Regulation Of Cancer Progression Research Articles

Reply to Comments: "Molecular Functions of Thyroid Hormone Signaling in Regulation of Cancer Progression and Anti-Apoptosis" Int. J. Mol. Sci., 2019, 20, 4986.

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Dysregulation of Rho GTPases in Human Cancers.

Rho GTPases play central roles in numerous cellular processes, including cell motility, cell polarity, and cell cycle progression, by regulating actin cytoskeletal dynamics and cell adhesion. Dysregulation of Rho GTPase signaling is observed in a broad range of human cancers, and is associated with cancer development and malignant phenotypes, including metastasis and chemoresistance. Rho GTPase activity is precisely controlled by guanine nucleotide exchange factors, GTPase-activating proteins, and guanine nucleotide dissociation inhibitors. Recent evidence demonstrates that it is also regulated by post-translational modifications, such as phosphorylation, ubiquitination, and sumoylation. Here, we review the current knowledge on the role of Rho GTPases, and the precise mechanisms controlling their activity in the regulation of cancer progression. In addition, we discuss targeting strategies for the development of new drugs to improve cancer therapy.

Correction: Lin, K.-H., et al. Molecular Functions of Thyroid Hormone Signaling in Regulation of Cancer Progression and Anti-Apoptosis. Int. J. Mol. Sci., 2019, 20, 4986.

The authors wish to make the following corrections to this paper [...].

MiR-451a restrains the growth and metastatic phenotypes of papillary thyroid carcinoma cells via inhibiting ZEB1

MicroRNAs (miRNAs) are known to be critical regulators in cancer progression. MiR-451a is reported to be involved in the progression of many different forms of cancers, including osteosarcoma, colorectal cancer, and breast carcinoma. In this study, we illuminated the possible roles of miR-451a in the development of papillary thyroid carcinoma (PTC) cells in vitro and in vivo. MiR-451a was markedly down-expressed in PTC sample compared with paratumor tissue. Upregulation of miR-451a repressed PTC cells proliferation, migration ability and inhibited the invasiveness of PTC cells in vitro. Additional, miR-451a suppressed PTC cells growth and the lung metastasis of PTC cells in vivo, whereas downregulation of miR-451a caused opposite outcomes. Importantly, miR-451a inversely modulated the expression of Zinc Finger E-Box Binding Homeobox 1 (ZEB1) by directly binding to the 3′ untranslated region (UTR) of ZEB1 in PTC cells. The level of ZEB1 was negatively associated with miR-451a level in PTC tissues, and ZEB1 silencing mimicked the suppressive impacts of miR-451a on the proliferation, mobility, and invasive phenotypes of PTC cells. ZEB1 overexpression abrogated the inhibitory impacts of miR-451a on PTC cells. Together, this study revealed that miR-451a restrained the growth and metastatic phenotypes of PTC cells through targeting ZEB1.

Comment on: Molecular Functions of Thyroid Hormone Signaling in Regulation of Cancer Progression and Anti-Apoptosis.

Dear Editor, I have found the article by Liu YC et al. very interesting, with great cognitive value [...].

CircHMCU Promotes Proliferation and Metastasis of Breast Cancer by Sponging the let-7 Family

Circular RNA (circRNA), as a kind of novel identified non-coding RNA, has become the focus of attention for its vital physiological and pathological roles. However, the function and mechanism of circRNAs in the regulation of cancer progression are largely unknown. In the present study we found a circRNA termed circHMCU whose expression was associated with poor prognosis. It was upregulated in cell lines with high metastatic potential compared with its parental cell line and in breast cancer tissues compared with normal tissues. In vitro results proved that circHMCU could significantly promote proliferation, migration, and invasion abilities of breast cancer cells via affecting the G1 phase cell cycle checkpoint and the epithelial-mesenchymal transition (EMT) pathway. Further in vivo studies showed that overexpression of circHMCU contributed to rapid proliferation and lung metastasis of breast cancer. For determination of the mechanisms, bioinformatics analysis revealed two complementary sequences within circHMCU for let-7 microRNAs, which was validated by a luciferase reporter assay. Finally, let-7 microRNAs could rescue the functions of circHMCU in breast cancer via suppressing the expression of MCY, HMGA2, and CCND1. Taken together, our findings demonstrated that circHMCU exerted oncogenic functions in breast cancer and could be a used as a novel biomarker in the diagnosis and prognosis of breast cancer.

