Inhibition of Glycolysis Suppresses Cell Proliferation and Tumor Progression In Vivo: Perspectives for Chronotherapy

A high rate of glycolysis is considered a hallmark of tumor progression and is caused by overexpression of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Therefore, we analyzed the possibility of inhibiting tumor and endothelial cell metabolism through the inhibition of PFKFB3 by a small molecule, (E)-1-(pyridin-4-yl)-3-(quinolin-2-yl)prop-2-en-1-one (PFK15), as a promising therapy. The effects of PFK15 on cell proliferation and apoptosis were analyzed on human umbilical vein endothelial cells (HUVEC) and the human colorectal adenocarcinoma cell line DLD1 through cytotoxicity and proliferation assays, flow cytometry, and western blotting. The results showed that PFK15 inhibited the proliferation of both cell types and induced apoptosis with decreasing the Bcl-2/Bax ratio. On the basis of the results obtained from in vitro experiments, we performed a study on immunodeficient mice implanted with DLD1 cells. We found a reduced tumor mass after morning PFK15 treatment but not after evening treatment, suggesting circadian control of underlying processes. The reduction in tumor size was related to decreased expression of Ki-67, a marker of cell proliferation. We conclude that inhibition of glycolysis can represent a promising therapeutic strategy for cancer treatment and its efficiency is circadian dependent.

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Circ_0001421 facilitates glycolysis and lung cancer development by regulating miR-4677-3p/CDCA3

Diagnostic Pathology ◽

10.1186/s13000-020-01048-1 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Koudong Zhang ◽

Hang Hu ◽

Juan Xu ◽

Limin Qiu ◽

Haitao Chen ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Tumor Progression ◽

Lactate Production ◽

Tumor Formation ◽

Luciferase Reporter ◽

Circular Rnas ◽

Glucose Assay

Abstract Background Lung cancer (LC) is a malignant tumor originating in the bronchial mucosa or gland of the lung. Circular RNAs (circRNAs) are proved to be key regulators of tumor progression. However, the regulatory effect of circ_0001421 on lung cancer tumorigenesis remains unclear. Methods The expression levels of circ_0001421, microRNA-4677-3p (miR-4677-3p) and cell division cycle associated 3 (CDCA3) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Methyl thiazolyl tetrazolium (MTT), Transwell and Tumor formation assays were performed to explore the role of circ_0001421 in LC. Glucose consumption and lactate production were examined by a Glucose assay kit and a Lactic Acid assay kit. Western blot was utilized to examine the protein levels of Hexokinase 2 (HK2) and CDCA3. The interaction between miR-4677-3p and circ_0001421 or CDCA3 was confirmed by dual-luciferase reporter assay. Results Circ_0001421 was increased in LC tissues and cells, and knockdown of circ_0001421 repressed cell proliferation, migration, invasion and glycolysis in vitro. Meanwhile, circ_0001421 knockdown inhibited LC tumor growth in vivo. Mechanistically, circ_0001421 could bind to miR-4677-3p, and CDCA3 was a target of miR-4677-3p. Rescue assays manifested that silencing miR-4677-3p or CDCA3 overexpression reversed circ_0001421 knockdown-mediated suppression on cell proliferation, migration, invasion and glycolysis in LC cells. Conclusion Circ_0001421 promoted cell proliferation, migration, invasion and glycolysis in LC by regulating the miR-4677-3p/CDCA3 axis, which providing a new mechanism for LC tumor progression.

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EBV-Encoded Mirnas Facilitate Inflammation and Tumor Formation Through Both Intra- and Inter-Cellular Regulation In Vivo Mouse Model

Blood ◽

10.1182/blood.v122.21.3735.3735 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3735-3735

Author(s):

Natsuko Yamakawa ◽

Jun Ogata ◽

Takashi Yahata ◽

Jun Lu ◽

Kazuaki Yokoyama ◽

...

