Molecular Oncology
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Molecular diversity in ductal carcinoma <i>in situ</i> (DCIS) and early invasive breast cancer Abstract Ductal carcinoma in situ (DCIS) is a non‐invasive form of breast cancer where cells restricted to the ducts exhibit an atypical phenotype. Some DCIS lesions are believed to rapidly transit to invasive ductal carcinomas (IDCs), while others remain unchanged. Existing classification systems for DCIS fail to identify those lesions that transit to IDC. We studied gene expression patterns of 31 pure DCIS, 36 pure invasive cancers and 42 cases of mixed diagnosis (invasive cancer with an in situ component) using Agilent Whole Human Genome Oligo Microarrays 44k. Six normal breast tissue samples were also included as controls. qRT‐PCR was used for validation. All DCIS and invasive samples could be classified into the “intrinsic” molecular subtypes defined for invasive breast cancer. Hierarchical clustering establishes that samples group by intrinsic subtype, and not by diagnosis. We observed heterogeneity in the transcriptomes among DCIS of high histological grade and identified a distinct subgroup containing seven of the 31 DCIS samples with gene expression characteristics more similar to advanced tumours. A set of genes independent of grade, ER‐status and HER2‐status was identified by logistic regression that univariately classified a sample as belonging to this distinct DCIS subgroup. qRT‐PCR of single markers clearly separated this DCIS subgroup from the other DCIS, and contains samples from several histopathological and intrinsic molecular subtypes. The genes that differentiate between these two types of DCIS suggest several processes related to the re‐organisation of the microenvironment. This raises interesting possibilities for identification of DCIS lesions both with and without invasive characteristics, which potentially could be used in clinical assessment of a woman's risk of progression, and lead to improved management that would avoid the current over‐ and under‐treatment of patients.
Molecular Oncology - Tập 4 Số 4 - Trang 357-368 - 2010
Exosome‐delivered circRNA promotes glycolysis to induce chemoresistance through the miR‐122‐PKM2 axis in colorectal cancer Malignant tumors, including colorectal cancer (CRC), usually rely on ATP generation through aerobic glycolysis for both rapid growth and chemotherapy resistance. The M2 isoform of pyruvate kinase (PKM2) has a key role in catalyzing glycolysis, and PKM2 expression varies even within a single tumor. In this study, we confirmed that expression of PKM2 is heterogeneous in CRC cells, namely high in oxaliplatin‐resistant cells but relatively low in sensitive cells, and found that chemoresistant cells had enhanced glycolysis and ATP production. In addition, we report a PKM2‐dependent mechanism through which chemosensitive cells may gradually transform into chemoresistant cells. The circular RNA hsa_circ_0005963 (termed ciRS‐122 in this study), which was determined to be a sponge for the PKM2‐targeting miR‐122, was positively correlated with chemoresistance. In vitro and in vivo studies showed that exosomes from oxaliplatin‐resistant cells delivered ciRS‐122 to sensitive cells, thereby promoting glycolysis and drug resistance through miR‐122 sponging and PKM2 upregulation. Moreover, si‐ciRS‐122 transported by exosomes could suppress glycolysis and reverse resistance to oxaliplatin by regulating the ciRS‐122–miR‐122–PKM2 pathway in vivo . Exosomes derived from chemoresistant CRC cells could transfer ciRS‐122 across cells and promote glycolysis to reduce drug susceptibility in chemosensitive cells. This intercellular signal delivery suggests a potential novel therapeutic target and establishes a foundation for future clinical applications in drug‐resistant CRC.