MP17-10 N 6 -METHYLADENOSINE MODIFICATION OF CIRCANKS1A ACCELERATES CYTOPLASMIC EXPORT AND STABILIZES RACGAP1 TO PROMOTE BLADDER CANCER CELL PROLIFERATION AND METASTASIS

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II (MP17)1 Apr 2020MP17-10 N6-METHYLADENOSINE MODIFICATION OF CIRCANKS1A ACCELERATES CYTOPLASMIC EXPORT AND STABILIZES RACGAP1 TO PROMOTE BLADDER CANCER CELL PROLIFERATION AND METASTASIS Qiangqiang Ge*, Yang Xun, Junlin Lu, and Shaogang Wang Qiangqiang Ge*Qiangqiang Ge* More articles by this author , Yang XunYang Xun More articles by this author , Junlin LuJunlin Lu More articles by this author , and Shaogang WangShaogang Wang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000842.010AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Circular RNAs (circRNAs) have been identified to serve as significant regulators in cancer progression. However, the role of circRNA in bladder cancer (BCa) remains largely unknown. Herein, we investigate the expression profiles of circRNA in 20 paired samples of BCa. METHODS: To investigate the the expression profiles of circRNA, we performed high-throughput CircRNA Microarray using 20 pairs of BCa and matched adjacent non-tumor tissue samples. To explore crucial circRNAs that involved in BCa, co-expression network analysis was performed between the top 100 mostly changed circRNAs. The network represented that 15 circRNAs might involve in BCa progression. Analysis of the correlation between the expression level of 15 circRNAs and clinical data was conducted and circANKS1A was chosen. Gain-of-function and loss-of-function experiments were used to analyze the effect of circANKS1A on cell proliferation and metastasis in vitro and in vivo. m6A-containing RNAs were precipitated from methylated RNA immunoprecipitation (MeRIP) assays. The role of m6A methylation of circANKS1A in BCa proliferation and metastasis was investigated. To explore the potential molecular mechanisms of circANKS1A in regulating BCa malignance, RNA pull-down assays and mass spectrometry analysis were performed to screen circANKS1A-interacting proteins. RESULTS: By evaluating the co-expression network of differentially expressed circRNAs, we identify an N6-methyladenosine (m6A) modified circRNA, circANKS1A, upregulated in serum samples and tumor tissues from BCa patients with muscle invasive bladder Cancer (MIBC). What's more, circANKS1A upregulation is correlated with higher TNM stage and larger tumor size in BCa patients, and predicts poorer patient survival. Elevated circANKS1A promotes cell proliferation both in vitro and in vivo. The upregulated expression of circANKS1A facilitates cancer cells migration in vitro and promotes lung metastasis and liver metastasis in PDX metastasis models in vivo. Of note, N6-methyladenosine modification of circANKS1A accelerates export to the cytoplasm. By forming a circANKS1A/FOXM1/RACGAP1 RNA-protein ternary complex in the cytoplasm, circANKS1A enhances the stability of RACGAP1 mRNA to promote BCa cell proliferation and metastasis progression. Clinically, the upregulated expressions of circANKS1A and RACGAP1 are more prevalent in MIBC tissues than in non-muscle invasive bladder Cancer (NMIBC) tissues. CONCLUSIONS: N6-methyladenosine modification of circANKS1A modulates cytoplasmic export, stabilizes RACGAP1 to promote BCa cell proliferation and metastasis, and indicate that circANKS1A could serve as a significant prognostic marker and therapeutic target for BCa. Source of Funding: National Foundation Committee of Natural Sciences of China (grant numbers 81570631 and 81770704) © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e229-e230 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Qiangqiang Ge* More articles by this author Yang Xun More articles by this author Junlin Lu More articles by this author Shaogang Wang More articles by this author Expand All Advertisement PDF downloadLoading ...

