Regulation Of Cancer Cell Growth Research Articles

Abstract A45: In silico drug discovery targeting Hippo pathway and YAP-TEAD protein-protein interactions for small-molecule anticancer agent

Abstract The Hippo pathway is one of the important pathways regulating tissue growth and proliferation. Dysregulation of this pathway can result in overgrowth of phenotypes because of a malfunction of stem cell proliferation, differentiation, and apoptosis, which are directly involved with components to cancer cell developments. Protein-protein interaction (PPI) in YAP (Yes-associated protein) and TEAD (transcriptional enhancer associate domain) is a key interaction that regulates cancer cell growth in the Hippo pathway. Regulating YAP-TEAD protein-protein interaction by small molecules could play an important role in cancer therapy. In this study, we identified small molecules inhibiting YAP-TEAD interactions by an in silico approach. Molecular hits were identified by pharmacophore-based virtual screening. The hit compounds from virtual screening were tested by surface plasmon resonance (SPR), Luciferase activity test. As a result, several hit compounds were identified to inhibit YAP-TEAD protein-protein interactions. These selected hit compounds were also evaluated by molecular docking study and FMO (fragment molecular orbital) binding energy calculations. In our overall results, we identified hit compounds to inhibit YAP-TEAD PPIs and also analyzed hit compounds’ binding interaction energy to TEAD protein. Citation Format: Kim Jongwan, Hocheol Lim, K.T. No. In silico drug discovery targeting Hippo pathway and YAP-TEAD protein-protein interactions for small-molecule anticancer agent [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A45.

Physical activity and advanced cancer: evidence of exercise-sensitive genes regulating prostate cancer cell proliferation and apoptosis.

Physical activity is known to protect against cancer. The resistance exercise method whole-body electromyostimulation (WB-EMS) has a significant anti-cancer effect. WB-EMS-conditioned serum from advanced prostate cancer patients decreased human prostate carcinoma cell growth and viability in vitro. Multiplex analysis revealed that genes associated with human prostate cancer cell proliferation and apoptosis are sensitive for exercise. Feasible exercise should be part of multimodal anti-cancer therapies, also for physically weakened patients. Regular physical activity is known to protect against cancer development. In cancer survivors, exercise reduces the risk of cancer recurrence and mortality. However, the link between exercise and decreased cancer risk and improved survival is still not well understood. Serum from exercising healthy individuals inhibits proliferation and activates apoptosis in various cancer cells, suggesting that mechanisms regulating cancer cell growth are affected by exercise. For the first time, we analysed serum from advanced-stage cancer patients with prostate (exercise group n = 8; control group n = 10) or colorectal (exercise n = 6; control n = 6) cancer, after a 12-week whole-body electromyostimulation training (20 min/session, 2×/week; frequency 85 Hz; pulse width 350 µs; 6 s stimulation, 4 s rest), a tolerable, yet effective, resistance exercise for physically weakened patients. We report that serum from these advanced cancer patients inhibits proliferation and enhances apoptosis of human prostate and colon cancer cells in vitro using cell growth and death assays (5-bromo-2'-deoxyuridine incorporation, cell counting, DNA fragmentation). Exercise-mimicking electric pulse stimulation of human primary myotubes showed that electric pulse stimulation-conditioned myotube medium also impairs human cancer cell viability. Gene expression analysis using a multiplex array of cancer-associated genes and subsequent quantitative RT-PCR revealed the presence of exercise-sensitive genes in human prostate cancer cells that potentially participate in the exercise-mediated regulation of malignant cell growth and apoptosis. Our data document the strong efficiency of the anti-oncogenic effects of physical activity and will further support the application of regular therapeutic exercise during cancer disease.

The Role of Nuclear Receptor Subfamily 1 Group H Member 4 (NR1H4) in Colon Cancer Cell Survival through the Regulation of c-Myc Stability.

