of BC. Our results demonstrate that DVL-1 is highly expressed in triple-negative BC compared to non-cancer tissues and associated with various clinical factors that may contribute to poor prognosis and survival rate. Another critical knowledge gap which remains poorly investigated involves the role of DVL-1 in the nucleus. While the cytoplasmic role of DVL-1 as a signaling hub has been extensively studied, the nuclear role of DVL-1 remains virtually unexplored. Herein for the first time, we have performed ChIP-Seq analyses to identify genomic regions targeted and regulated by DVL-1, thus highlighting its potential role as a regulator of transcription. Furthermore, we observed that DVL-1 peaks co-localize with H3K27me3 and EZH2, a repressive epigenetic mark and a histone methyltransferase respectively. Overall, our findings emphasize the importance of DVL-1 with TNBC-related pathology and identified unexpected gene targets of DVL-1, that may help explain the complexity of aberrant Wnt signaling in cancer.

Cancer is a highly malignant disease, killing approximately 10 million people worldwide in 2020. Cancer patient survival substantially relies on early diagnosis. In this study, we evaluated whether genes involved in glucose metabolism could be used as potential diagnostic markers for cancer. In total, 127 genes were examined for their gene expression levels and pairwise gene correlations. Genes ADH1B and PDHA2 were differentially expressed in most of the 12 types of cancer and five pairs of genes exhibited consistent correlation changes (from strong correlations in normal controls to weak correlations in cancer patients) across all types of cancer. Thus, the two differentially expressed genes and five gene pairs could be potential diagnostic markers for cancer. Further preclinical and clinical studies are warranted to prove whether these genes and/or gene pairs would indeed aid in early diagnosis of cancer.

In 2016, encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). In 2018 the criteria for NIFTP were widened by the inclusion of the complete lack of papillae. Secondary criteria, which include molecular examination, are helpful but not required for NIFTP diagnose. The aim of this study was to assess the molecular background of NIFTP and to answer the question if the aplication of revised criteria for NIFTP diagnosis is associated with the lack of oncogenic mutation. Repeat histopathological assessment of 1117 cases of papillary thyroid carcinoma (PTC) from 2000-2016 was conducted. Using initial (2016) and revised (2018) diagnostic criteria, NIFTP was diagnosed in 23 and 13 patients respectively. 50 tumor genes hotspots mutation analysis was conducted. BRAF ^V600E mutations were detected in patients who fulfilled only initial NIFTP criteria. Other high-risk mutations (TP53) were found in both groups of patients. The application of restrictive, revised diagnostic criteria for NIFTP negates the need for BRAF ^V600E examination, but these tumors still can harbor other high-risk oncogenic mutations nonetheless. Thus, molecular examination should be considered as a necessary step in NIFTP diagnostic process.

Prophylactic cranial irradiation (PCI) can reduce the incidence of brain metastasis and improve overall survival in some patients with acute lymphoblastic leukemia or small-cell lung cancer. We examined the potential effects of PCI in a mouse model of breast cancer brain metastasis. The HER2+ inflammatory breast cancer cell line MDA-IBC3 was labeled with green fluorescent protein and injected via tail-vein into female SCID/Beige mice. Mice were then given 0 Gy or 4 Gy of whole-brain irradiation 2 days before tumor-cell injection or 5 days, 3 weeks, or 6 weeks after tumor-cell injection. Mice were sacrificed 4-weeks or 8-weeks after injection and brain tissues were examined for metastasis by fluorescent stereomicroscopy. In the unirradiated control group, brain metastases were present in 77% of mice at 4 weeks and in 90% of mice at 8 weeks; by comparison, rates for the group given PCI at 5 days after tumor-cell injection were 20% at 4 weeks (p=0.01) and 30% at 8 weeks (p=0.02). The PCI group also had fewer brain metastases per mouse at 4 weeks (p=0.03) and 8 weeks (p=0.006) versus the unirradiated control as well as a lower metastatic burden (p=0.01). Irradiation given either before tumor-cell injection or 3-6 weeks afterward had no significant effect on brain metastases compared to the unirradiated control. These results underscore the importance of timing for irradiating subclinical disease. Clinical whole brain strategies to target subclinical brain disease as safely as possible may warrant further study.

[This corrects the article DOI: 10.18632/genesandcancer.24.].

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal type of cancer. In this study, we undertook a pairwise comparison of gene expression pattern between tumor tissue and its matching adjacent normal tissue for 45 PDAC patients and identified 22 upregulated and 32 downregulated genes. PPI network revealed that fibronectin 1 and serpin peptidase inhibitor B5 were the most interconnected upregulated-nodes. Virtual screening identified bleomycin exhibited reasonably strong binding to both proteins. Effect of bleomycin on cell viability was examined against two PDAC cell lines, AsPC-1 and MIA PaCa-2. AsPC-1 did not respond to bleomycin, however, MIA PaCa-2 responded to bleomycin with an IC₅₀ of 2.6 μM. This implicates that bleomycin could be repurposed for the treatment of PDAC, especially in combination with other chemotherapy agents. In vivo mouse xenograft studies and patient clinical trials are warranted to understand the functional mechanism of bleomycin towards PDAC and optimize its therapeutic efficacy. Furthermore, we will evaluate the antitumor activity of the other identified drugs in our future studies.

The Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) is a more aggressive tumor with 5 years median survival rates after metastasis. Despite successful treatment, unfortunately, the majority of affected patients die. Defects in cell cycle and transcription regulation phases which are governed by cyclin-dependent kinases (CDKs) are the hallmark of many cancers that underpinning the progression of the disease. Therefore, the current study looked at the alteration of six CDKs mRNA expression levels in pre- and postmenopausal lung metastasis BC groups; the majority were HER2+. Two hundred pre-and postmenopausal lung metastasis breast cancer and healthy control blood samples were taken for RNA isolation. Quantitative PCR was done for CDKs mRNA expressions. We observed overexpression of CDK11, CDK12, CDK17, CDK18, and CDK19 in both pre- and postmenopausal groups. However, CDK20 showed progressive downregulation from early to advanced stages in both groups of patients. Collectively, this data revealed that CDKs overexpression levels may predict BC disease progression and provide further rationale for novel anticancer strategies for HER2+ BC cancers.