Abstract IA11: The LXR/ApoE pathway regulates the innate immune system in cancer

Abstract Harnessing of the adaptive immune system, either by adoptive transfer of engineered T cells or by direct activation of endogenous T cells via checkpoint blockade, has yielded unprecedented clinical benefit in cancer. However, the full potential of these therapies is hampered by a system of elaborate molecular and cellular mechanisms that tumors orchestrate as they evolve to evade T-cell attack during metastatic cancer progression. These mechanisms, collectively referred to as the immune-suppressive tumor microenvironment, rely on cancer co-opting signaling pathways that regulate immunity in noncancer settings, including those implicated in normal physiology or in other disease states. Using an unbiased experimental approach to identify key drivers of cancer metastasis, apolipoprotein E (ApoE) was revealed as a regulator of cancer progression and tumor immunity. As tumors grow and metastasize, ApoE expression becomes silenced via the activity of a group of microRNAs that become switched on during cancer progression. The silencing of ApoE expression in tumors is associated with significantly greater metastatic potential, worse clinical prognosis, and increased accumulation of innate immunosuppressive myeloid cells known as myeloid-derived suppressor cells (MDSCs). The ApoE pathway has previously been associated with the pathophysiology of atherosclerosis and Alzheimer’s disease, both of which are characterized histologically, in part, by aberrant inflammatory myeloid cell accumulation in the form of myeloid-derived foam cells and myeloid-derived microglia, respectively. In cancer, MDSCs accumulate in tumors and in the circulation, where they inhibit the activity of cytotoxic T cells via the expression of multiple immunosuppressive molecules. Their high abundance in the circulation has been associated with resistance to checkpoint blockade, highlighting their clinical relevance. MDSC abundance was found to be regulated via ApoE signaling through the ApoE receptor LRP8. Therapeutic activation of silenced ApoE expression can be accomplished pharmacologically by the administration of Liver X Receptor (LXR) agonists, which drive ApoE expression transcriptionally. RGX-104, a potent and selective LXR agonist, reversed cancer immune evasion in tumor models and in advanced cancer patients harboring a diverse array of refractory malignancies, including checkpoint inhibitor-refractory cancers. RGX-104 rapidly depleted MDSCs, resulting in restoration of antitumor immunity via activation of PD-1+ CD8+ T cells, which ultimately resulted in clinical antitumor activity. Citation Format: Masoud Tavazoie. The LXR/ApoE pathway regulates the innate immune system in cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA11.

Nitric Oxide in Hematological Cancers: Partner or Rival?

Significance: Hematological malignancies represent the fourth most diagnosed cancer. Relapse and acquired resistance to anticancer therapy constitute two actual issues that need to be overcome. Nitric oxide (NO) plays a pivotal role in regulating cancer progression. At present, many studies are attempting to uncover the potentials of modulating NO levels to improve the efficacy of currently available treatments against lymphoma, leukemia, and myeloma. Recent Advances: It is becoming progressively clear that NO modulation may help hematological cancer management, either by targeting directly tumor cells or by driving the immune system to eliminate cancer cells. Critical Issues: NO is a dual molecule that can have a tumor-protecting or stimulating effect, depending on its local concentration. Moreover, NO is able to target a wide range of molecules involved in both cancer genesis and evolution. In this review, an overview of the recent findings regarding the pivotal role played by NO and nitric oxide synthase in cancer progression and anticancer therapy is presented, with particular focus on hematological malignancies. Future Directions: It is critical to establish the cancer-specific function of NO and critically drive its modulation to improve cancer management toward a personalized approach. This has a special importance in hematological tumors, where the urgency of finding eradicative therapies is constant. Antioxid. Redox Signal. 34, 383-401.

Profiles of immune cell infiltration and their clinical significance in head and neck squamous cell carcinoma

It is well established that there exist comprehensive interactions between tumor immunology and tumor biology. Tumor-infiltrating immune cells (TIICs) have been appealing therapeutic targets due to their significance in regulating cancer progression. The purpose of this study was to illustrate the comprehensive landscape of TIICs composition in head and neck squamous cell carcinoma (HNSCC) and their clinical significance. CIBERSORT was applied to calculate the 22 immune cell types proportion in HNSCC and further analysis suggested that six kinds of immune cells (resting memory CD4 T cells, M1 macrophages, resting dendritic cells, resting mast cells, monocytes, and eosinophils) were closely correlated with HNSCC progression. Moreover, memory CD4 T cells may serve as prognosis indicator for HNSCC patients. Collectively, this study uncovered the immune cells infiltration landscape in HNSCC and illustrated their potential relationships with clinical parameters, thereby contributing to the development of customized treatment strategy.

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer.