Keyword(s):

Cell Proliferation ◽

Tumor Cells ◽

Small Rnas ◽

Conflicts Of Interest ◽

Functional Characterization ◽

Tumor Formation ◽

Sequencing Analysis ◽

Immunodeficient Mice

Abstract Introduction EB virus (EBV) is associated with heterogeneous lymphomas. Hodgkin's lymphoma (HL) cells are embedded in non-neoplastic bystanders: B, T cells, and macrophages. Without these bystander cells, the lymphoma cells are incapable of being engrafted in immunodeficient mice. In this context, the bystanders are tumor-supportive “inflammatory niche”. Recently, EBV-infected cells produce exosomes that contain EBV specifically encoded miRNAs (EBV-miRNAs). The miRNAs are transferred to cells, and involved in tumor metastasis. However, the detailed mechanism is unknown. Accordingly, we hypothesized that exosomal EBV-miRNAs might redirect tumor surrounding immune cells from tumor reactive into tumor-supportive “inflammatory niche”. Methods We evaluated the expression of EBV-miRNAs in EBV+HL clinical specimens by in situ hybridization, their functional characterization in vitro, and their effects on persistent infection and tumor development in vivo humanized NOG mice model. Moreover, in order to clarify its sorting mechanism, trans factor and cis factor which determined secreted and non-secreted miRNAs was analyzed by use of mass-spectrograhy and next-generation sequencing. Results and Discussion The EBV-miRNAs effects were potent on monocyte/macrophage Mo/Mf in inducing CD69, IL-10, and TNF, suggesting that EBV-miRNAs might polarize Mo/Mf into tumor associated Mf (TAM). EBV-miRNAs suppress tumor cell proliferation in vitro, implying that it works as tumor-suppressor in the tumor cells, while they are required to develop LPD in vivo, which seems contradict to the result in vitro. These results suggest that EBV-miRNAs intra-cellularly regulate the tumor cells to adjust to the surrounding circumstances, for example, to escape from immune surveillance, and inter-cellularly regulate Mo/Mf to support the tumor survival or development. Most importantly, exosomal EBV-miRNAs derived from the tumor cells were transferred to Mf in human EBV+ HL samples. Interestingly, one EBV coded miRNA was not secreted at all, though it abundantly expresses in the cells. The miRNA has been reported to strongly promote cell proliferation in EBV infected tumor cells. It made us hypothesized that the sorting system of secretary and non-secretary miRNAs is critical in the formation of “inflammatory niche”. In order to clarify the mechanism of the sorting, the chimeric miRNA was constructed then, we determined the sequence, which regulates secretion and non-secretion, and purified the protein complex, which specifically bound to the sequence. Mass spectrography and successive knockdown assay, the trans factor which inhibits secretion was identified. Moreover, the next sequencing analysis for the small RNAs revealed that abundant EBV-coded small RNAs occupied RNA-induced silencing complex (RISC), and that non-secreted EBV-miRNA was specifically modified. It is now under investigation whether the modification is involved in the sort mechanism between secretary and non-secretary miRNAs. Taken together, EBV-miRNAs have critical roles in intra- and inter-cellular manner. Especially, the functions as an inter-cellular communicator might be important in the tumor formation and the mechanism needs further investigation. Disclosures: No relevant conflicts of interest to declare.

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Characterization and Evaluation of Two Novel Fluorescent Sigma-2 Receptor Ligands as Proliferation Probes

Molecular Imaging ◽

10.2310/7290.2011.00009 ◽

2011 ◽

Vol 10 (6) ◽

pp. 7290.2011.00009 ◽

Cited By ~ 24

Author(s):

Chenbo Zeng ◽

Suwanna Vangveravong ◽

Lynne A. Jones ◽

Krzysztof Hyrc ◽

Katherine C. Chang ◽

...

Keyword(s):

Cell Proliferation ◽

Plasma Membrane ◽

Mononuclear Cells ◽

In Vivo Studies ◽

Ki 67 ◽

Peripheral Blood Mononuclear ◽

Fluorescent Intensity ◽

Fluorescent Markers

We synthesized and characterized two novel fluorescent sigma-2 receptor selective ligands, SW120 and SW116, and evaluated these ligands as potential probes for imaging cell proliferation. Both ligands are highly selective for sigma-2 receptors versus sigma-1 receptors. SW120 and SW116 were internalized into MDA-MB-435 cells, and 50% of the maximum fluorescent intensity was reached in 11 and 24 minutes, respectively. In vitro studies showed that 50% of SW120 or SW116 washed out of cells in 1 hour. The internalization of SW120 was reduced ≈30% by phenylarsine oxide, an inhibitor of endocytosis, suggesting that sigma-2 ligands are internalized, in part, by an endocytotic pathway. Subcellular localization studies using confocal and two-photon microscopy showed that SW120 and SW116 partially colocalized with fluorescent markers of mitochondria, endoplasmic reticulum, lysosomes, and the plasma membrane, suggesting that sigma-2 receptors localized to the cytoplasmic organelles and plasma membrane. SW120 did not colocalize with the nuclear dye 4′,6-diamidino-2-phenylindole. In vivo studies showed that the uptake of SW120 in solid tumors and peripheral blood mononuclear cells of mice positively correlated with the expression level of the cell proliferation marker Ki-67, suggesting that sigma-2 fluorescent probes may be used to image cell proliferation in mice.

