Despite effective strategies, resistance in HER2+ breast cancer remains a challenge. While the mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2+ models, its potential role in resistance to HER2-targeted therapy is unknown. Parental HER2+ breast cancer cells and their lapatinib-resistant and lapatinib + trastuzumab–resistant derivatives were used for this study. MVA activity was found to be increased in lapatinib-resistant and lapatinib + trastuzumab–resistant...
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Clinical data suggest that many malignant cancers are associated with hypercalcemia. Hypercalcemia can facilitate the proliferation and metastasis of gastric and colon tumors, and has been considered a hallmark of end-stage disease. However, it has also been reported that dietary calcium or vitamin D supplementation could reduce the risk of many types of cancers. In particular, the intestines can absorb considerable amounts of calcium via Ca2+-permeable ion channels, and hypercalcemia is common in...
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EMT is a pivotal mechanism involved in tumor metastasis, which is the leading cause of poor prognosis for hepatocellular carcinoma (HCC). Sirtuin family members function as NAD+-dependent deacetylases that are essential for tumor metastasis and epithelial–mesenchymal transition (EMT). However, no causal association has been established between Sirtuin6 (SIRT6) and HCC metastasis. SIRT6 expression pattern and its association with HCC metastasis were investigated by informatic analysis, and verified...
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The incidence of treatment-related neuroendocrine prostate cancer (t-NEPC) is rising as more potent drugs targeting the androgen signaling axis are clinically implemented. Neuroendocrine transdifferentiation (NEtD), an putative initial step in t-NEPC development, is induced by androgen-deprivation therapy (ADT) or anti-androgens, and by activation of the β2-adrenergic receptor (ADRB2) in prostate cancer cell lines. Thus, understanding whether ADRB2 is involved in ADT-initiated NEtD may assist in...
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ZEB1 (a positive enhancer) and KLF5 (a negative silencer) affect transcription factors and play inherently conserved roles in tumorigenesis and multidrug resistance. In humans, the rs2295080T-allele at the mTOR promoter locus has been associated with human cancer risk; however, the 63 bp spacing of another SNP rs2295079 has not been identified. Here, we discovered, for the first time, that rs2295079 (-78C/G) and rs2295080 (-141G/T) formed linkage haplotypes, with Ht1 (-78C/-141G) and Ht2 (-78G/-141T)...
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Intestinal-type gastric cancer often results from Helicobacter pylori infection through intestinal metaplasia, a transdifferentiated premalignant phenotype. Because H. pylori virulence factor CagA has been associated with aberrant expression of the transcription factor CDX1, which regulates intestinal differentiation, we explored its relationship with H. pylori infection and function during gastric carcinogenesis in normal gastric epithelial cells and gastric cancer cell lines. Infection of HFE 145...
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RNA polymerase I (RNA Pol. I) activity is consistently expanded in multiplying cells to continue the expanded interest for ribosome generation and protein synthesis, which are fundamental for cell development and division. Thus, selective inhibitors of RNA Pol. I may offer a general helpful intends to block cancer cell multiplication. Hernandonine, isolated from the root wood of Hernandia nymphaeifolia, causes rearrangement of nucleolar proteins consistent with segregation of the nucleolus, a hallmark...
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STAT3 is constitutively activated in many malignant tumor types and plays an important role in multiple aspects of cancer aggressiveness. In this study, we found that estrogen-related receptor α (ERR-α) correlating with STAT3 was highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues, which was associated with both the pathologic stage and prognosis of patients with TNBC. In vitro studies showed that ERR-α promoted TNBC cell migration and invasion, which was regulated by...
09:05
Drug resistance continues to be a major obstacle of effective therapy for colorectal cancer, leading to tumor relapse or treatment failure. Cancer stem cells (CSC) or tumor-initiating cells are a subpopulation of tumor cells which retain the capacity for self-renewal and are suggested to be implicated in drug resistance. LGR5 is highly expressed in colorectal cancer and marks CSCs that drive tumor growth and metastasis. LGR5(+) CSCs cells were shown to interconvert with more drug-resistant LGR5(–)...
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ZEB1 has intrinsic oncogenic functions that control the epithelial-to-mesenchymal transition (EMT) of cancer cells, impacting tumorigenesis from its earliest stages. By integrating microenvironment signals and being implicated in feedback regulatory loops, ZEB1 appears to be a central switch that determines EMT and metastasis of cancer cells. Here, we found that ZEB1 collaborates with ELK3, a ternary complex factor belonging to the ETS family, to repress E-cadherin expression. ZEB1 functions as a...
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The epidermal growth factor receptor (EGFR) is overexpressed in numerous solid tumors and is the subject of extensive therapeutic efforts. Much of the research on EGFR is focused on protein dynamics and downstream signaling; however, few studies have explored its transcriptional regulation. Here, we identified two enhancers (CE1 and CE2) present within the first intron of the EGFR gene in models of glioblastoma (GBM) and head and neck squamous cell carcinoma (HNSCC). CE1 and CE2 contain open chromatin...
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High-grade serous ovarian cancer (HGSOC) is often sensitive to initial treatment with platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. To systematically identify genes modulating chemotherapy response, we performed pooled functional genomic screens in HGSOC cell lines treated with cisplatin, paclitaxel, or cisplatin plus paclitaxel. Genes in the intrinsic pathway of apoptosis were among the top candidate resistance genes in both gain-of-function...
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Nuclear receptor 4A1 (NR4A1, Nur77) is overexpressed in rhabdomyosarcoma (RMS), and inactivation of NR4A1 (siNR4A1) or treatment with the NR4A1 antagonist 1,1-bis(3'-indoly)-1-(p-hydroxy-phenyl)methane (DIM-C-pPhOH) has antiproliferative and proapoptotic effects on RMS cells. However, the mechanism by which NR4A1 inhibition exerts these effects is poorly defined. Here, we report that NR4A1 silencing or inhibition resulted in accumulation of reactive oxygen species (ROS) and ROS-dependent induction...
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Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer and the major cause of mortality for individuals with von Hippel-Lindau (VHL) disease. ccRCC is characterized most frequently by inactivation of VHL tumor suppressor protein that mediates degradation of the alpha subunit of the hypoxia-inducible factor (HIF) transcription factor family. HIF has been implicated in disease progression and the aim of this study was to identify novel HIF target genes that may contribute...
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Despite the worldwide approval of three generations of EGFR tyrosine kinase inhibitors (TKI) for advanced non–small cell lung cancers with EGFR mutations, no TKI with a broad spectrum of activity against all clinically relevant mutations is currently available. In this study, we sought to evaluate a covalent mutation-specific EGFR TKI, TAS6417 (also named CLN-081), with the broadest level of activity against EGFR mutations with a prevalence of ≥1%. Lung cancer and genetically engineered cell lines,...
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Multiple myeloma (MM) is a plasma cell neoplasia commonly treated with proteasome inhibitors such as bortezomib. Although bortezomib has demonstrated enhanced survival benefit, some patients relapse and subsequently develop resistance to such therapy. Here, we investigate the mechanisms underlying relapse and refractory MM following bortezomib treatment. We show that bortezomib-exposed proinflammatory macrophages promote an enrichment of MM-tumor-initiating cells (MM-TIC) both in vitro and in vivo....
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