The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and others with minimal to no clinical benefit. An important aspect associated with this discrepancy in patient response is the immune-suppressive effects elicited by the tumour microenvironment (TME). Immune suppression plays a pivotal role in regulating cancer progression, metastasis, and reducing immunotherapy success. Most notably, myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have potent mechanisms to inhibit T-cell and NK-cell activity to promote tumour growth, development of the pre-metastatic niche, and contribute to resistance to immunotherapy. Accumulating research indicates that MDSC can be a therapeutic target to alleviate their pro-tumourigenic functions and immunosuppressive activities to bolster the efficacy of checkpoint inhibitors. In this review, we provide an overview of the general immunotherapeutic approaches and discuss the characterisation, expansion, and activities of MDSCs with the current treatments used to target them either as a single therapeutic target or synergistically in combination with immunotherapy.

Integrative analyses identify a DNA damage repair gene signature for prognosis prediction in lower grade gliomas.

Background: The DNA damage repair (DDR) pathways play important roles for regulating cancer progression and therapeutic response. IDH mutations, well-known prognosis biomarkers for glioma, lead to hypermethylation of tumor cells and affect genes' expression. Whether IDH mutations affect glioma prognosis through influencing the expression of DDR genes remains unclear. Methods: A total of 272 DDR genes were selected for differential expression and survival analysis. The identified genes were then utilized to construct the prognosis predicting model. Results: PARPBP, PLK3, POLL and WEE1 were found differential expressed between IDH mutations carriers and wild-type carriers, and were associated with survival of low grade glioma (LGG) patients. The predicting algorithm can predicts the prognosis of LGG patients. Conclusion: IDH mutations may affect LGG prognosis through regulation of DDR pathways.

LncRNA PVT1 regulates gallbladder cancer progression through miR-30d-5p.

Gallbladder cancer (GBC) is a malignant tumors that develops insidiously and rapidly. In this work, we explored the function of long non-coding RNA plasmacytoma variant translocation 1 (lncRNA PVT1) in modulating GBC development. PVT1 and miR-30d-5p expression were detected by real-time fluorescent quantitative polymerase chain reaction (qRT-PCR). The relationship of PVT1 and miR-30d-5p was analyzed by Dual luciferase activity and Spearman correlation analysis. The effect of PVT1 on GBC progression was detected by cell counting kit-8 (CCK-8) and Transwell assay. In GBC tissues and cell lines, upregulation of PVT1 and downregulation of miR-30d-5p were observed. PVT1 silencing suppressed cell proliferation and invasion of GBC cells. Based on the analysis of Dual luciferase activity and Spearman correlation, miR-30d-5p was confirmed as a target of PVT1, and their expression had a negative correlation in GBC tissues. Additionally, miR-30d-5p inhibitor could reverse the effects of PVT1 knockdown. These data demonstrated that PVT1 facilitated to GBC tumorigenesis by promoting cell proliferation and invasion via miR-30d-5p, indicating that PVT1 may be a potential biomarker of GBC diagnosis and treatment.

A Novel Method to Efficiently Highlight Nonlinearly Expressed Genes.

For precision medicine, there is a need to identify genes that accurately distinguish the physiological state or response to a particular therapy, but this can be challenging. Many methods of analyzing differential expression have been established and applied to this problem, such as t-test, edgeR, and DEseq2. A common feature of these methods is their focus on a linear relationship (differential expression) between gene expression and phenotype. However, they may overlook nonlinear relationships due to various factors, such as the degree of disease progression, sex, age, ethnicity, and environmental factors. Maximal information coefficient (MIC) was proposed to capture a wide range of associations of two variables in both linear and nonlinear relationships. However, with MIC it is difficult to highlight genes with nonlinear expression patterns as the genes giving the most strongly supported hits are linearly expressed, especially for noisy data. It is thus important to also efficiently identify nonlinearly expressed genes in order to unravel the molecular basis of disease and to reveal new therapeutic targets. We propose a novel nonlinearity measure called normalized differential correlation (NDC) to efficiently highlight nonlinearly expressed genes in transcriptome datasets. Validation using six real-world cancer datasets revealed that the NDC method could highlight nonlinearly expressed genes that could not be highlighted by t-test, MIC, edgeR, and DEseq2, although MIC could capture nonlinear correlations. The classification accuracy indicated that analysis of these genes could adequately distinguish cancer and paracarcinoma tissue samples. Furthermore, the results of biological interpretation of the identified genes suggested that some of them were involved in key functional pathways associated with cancer progression and metastasis. All of this evidence suggests that these nonlinearly expressed genes may play a central role in regulating cancer progression.