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CircTP63 Promotes Cell Proliferation and Invasion by Regulating EZH2 via Sponging miR-217 in Gallbladder Cancer

10.21203/rs.3.rs-553740/v2 ◽

2021 ◽

Author(s):

Shouhua Wang ◽

Huanjun Tong ◽

Tingting Su ◽

Di Zhou ◽

Weibin Shi ◽

...

Keyword(s):

Cell Proliferation ◽

Tumor Progression ◽

Gallbladder Cancer ◽

In Vivo Studies ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Ezh2 Expression ◽

Proliferation And Invasion

Abstract Background: Gallbladder cancer (GBC) is the most common biliary tract malignancy and has a poor prognosis in patients with GBC. CircRNA TP63 (circTP63) has been implicated in some tumor proliferation and invasion in some tumors. The study aims to investigate the clinical significance and functional role of circTP63 in GBC.Methods: The expression of circTP63 in GBC was detected by qRT-PCR and the association between circTP63 expression and prognosis of GBC patients was analyzed. CCK8 assay, flow cytometry analysis, transwell assay and in vivo studies were used to evaluated the cell proliferation and invasion after circTP63 knockdown in GBC cells. Luciferase reporter assays and RNA pull-down assay were used to determine the correlation between circTP63 and miR-217. Besides, western blot analysis was also performed.Results: In the present study, we showed that circTP63 expression was upregulated in GBC tissues and cells. Higher circTP63 expression was associated with lymph node metastasis and short overall survival (OS) in patients with GBC. In vitro, knockdown of circTP63 inhibited cell proliferation, cell cycle progression, migration and invasion in GBC. Besides, we demonstrated that knockdown of circTP63 inhibited GBC cell EMT process. In vivo, knockdown of circTP63 inhibited tumor growth in GBC. Mechanistically, we demonstrated that circTP63 competitively bind to miR-217 and promoted EZH2 expression and finally facilitated tumor progression.Conclusions: Our findings demonstrated that circTP63 sponge miR-217 and regulated EZH2 expression and finally facilitates tumor progression. Thus, targeting circTP63 may be a therapeutic strategy for the treatment of GBC.

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Sphingosine Kinases (SK): Key Molecules Associated with the Activation, Proliferation and Ibrutinib-Induced Cell Death of Chronic Lympocytic Leukemia Cells

Blood ◽

10.1182/blood.v126.23.1714.1714 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1714-1714

Author(s):

Maria Belen Almejun ◽

Mercedes Borge ◽

Ana Colado ◽

Enrique Podaza ◽

Denise Risnik ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Leukemic Cells ◽