Nuclear receptor subfamily group H member 4 (NR1H4), also known as farnesoid X receptor, has been implicated in several cellular processes in the liver and intestine. Preclinical and clinical studies have suggested a role of NR1H4 in colon cancer development; however, how NR1H4 regulates colon cancer cell growth and survival remains unclear. We generated NR1H4 knockout (KO) colon cancer cells using clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 nuclease (CAS9) technology and explored the effects of NR1H4 KO in colon cancer cell proliferation, survival, and apoptosis. Interestingly, NR1H4 KO cells showed impaired cell proliferation, reduced colony formation, and increased apoptotic cell death compared to control colon cancer cells. We identified MYC as an important mediator of the signaling pathway alterations induced by NR1H4 KO. NR1H4 silencing in colon cancer cells resulted in reduced MYC protein levels, while NR1H4 activation using an NR1H4 ligand, chenodeoxycholic acid, resulted in time- and dose-dependent MYC induction. Moreover, NR1H4 KO enhanced the anti-cancer effects of doxorubicin and cisplatin, supporting the role of MYC in the enhanced apoptosis observed in NR1H4 KO cells. Taken together, our findings suggest that modulating NR1H4 activity in colon cancer cells might be a promising alternative approach to treat cancer using MYC-targeting agents.

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

The p53 tumor suppressor protein and its major negative regulators MDM2 and MDMX oncoproteins form the MDM2/MDMX-p53 circuitry, which plays critical roles in regulating cancer cell growth, proliferation, cell cycle progression, apoptosis, senescence, angiogenesis, and immune response. Recent studies have shown that the stabilities of p53, MDM2, and MDMX are tightly controlled by the ubiquitin-proteasome system. Ubiquitin specific protease 7 (USP7), one of the most studied deubiquitinating enzymes plays a crucial role in protecting MDM2 and MDMX from ubiquitination-mediated proteasomal degradation. USP7 is overexpressed in human cancers and contributes to cancer initiation and progression. USP7 inhibition promotes the degradation of MDM2 and MDMX, activates the p53 signaling, and causes cell cycle arrest and apoptosis, making USP7 a potential target for cancer therapy. Several small-molecule inhibitors of USP7 have been developed and shown promising efficacy in preclinical settings. In the present review, we focus on recent advances in the understanding of the USP7-MDM2/MDMX-p53 network in human cancers as well as the discovery and development of USP7 inhibitors for cancer therapy.

A tumor-specific modulation of heterogeneous ribonucleoprotein A0 promotes excessive mitosis and growth in colorectal cancer cells

RNA regulation mediating RNA-binding proteins (RBPs) have been shown to be related to the maintenance of homeostasis as well as cancer progression. However, the tumor-associated functions as well as the detailed mechanisms underlying the anti-tumor effects of most RBPs have yet to be explored. We herein report that the phosphorylated heterogeneous ribonucleoprotein (hnRNP) A0 promotes mitosis through the RAS-associated protein 3 GTPase-activating protein catalytic subunit 1 (RAB3GAP1)-Zeste white 10 interactor (ZWINT1) cascade. The downregulation assay of 20 representative hnRNPs, a major family of RNA-binding proteins, in colorectal cancer cells revealed that hnRNPA0 is a strong regulator of cancer cell growth. The tumor promotive function of hnRNPA0 was confirmed in gastrointestinal cancer cells, including pancreatic, esophageal, and gastric cancer cells, but not in non-cancerous cells. Flow cytometry and Western blotting analyses revealed that hnRNPA0 inhibited the apoptosis through the maintenance of G2/M phase promotion in colorectal cancer cells. A comprehensive analysis of mRNAs regulated by hnRNP A0 and immunostaining revealed that mitotic events were regulated by the hnRNPA0-RAB3GAP1 mRNA-mediated ZWINT-1 stabilization in colorectal cancer cells, but not in non-tumorous cells. The interaction of hnRNP A0 with mRNAs was dramatically changed by the deactivation of its phosphorylation site in cancer cells, but not in non-tumorous cells. Therefore, the tumor-specific biological functions characterized by the abnormal phosphorylation of RBPs are considered to be an attractive target for tumor treatment.