Molecular Oncology - Tập 14 Số 3 - Trang 539-555 - 2020
Identification of major factors associated with failed clinical molecular oncology testing performed by next generation sequencing (NGS) Purpose DNA analysis by NGS has become important to direct the clinical care of cancer patients. However, NGS is not successful in all cases, and the factors responsible for test failures have not been systematically evaluated. Materials and methods A series of 1528 solid and hematolymphoid tumor specimens was tested by an NGS comprehensive cancer panel during 2012–2014. DNA was extracted and 2×101 bp paired‐end sequence reads were generated on cancer‐related genes utilizing Illumina HiSeq and MiSeq platforms. Results Testing was unsuccessful in 343 (22.5%) specimens. The failure was due to insufficient tissue (INST) in 223/343 (65%) cases, insufficient DNA (INS‐DNA) in 99/343 (28.9%) cases, and failed library (FL) in 21/343 (6.1%) cases. 87/99 (88%) of the INS‐DNA cases had below 10 ng DNA available for testing. Factors associated with INST and INS‐DNA failures were site of biopsy (SOB) and type of biopsy (TOB) (both p < 0.0001), and clinical setting of biopsy (CSB, initial diagnosis or recurrence) (p < 0.0001). Factors common to INST and FL were age of specimen (p ≤ 0.006) and tumor viability (p ≤ 0.05). Factors common to INS‐DNA and FL were DNA purity and DNA degradation (all p ≤ 0.005). In multivariate analysis, common predictors for INST and INS‐DNA included CSB (p = 0.048 and p < 0.0001) and TOB (both p ≤ 0.003), respectively. SOB (p = 0.004) and number of cores (p = 0.001) were specific for INS‐DNA, whereas TOB and DNA degradation were associated with FL (p = 0.04 and 0.02, respectively). Conclusions Pre‐analytical causes (INST and INS‐DNA) accounted for about 90% of all failed cases; independent of test design. Clinical setting; site and type of biopsy; and number of cores used for testing all correlated with failure. Accounting for these factors at the time of tissue biopsy acquisition could improve the analytic success rate.
Molecular Oncology - Tập 9 - Trang 1737-1743 - 2015
MicroRNA and cancer With the advent of next generation sequencing techniques a previously unknown world of non‐coding RNA molecules have been discovered. Non‐coding RNA transcripts likely outnumber the group of protein coding sequences and hold promise of many new discoveries and mechanistic explanations for essential biological phenomena and pathologies. The best characterized non‐coding RNA family consists in humans of about 1400 microRNAs for which abundant evidence have demonstrated fundamental importance in normal development, differentiation, growth control and in human diseases such as cancer. In this review, we summarize the current knowledge and concepts concerning the involvement of microRNAs in cancer, which have emerged from the study of cell culture and animal model systems, including the regulation of key cancer‐related pathways, such as cell cycle control and the DNA damage response. Importantly, microRNA molecules are already entering the clinic as diagnostic and prognostic biomarkers for patient stratification and also as therapeutic targets and agents.
Molecular Oncology - Tập 6 Số 6 - Trang 590-610 - 2012
HRD1 inhibits fatty acid oxidation and tumorigenesis by ubiquitinating CPT2 in triple‐negative breast cancer Dependence on glutamine and acceleration of fatty acid oxidation (FAO) are both metabolic characteristics of triple‐negative breast cancer (TNBC). With the rapid growth of tumors, accelerated glutamine catabolism depletes local glutamine, resulting in glutamine deficiency. Studies have shown that the use of alternative energy sources, such as fatty acids, enables tumor cells to continue to proliferate rapidly in a glutamine‐deficient microenvironment. However, the detailed mechanisms behind this metabolic change are still unclear. Herein, we identified HRD1 as a regulatory protein for FAO that specifically inhibits TNBC cell proliferation under glutamine‐deficient conditions. Furthermore, we observed that HRD1 expression is significantly downregulated under glutamine deprivation and HRD1 directly ubiquitinates and stabilizes CPT2 through K48‐linked ubiquitination. In addition, the inhibition of CPT2 expression dramatically suppresses TNBC cell proliferation mediated by HRD1 knockdown in vitro and in vivo . Finally, we found that the glutaminase inhibitor CB839 significantly inhibited TNBC cell tumor growth, but not in the HRD1 knock‐downed TNBC cells. These findings provide an invaluable insight into HRD1 as a regulator of lipid metabolism and have important implications for TNBC therapeutic targeting.