Lymphoid Tissues ◽

Effective Treatment Option ◽

Ki 67 ◽

Sphingosine Kinases ◽

Leukemic Clone

Abstract Leukemic cells from CLL patients can survive and proliferate within lymphoid tissues where the supportive microenvironment favors their accumulation. We have previously reported that the activation of CLL cells reduces the expression of the main receptor for sphingosine 1-phosphate (S1P) (Borge M, J Immunol, 2014), a bioactive phospholipid that participates in lymphocyte egress from lymphoid tissues. S1P also mediates several biological functions, including cell growth stimulation and protection of apoptosis, through receptor independent intracellular mechanisms. S1P is generated by two isoforms of sphingosine kinases (SK1/2) and its levels are tightly controlled via degradation by intracellular S1P lyases (S1PL). Several studies have implicated the SK/S1P/S1PL pathway as an essential regulator of cell proliferation and survival in different cancer cells. The aims of our study were: a) to evaluate the expression of SK and S1PL in CLL cells, b) to assess whether key microenvironment signals are able to modulate this expression and c) to evaluate the effect of SK inhibitors on the activation and survival of the leukemic clone. We measured the basal expression of SK and S1PL by qRT-PCR on purified B cells from CLL patients (n=22) and aged-matched healthy donors (n=9), and found that CLL cells express high levels of SK1, favoring an increased SK1/S1PL ratio in the malignant clone compared to healthy B lymphocytes ( p<0.05). Similar results were obtained when SK2 was evaluated. The in vitro activation of CLL cells with anti-IgM+CD40L increased SK1/S1PL ratio (n=10, p<0.01) and the expression of the activation marker CD69. To evaluate the expression of SK1/S1PL within in vivo activated CLL cell subpopulations, we segregated the proliferative fraction (PF) of circulating CLL cells from the quiescent fraction (QF) in the same sample. As it was previously described, this PF is characterized by the presence of an active class-switch recombination process and a high expression of proliferation-related genes, such as Ki-67, c-myc, CD49d, and p27-Kip1 (Palacios F, Blood, 2010). Interestingly, SK1/S1PL ratio was increased in the PF compared with the QF (n=3). Additionally, bone marrow leukemic cells expressing high levels of CD38, which defines a subpopulation of activated lymphocytes, showed a higher S1P/S1PL ratio compared to CD38 low or negative counterparts (n=3),showing that the in vivo activated CLL cells expressed higher ratios of SK1/S1PL compared with the rest of the leukemic clone. Finally, we wondered whether the inhibition of SK impairs the survival, activation and proliferation of the leukemic clone. To this aim we employed a commercial selective SK1 and SK2 inhibitor (SKI-II, 5 and 15μM), which did not affect cell viability (n=10, evaluated at 24, 48, 72 and 96hs). However, it was able to impair the expected upregulation of CD69 induced by IgM+CD40L at 24hs (n=10, p<0.001) and the leukemic cell proliferation evaluated by CFSE dilution assay at 96hs (n=10 , p<0.001). Moreover, while SKI-II did not increase the sensitivity of CLL cells to Fludarabine or Bendamustine, it was able to enhance the cell death induced by Ibrutinib (0.3 and 3μM) (n=5, p<0.05 and p<0.01 respectively). Taking together, our results suggest that SK/S1P/S1PL axis might participate in the accumulation of the malignant clone in CLL patients and the disruption of this pathway might be a potentially effective treatment option in the future. Disclosures Bezares: Janssen: Honoraria. Gamberale:Janssen: Honoraria.

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Increased FSHD region gene1 expression reduces in vitro cell migration, invasion, and angiogenesis, ex vivo supported by reduced expression in tumors

Bioscience Reports ◽

10.1042/bsr20171062 ◽

2017 ◽

Vol 37 (5) ◽

Cited By ~ 5

Author(s):

Ankit Tiwari ◽

Niharika Pattnaik ◽

Archita Mohanty Jaiswal ◽

Manjusha Dixit

Keyword(s):

Cell Proliferation ◽

Cell Migration ◽

Tumor Progression ◽

Tumor Angiogenesis ◽

Umbilical Vein ◽

Ectopic Expression ◽

Migration And Invasion ◽

Rt Pcr ◽

Cell Functions

Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a candidate gene for FSHD. FRG1 regulates various muscle-related functions, but studies have proposed its role in development and angiogenesis also, where it is involved with tumor-associated molecules. Therefore, we decided to look into its role in tumor progression, tumor angiogenesis, and its impact on cellular properties. Cell proliferation, migration, invasion and in vitro angiogenesis assays were performed to decipher the effect of FRG1 on endothelial and epithelial cell functions. Q-RT PCR was done for human embyonic kidney (HEK293T) cells with altered FRG1 levels to identify associated molecules. Further, immunohistochemistry was done to identify FRG1 expression levels in various cancers and its association with tumor angiogenesis. Subsequently, inference was drawn from Oncomine and Kaplan–Meier plotter analysis, for FRG1 expression in different cancers. Ectopic expression of FRG1 affected cell migration and invasion in both HEK293T and human umbilical vein endothelial cells (HUVECs). In HUVECs, FRG1 overexpression led to reduced angiogenesis in vitro. No effect was observed in cell proliferation in both the cell types. Q-RT PCR data revealed reduction in granulocyte-colony stimulating factor (G-CSF) expression with FRG1 overexpression and increased expression of matrix metalloproteinase 10 (MMP10) with FRG1 knockdown. Immunohistochemistry analysis showed reduced FRG1 levels in tumors which were supported by in silico analysis data. These findings suggest that reduction in FRG1 expression in gastric, colon and oral cavity tumor might have a role in tumor progression, by regulating cell migration and invasiveness. To elucidate a better understanding of molecular signaling involving FRG1 in angiogenesis regulation, further study is required.