Assessing the Global Impact of an Adenylate Kinase Isoenzyme on AMPK and mTOR Signaling Pathways Through Metabolic Profiling in both Brain and Lung Cancer Cell Lines

In a variety of human cancers, it is well observed that specific altered bioenergetic programs must be sustained in order to maintain the cancer cell phenotype. Well‐described genes play a role in sustaining energy flux for the cancer cell and recent studies add the regulation of AK4 expression, an adenylate kinase localized to the mitochondrial matrix, to the list. Our results demonstrate that in response to altered AK4 expression in cancer cells, intracellular ATP levels drastically increase. Secondly, we demonstrate that in response to perturbed AK4 expression in cancer cells, two critical homeostatic signaling pathways, the 5′ AMP‐activated protein kinase (AMPK) and a mammalian target of rapamycin (mTOR) pathways, are significantly altered. Both mTOR and AMPK proteins govern a metabolic pathway in which they sense cellular energy levels and nutrient status in response to regulate cancer cell growth and/or proliferation. Lastly, AK4 also has an impact on other bioenergetic pathways. For instance, AK4 can catalyze the reaction GTP + AMP ↔ GDP + ADP24 and sustain critical energy flux of nucleotides in the cell. Because AK4 expression appears to regulate cellular metabolic responses at multiple levels, further analyses by obtaining a metabolomic profile is necessary to highlight the global impact AK4 exerts on all the metabolites in the cancer cell. To do this, cell lines will be engineered without the AK4 gene in glioblastomas, lung adenocarcinomas, and HeLa cells then analyzed to identify all known metabolites in the system. It is hypothesized that without the expression of an AK4 protein there will be indirect or direct disruptions in the global nucleotide pools by either increasing nucleotide biosynthesis or decreasing nucleotide consumption. The outcome of this study will add to the small library of research on AK4 as well as provide a comprehensive understanding on the enzymatic activity and interactions where AK4 exerts its biological effects on cancer cell metabolism.Support or Funding InformationFunded by National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS) Grant 1R15GM123382‐01.

Identification of Core Gene Expression Signature and Key Pathways in Colorectal Cancer.

ObjectiveColorectal cancer (CRC) is considered the most prevalent malignant tumor that contributes to high cancer-related mortality. However, the signaling pathways involved in CRC and CRC-driven genes are largely unknown. We sought to discover a novel biomarker in CRC.Materials and MethodsAll clinical CRC samples (n = 20) were from Renmin Hospital of Wuhan University. We first selected MAD2L1 by integrated bioinformatics analysis of a GSE dataset. Next, the expression of MAD2L1 in tissues and cell lines was verified by quantitative real-time PCR. The effects of MAD2L1 on cell growth, proliferation, the cell cycle, and apoptosis were examined by in vitro assays.ResultsWe identified 683 shared DEGs (420 upregulated and 263 downregulated), and the top twenty genes (CDK1, CCNA2, TOP2A, PLK1, MAD2L1, AURKA, BUB1B, UBE2C, TPX2, RRM2, KIF11, NCAPG, MELK, NUSAP1, MCM4, RFC4, PTTG1, CHEK1, CEP55, DTL) were selected by integrated analysis. These hub genes were significantly overexpressed in CRC samples and were positively correlated. Our data revealed that the expression of MAD2L1 in CRC tissues is higher than that in normal tissues. MAD2L1 knockdown significantly suppressed CRC cell growth by impairing cell cycle progression and inducing cell apoptosis.ConclusionMAD2L1, as a novel oncogenic gene, plays a role in regulating cancer cell growth and apoptosis and could be used as a new biomarker for diagnosis and therapy in CRC.