Molecular Oncology - Tập 15 Số 2 - Trang 642-656 - 2021
KLF4 overexpression and apigenin treatment down regulated anti‐apoptotic Bcl‐2 proteins and matrix metalloproteinases to control growth of human malignant neuroblastoma SK‐N‐DZ and IMR‐32 cells Neuroblastoma is a childhood tumor that arises from immature neuroblasts of the sympathetic nervous system. Krüpple‐like factor 4 (KLF4) is a transcription factor, the precise function of which in neuroblastoma is unclear. We examined the effects of KLF4 overexpression and apigenin (APG) treatment in human malignant neuroblastoma SK‐N‐DZ and IMR‐32 cell lines. KLF4 overexpression in both SK‐N‐DZ and IMR‐32 cell lines was confirmed by laser scanning immunofluorescent confocal microscopy and Western blotting. We found that 100 nM KLF4 plasmid and 25 μM APG synergistically inhibited the growth of SK‐N‐DZ and IMR‐32 cells. We also found increase in KLF4 expression in response to treatment with various concentrations of APG. Combination of KLF4 plasmid and APG treatment significantly increased the amounts of apoptosis in both cell lines when compared with control vector or single treatment. We also noticed that the combination therapy decreased expression of the anti‐apoptotic proteins Bcl‐2 and Mcl‐1, increased expression of the pro‐apoptotic proteins Bax, Noxa, and Puma, upregulated p53, and caused activation of caspase‐3 for cleavage of the inhibitor of caspase‐activated DNase (ICAD) leading to completion of apoptosis machinery. Further, combination of KLF4 overexpression and APG treatment was highly effective in inhibiting migration of both neuroblastoma cell lines and was associated with down regulation of matrix metalloproteinases (MMPs) such as MMP‐2 and MMP‐9. Collectively, our results from this investigation strongly suggest that KLF4 functions as a tumor suppressor and potentiates the anti‐cancer activities of APG in two different human malignant neuroblastoma cell lines.
Molecular Oncology - Tập 7 - Trang 464-474 - 2013
Hypoxia‐inducible factor‐2α directly promotes <i><scp>BCRP</scp></i> expression and mediates the resistance of ovarian cancer stem cells to adriamycin Ovarian cancer stem cells (OCSC s) are sources of tumor chemoresistance and recurrence. A hypoxic microenvironment contributes to the chemoresistance of cancer stem cells (CSC s), but the underlying mechanism is not fully understood yet. Here, we show that increased HIF ‐2α expression is associated with enhanced stemness of OCSC s and poor outcomes in ovarian cancer patients. OVCAR ‐3 and CAOV ‐3 sphere‐forming (OVCAR ‐3 S and CAOV ‐3 S) cells with OCSC ‐like properties showed strong resistance to adriamycin (ADR ). Hypoxia (1% O2 ) induced high expression of both HIF ‐1α and especially HIF ‐2α, and increased the resistance of OVCAR ‐3 S and CAOV ‐3 S cells to ADR . Notably, treatment with ADR further increased the expression of HIF ‐2α, but not that of HIF ‐1α. Knockdown of HIF ‐2OVCAR ‐3 S and CAOV ‐3 S cells to ADR , and the HIF ‐2OCSC s, HIF ‐2OCSC s to ADR in vivo . Mechanistically, HIF ‐2α directly promotes transcription/expression of BCRP ADR ) out of cells, which in turn increases drug resistance due to increased drug transportation. Collectively, our studies reveal a novel drug‐resistant mechanism in ovarian cancer by which hypoxia (and ADR treatment)‐induced HIF ‐2α overexpression endows OCSC s with resistance to ADR by promoting BCRP ADR transportation. Therefore, targeting the HIF ‐2α/BCRP axis holds therapeutic potential for treating drug‐resistant ovarian cancer.