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Novel Oxovanadium Complex VO(hntdtsc)(NPIP): Anticancer Activity and Mechanism of Action on HeLa Cells

Frontiers in Pharmacology ◽

10.3389/fphar.2020.608218 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yinliang Bai ◽

Honghua Zhang ◽

Yali Wang ◽

Longqing Zhu ◽

Tao Shi ◽

...

Keyword(s):

Cell Proliferation ◽

Hela Cells ◽

Pathological Examination ◽

Cancer Drug ◽

Mechanism Study ◽

Ki 67 ◽

Apoptosis Pathway ◽

Multiple Tumor

Oxovanadium complexes, particularly vanadyl (IV) derivatives with hybrid ligands of Schiff base and polypyridyl, have been demonstrated to possess great anticancerous therapeutic efficacy. However, most of the studies on the activity of these oxovanadium complexes have mainly focused on in vitro studies, and animal studies in vivo are extremely scarce. Based on the antitumor test results of four novel oxovanadium complexes in our previous work, this work further conducted a comprehensive antitumor activity study in vitro and in vivo on VO(hntdtsc)(NPIP), which owned the strongest inhibitory activity in vitro on multiple tumor cell proliferation. The cellular mechanism study suggested that VO(hntdtsc)(NPIP) inhibited the cell proliferation via arresting the cell cycle at G0/G1 phase through the p16-cyclin D1-CDK4-p-Rb pathway and inducing cell apoptosis through mitochondrial-dependent apoptosis pathway on HeLa cells. Inconsistent with the effects in vitro, VO(hntdtsc)(NPIP) significantly inhibited the growth of tumor and induced the apoptosis of cancer cells in mice xenograft models according to the results of nude mice in vivo image detection, H&E pathological examination, and immunohistochemical detection of p16/Ki-67 protein expression. Collectively, all the results, particularly studies in vivo, demonstrated that VO(hntdtsc)(NPIP) hold a potential to be the lead compound and further to be an anticervical cancer drug.

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Preclinical antitumor and antiangiogenic activity of a metronomic schedule of cisplatin against human transitional cell carcinoma (TCC)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e16018 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e16018-e16018

Author(s):

W. Jian ◽

J. M. Levitt ◽

S. P. Lerner ◽

G. Sonpavde

Keyword(s):

Tumor Growth ◽

Histopathological Examination ◽

Umbilical Vein ◽

Transitional Cell ◽

Chemotherapeutic Agents ◽

Preclinical Model ◽

Ki 67 ◽

Anti Tumor Activity

e16018 Background: Conventional cisplatin every 3 weeks is frequently precluded in patients with TCC due to renal dysfunction. A metronomic schedule of other chemotherapeutic agents demonstrates anti-angiogenic and anti-tumor activity coupled with better tolerability. A rationale can be made to preclinically evaluate the activity of a metronomic (weekly or 3 days a week) schedule of cisplatin in a preclinical system of TCC. Methods: The activity of cisplatin was assessed in vitro against HUVECs (human umbilical vein endothelial cells). MTT, flow cytometry with Annexin-FITC and scratch assays were employed to assess proliferation, apoptosis and migration, respectively. The activity of cisplatin was evaluated in vivo in murine xenograft models of TCC. The subcutaneous xenografts included 5 × 106 RT4 or 5637 human TCC cells injected into 6- to 8-week-old female athymic BALB/c nu/nu mice. Cisplatin was administered 4 mg/kg IP (intraperitoneal) weekly for up to 6 weeks and compared with untreated mice. Then, 3 groups of tumor-bearing mice received either no therapy, cisplatin 6 mg/kg weekly or cisplatin 2 mg/kg for 3 days a week for up to 6 weeks. Tumor size is measured twice a week. Nephrotoxicity is assessed by serum creatinine and kidney histopathological examination. IHC (immunohistochemistry) of xenografts is performed to measure proliferation (ki-67), apoptosis (cleaved caspase-3) and angiogenesis (CD31). Results: Cisplatin demonstrated significant anti-proliferative, anti-migration and pro-apoptotic activity against HUVECs in vitro. Cisplatin 4 mg/kg weekly inhibited tumor growth, induced higher apoptosis and down-regulated angiogenesis and proliferation in vivo compared to controls. Results from the experiment comparing cisplatin 6 mg/kg weekly with 2 mg/kg 3 days a week (i.e. more metronomic, with potentially more anti-angiogenic and anti-tumor activity and less nephrotoxic) will be presented. Conclusions: A metronomic schedule of cisplatin inhibits tumor growth and demonstrates anti-angiogenic activity in a preclinical model of human TCC. The clinical evaluation of a metronomic schedule of cisplatin may be warranted. No significant financial relationships to disclose.