Diallyl trisulfide, a H2 S donor, inhibits cell growth of human papillary thyroid carcinoma KTC-1 cells through a positive feedback loop between H2 S and cystathionine-gamma-lyase.

Diallyl trisulfide (DATS), derived from garlic, is a well-known hydrogen sulfide (H2 S) donor. H2 S has recently emerged as a novel gasotransmitter involved in the regulation of cancer progression. The present study demonstrated that DATS along with other two H2 S donors, NaHS and GYY4137, significantly inhibited papillary thyroid carcinoma KTC-1 cells growth. DATS treatment triggered a rapid H2 S generation within 5 min in KTC-1 cells. Iodoacetamide, a potent thiol blocker reagent, partially rescued the cell membrane damage and ultimate cell death induced by DATS, indicating H2 S contributed to the apoptosis-inducing efficacy of DATS on thyroid cancer cells. Specifically, DATS treatment significantly upregulated the expression and enzymatic activity of cystathionine gamma-lyase (CTH), one of H2 S-producing enzymes, which was responsible for endogenous H2 S generation. After DATS treatment, H2 S quickly permeated cell membranes and activated NF-κΒ/p65 signaling pathway in KTC-1 cells. Nuclear translocated NF-κB bound to the promoter of CTH to enhance its transcription. These evidences proved that exogenous H2 S elevated CTH expression. CTH, in turn, catalytically generated a much higher level of endogenous H2 S. This positive feedback sustained excess H2 S production, which resulted in PTC cells growth inhibition. These findings may shed light on the development of novel H2 S-based antitumor agents.

N6-Methyladenosine Regulates the Expression and Secretion of TGFβ1 to Affect the Epithelial-Mesenchymal Transition of Cancer Cells.

N6-methyladenosine (m6A) is the most abundant modification on eukaryotic mRNA, which regulates all steps of the mRNA life cycle. An increasing number of studies have shown that m6A methylation plays essential roles in tumor development. However, the relationship between m6A and the progression of cancers remains to be explored. Here, we reported that transforming growth factor-β (TGFβ1)-induced epithelial–mesenchymal transition (EMT) was inhibited in methyltransferase-like 3 (METTL3) knockdown (Mettl3Mut/−) cells. The expression of TGFβ1 was up-regulated, while self-stimulated expression of TGFβ1 was suppressed in Mettl3Mut/− cells. We further revealed that m6A promoted TGFB1 mRNA decay, but impaired TGFB1 translation progress. Besides this, the autocrine of TGFβ1 was disrupted in Mettl3Mut/− cells via interrupting TGFβ1 dimer formation. Lastly, we found that Snail, which was down-regulated in Mettl3Mut/− cells, was a key factor responding to TGFβ1-induced EMT. Together, our research demonstrated that m6A performed multi-functional roles in TGFβ1 expression and EMT modulation, suggesting the critical roles of m6A in cancer progression regulation.

The aberrant expression of rhythm genes affects the genome instability and regulates the cancer immunity in pan-cancer.

Although emerging studies showed that certain rhythm genes regulate cancer progression, the expression and roles of the vast majority of rhythm genes in human cancer are largely unknown, and the hallmarks of cancer regulated by rhythm genes have not been detected. In this study, we detected the expression changes of rhythm genes in pan‐cancer and found that almost all rhythm genes mutated in all cancer types, and their expression level was significantly altered partially due to abnormal methylation, and several rhythm genes regulate the expression of other rhythm genes in various cancer types. Furthermore, we revealed that rhythm genes are significantly enriched in genome instability and the expression of certain rhythm genes is correlated with the tumor mutation burden, microsatellite instability, and the expression of DNA damage repair genes in most of the detected cancer types. Moreover, rhythm genes are associated with the infiltration of immune cells and the efficiency of immune blockade therapy. This study provides a comprehensive understanding of the roles of rhythm genes in cancer immunity, which may provide a novel method for the diagnosis and treatment of cancer.

CCN5 inhibits proliferation and promotes apoptosis of oral squamous cell carcinoma cells.