Molecular Oncology - Tập 13 Số 2 - Trang 403-421 - 2019
Biological challenges of BRAF inhibitor therapy Activating mutations in BRAF, a constituent of the map kinase pathway, were first discovered as being most prevalent in melanoma in 2002. Only recently have potent and selective, orally available inhibitors of BRAF emerged for clinical testing and demonstrated clear evidence of tumor regression in the majority of patients whose tumors harbor a BRAF mutation. While these early observations suggest that the BRAF targeted therapy will become part of the standard treatment paradigm for patients with advanced melanoma, it is also clear that a majority of these responses are incomplete and temporary. Therefore, the focus of the melanoma field has shifted to understanding the limits of the first generation of selective BRAF inhibitors with regard to safety and efficacy, the context of somatic genetic changes that accompany BRAF, and the combination regimens that target distinct elements of melanoma pathophysiology.
Molecular Oncology - Tập 5 - Trang 116-123 - 2011
Targeting leukemic stem cells by breaking their dormancy Abstract Transient or long‐term quiescence, the latter referred to as dormancy are fundamental features of at least some adult stem cells. The status of dormancy is likely a critical mechanism for the observed resistance of normal HSCs and leukemic stem cells (LSCs) to anti‐proliferative chemotherapy. Recent studies have revealed cytokines such as Interferon‐alpha (IFNα) and G‐CSF as well as arsenic trioxide (As2O3) to be efficient agents for promoting cycling of dormant HSCs and LSCs. Most interestingly, such cell cycle activated stem cells become exquisitely sensitive to killing by different chemotherapeutic agents, suggesting that dormant LSCs in patients may be targeted by a sequential two‐step protocol involving an initial activation by IFNα, G‐CSF or As2O3, followed by targeted chemotherapy.
Molecular Oncology - Tập 4 - Trang 443-450 - 2010
The canonical Wnt pathway regulates the metastasis‐promoting mucin MUC4 in pancreatic ductal adenocarcinoma Aberrant Wnt signaling frequently occurs in pancreatic cancer (PC) and contributes to disease progression/metastases. Likewise, the transmembrane‐mucin MUC4 is expressed de novo in early pancreatic intraepithelial neoplasia (PanINs) and incrementally increases with PC progression, contributing to metastasis. To determine the mechanism of MUC4 upregulation in PC, we examined factors deregulated in early PC progression, such as Wnt/β‐catenin signaling. MUC4 promoter analysis revealed the presence of three putative TCF/LEF‐binding sites, leading us to hypothesize that MUC4 can be regulated by β‐catenin. Immunohistochemical (IHC) analysis of rapid autopsy PC tissues showed a correlation between MUC4 and cytosolic/nuclear β‐catenin expression. Knock down (KD) of β‐catenin in CD18/HPAF and T3M4 cell lines resulted in decreased MUC4 transcript and protein. Three MUC4 promoter luciferase constructs, p3778, p3000, and p2700, were generated. The construct p3778, encompassing the entire MUC4 promoter, elicited increased luciferase activity in the presence of stabilized β‐catenin. Mutation of the TCF/LEF site closest to the transcription start site (i.e., −2629/−2612) and furthest from the start site (i.e., −3425/−3408) reduced MUC4 promoter luciferase activity. Transfection with dominant negative TCF4 decreased MUC4 transcript and protein levels. Chromatin immunoprecipitation confirmed enrichment of β‐catenin on −2629/−2612 and −3425/−3408 of the MUC4 promoter in CD18/HPAF. Functionally, CD18/HPAF and T3M4 β‐catenin KD cells showed decreased migration and decreased Vimentin, N‐cadherin, and pERK1/2 expression. Tumorigenicity studies in athymic nude mice showed CD18/HPAF β‐catenin KD cells significantly reduced primary tumor sizes and metastases compared to scrambled control cells. We show for the first time that β‐catenin directly governs MUC4 in PC.
Molecular Oncology - Tập 10 Số 2 - Trang 224-239 - 2016
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