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Notch3 inhibits cell proliferation and tumorigenesis and predicts better prognosis in breast cancer through transactivating PTEN

Cell Death and Disease ◽

10.1038/s41419-021-03735-3 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Yong-Qu Zhang ◽

Yuan-Ke Liang ◽

Yang Wu ◽

Min Chen ◽

Wei-Ling Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Malignant Tumors ◽

Breast Cancer Cell Lines ◽

Breast Cancer Patients ◽

Loss Of Function ◽

Ki 67 ◽

Cancer Subtypes

AbstractNotch receptors (Notch1–4) play critical roles in tumorigenesis and metastasis of malignant tumors, including breast cancer. Although abnormal Notch activation is related to various tumors, the importance of single receptors and their mechanism of activation in distinct breast cancer subtypes are still unclear. Previous studies by our group demonstrated that Notch3 may inhibit the emergence and progression of breast cancer. PTEN is a potent tumor suppressor, and its loss of function is sufficient to promote the occurrence and progression of tumors. Intriguingly, numerous studies have revealed that Notch1 is involved in the regulation of PTEN through its binding to CBF-1, a Notch transcription factor, and the PTEN promoter. In this study, we found that Notch3 and PTEN levels correlated with the luminal phenotype in breast cancer cell lines. Furthermore, we demonstrated that Notch3 transactivated PTEN by binding CSL-binding elements in the PTEN promoter and, at least in part, inhibiting the PTEN downstream AKT-mTOR pathway. Notably, Notch3 knockdown downregulated PTEN and promoted cell proliferation and tumorigenesis. In contrast, overexpression of the Notch3 intracellular domain upregulated PTEN and inhibited cell proliferation and tumorigenesis in vitro and in vivo. Moreover, inhibition or overexpression of PTEN partially reversed the promotion or inhibition of cell proliferation induced by Notch3 alterations. In general, Notch3 expression positively correlated with elevated expression of PTEN, ER, lower Ki-67 index, and incidence of involved node status and predicted better recurrence-free survival in breast cancer patients. Therefore, our findings demonstrate that Notch3 inhibits breast cancer proliferation and suppresses tumorigenesis by transactivating PTEN expression.

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The nucleolar protein NIFK promotes cancer progression via CK1α/β-catenin in metastasis and Ki-67-dependent cell proliferation

eLife ◽

10.7554/elife.11288 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 20

Author(s):

Tsung-Chieh Lin ◽

Chia-Yi Su ◽

Pei-Yu Wu ◽

Tsung-Ching Lai ◽

Wen-An Pan ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Nucleolar Protein ◽

Fha Domain ◽

Ki 67 ◽

Interacting Protein ◽

Dependent Cell

Nucleolar protein interacting with the FHA domain of pKi-67 (NIFK) is a Ki-67-interacting protein. However, its precise function in cancer remains largely uninvestigated. Here we show the clinical significance and metastatic mechanism of NIFK in lung cancer. NIFK expression is clinically associated with poor prognosis and metastasis. Furthermore, NIFK enhances Ki-67-dependent proliferation, and promotes migration, invasion in vitro and metastasis in vivo via downregulation of casein kinase 1α (CK1α), a suppressor of pro-metastatic TCF4/β-catenin signaling. Inversely, CK1α is upregulated upon NIFK knockdown. The silencing of CK1α expression in NIFK-silenced cells restores TCF4/β-catenin transcriptional activity, cell migration, and metastasis. Furthermore, RUNX1 is identified as a transcription factor of CSNK1A1 (CK1α) that is negatively regulated by NIFK. Our results demonstrate the prognostic value of NIFK, and suggest that NIFK is required for lung cancer progression via the RUNX1-dependent CK1α repression, which activates TCF4/β-catenin signaling in metastasis and the Ki-67-dependent regulation in cell proliferation.

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