Oral squamous cell carcinoma (OSCC) is a common cancer with poor prognosis and high mortality. The role of CCN5 has attracted a great focus on the regulation of cancer progression. However, the biological function and mechanism of CCN5 in OSCC are still not well elucidated. The current study was designed to determine the effects of CCN5 on OSCC cell proliferation and apoptosis using two OSCC cell lines. Further, LY294002, a PI3K/AKT antagonist, was employed to explore the mechanism underlying the effects of CCN5 in the regulation of OSCC. The results showed that overexpression of CCN5 in TSCCa cells significantly reduced viable cell number, arrested cell cycle, and suppressed cell-cycle regulators (cyclin D1, cyclin E, and CDK2). CCN5 overexpression increased the apoptotic ratio and Hoechst-positive cell number, and altered the apoptotic-related proteins (caspase-3/9, Bax, and Bcl-2). However, CCN5 silencing induced opposite effects on cell proliferation and apoptosis in Tca-8113 cells. In addition, we observed that CCN5 knockdown increased the expression levels of PI3K (p85α and p110α) and phosphorylated AKT at serine 473 (p-AKT Ser473) in Tca-8113 cells. Inhibiting PI3K/AKT signaling with LY294002 rescued the apoptotic process in CCN5-silenced OSCC cells. Finally, xenograft analysis showed that CCN5 represses tumorigenesis of OSCC cells. These findings together suggest that CCN5 functions as a tumor suppressor for OSCC cell development through inactivation of PI3K/AKT signaling pathway, providing a potential candidate for OSCC therapy.

MicroRNA‑3651 promotes colorectal cancer cell proliferation through directly repressing T‑box transcription factor 1.

Colorectal cancer is a commonly diagnosed gastrointestinal malignancy worldwide with a high mortality rate. Accumulating evidence has indicated that the expression of a number of microRNAs (miRNAs) is associated with the development of colorectal cancer. However, the precise molecular mechanism of these miRNAs in regulating cancer progression is yet to be determined. In the present study, miR‑3651 was demonstrated to be overexpressed in colorectal cancer tissues compared with normal tissues, and to be associated with the tumor‑node‑metastasis stage. The downregulation of miR‑3651 was found to induce growth arrest and apoptosis in colorectal cancer cells. In addition, western blot analysis demonstrated that the downregulation of miR‑3651 inactivated PI3K/AKT and MAPK/ERK signaling in colorectal cancer cells. Bioinformatics analysis predicted T‑box transcription factor 1 (TBX1) as a potential target gene of miR‑3651, and a dual‑luciferase reporter assay confirmed that TBX1 was directly repressed by miR‑3651. The results of the current study also indicated that TBX1 was associated with the miR‑3651 mediated activation of oncogenic signaling and colorectal cancer cell proliferation. In conclusion, the results of the current study revealed the oncogenic potential of miR‑3651 in colorectal cancer.

The transcription factor FLI1 promotes cancer progression by affecting cell cycle regulation.

Binding of transcription factors to mutated DNA sequences is a likely regulator of cancer progression. Noncoding regulatory mutations such as those on the core promoter of the gene encoding human telomerase reverse transcriptase have been shown to affect gene expression in cancer. Using a protein microarray of 667 transcription factor DNA-binding domains and subsequent functional assays, we looked for transcription factors that preferentially bind the mutant hTERT promoter and characterized their downstream effects. One of them, friend leukemia integration 1 (FLI1), which belongs to the E26 transforming-specific family of transcription factors, exhibited particularly strong effects with respect to regulating hTERT expression, while the even better binding ELK3 did not. Depletion of FLI1 decreased expression of the genes for cyclin D1 (CCND1) and E2F transcription factor 2 (E2F2) resulting in a G1/S cell cycle arrest and in consequence a reduction of cell proliferation. FLI1 also affected CMTM7, another gene involved in G1/S transition, although by another process that suggests a balanced regulation of the tumor suppressor gene's activity via opposing regulation processes. FLI1 expression was found upregulated and correlated with an increase in CCND1 expression in pancreatic cancer and brain tumors. In non-neoplastic lung cells, however, FLI1 depletion led to rapid progression through the cell cycle. This coincides with the fact that FLI1 is downregulated in lung tumors. Taken together, our data indicate a cell cycle regulatory hub involving FLI1, hTERT, CCND1 and E2F2 in a tissue- and context-dependent manner.