Circ_0000079 Decoys the RNA-Binding Protein FXR1 to Interrupt Formation of the FXR1/PRCKI Complex and Decline Their Mediated Cell Invasion and Drug Resistance in NSCLC

Nonsmall cell lung cancer (NSCLC) has gradually become one of the deadliest threats to human health and life worldwide. Although reports have shown that circular RNAs (circRNAs) are associated with progression and metastasis of NSCLC, the biological functions of circRNAs during these processes remain largely unknown. Our study showed that circ_0000079 (CiR79) levels were significantly downregulated in NSCLC patients, especially in cisplatin (DDP)-resistant NSCLC patients, and low circ_0000079 levels were significantly associated with poor overall survival of NSCLC patients. Then, results from Cell Counting Kit-8 (CCK-8) cell viability assay and transwell cell invasion assay in A549/DDP and H460/DDP cells transfected with pCDH-CiR79 expression vector showed that circ_0000079 overexpression significantly inhibited cell proliferation and invasion of these DDP-resistant NSCLC cells. The online bioinformatic program StarBase and RNA-binding protein immunoprecipitation predicted and demonstrated that circ_0000079 could bind with the Fragile X-Related 1 (FXR1) protein rather than with protein kinase C, iota (PRKCI), which was shown to form a complex with FXR1 to promote invasion and growth of NSCLC cells. Co-immunoprecipitation combined with Western blot assays indicated that FXR1 levels were remarkably decreased, but PRKCI levels remained unchanged in pCDH-ciR79 transfected NSCLC cells. Moreover, circ_0000079 negatively regulated FXR1/PRKCI-mediated phosphorylation of glycogen synthesis kinase 3β and activator protein 1, thus suppressing the protein level of the Snail gene, an important promoter gene regulating cancer cell growth and epithelial-mesenchymal transition. Furthermore, DDP resistance of A549/DDP and H460/DDP cells was inhibited by circ_0000079 overexpression but was restored by FXR1. Hence, our findings demonstrated that circ_0000079 might inhibit cell invasion and drug resistance in NSCLC by interrupting the formation of the FXR1/PRCKI complex by interacting with FXR1, and circ_0000079 could act as a potential biomarker and therapeutic target for NSCLC.

A tumor suppressor DLC1: The functions and signal pathways.

Deleted in liver cancer-1 (DLC1), a potential tumor suppressor, acts as a GTPase-activating protein for Rho family members. In many human cancers, the DLC1 expression is frequently downregulated or inactivated, which allows cancer cells to proliferate and disseminate. In this review, we describe the characteristics and other members of the DLC1 family and delineate the signal pathways DLC1 involved in regulating cancer cell growth, colony formation, apoptosis, senescence, autophagy, migration and invasion. In addition, we explore the clinical data of DLC1 and the mechanisms that natural products upregulate the DLC1 expression to inhibit cancer. Despite these insights, many important unanswered questions remain about the exact mechanisms of DLC1-mediated cancer suppression.

MicroRNA‑381 regulates the growth of gastric cancer cell by targeting TWIST1.

Gastric cancer (GC) has one of the highest mortality rates among all types of cancer in the world. At present, an efficient treatment for GC remains elusive. Studies have demonstrated that microRNAs (miRs) are abnormally expressed in cancer, and that these serve important roles in the development and metastasis of various human tumors, including GC. It has been suggested that regulation of miRs may bring about new developments in GC therapy. miR‑381 has been reported to be downregulated in human cancer, and it regulates cancer cell growth in numerous types of cancer. The present study reports that miR‑381 was downregulated in GC cells, and upregulation of miR‑381 may inhibit GC cell growth, which may be attributed to the inhibition of cell proliferation and the promotion of apoptosis. Furthermore, Twist‑related protein 1 (TWIST1) was predicted and confirmed to be a direct target of miR‑381 by dual‑luciferase assay in GC. Upregulation of miR‑381 caused a decrease in the expression of TWIST1 at the mRNA and protein levels in GC cells. Taken together, the present study demonstrated that miR‑381 is downregulated in GC cells, and that miR‑381 may inhibit GC cell growth. Therefore, miR‑381 may serve as a novel target for the clinical treatment of GC in the future.

A turn-on fluorescent GFP chromophore analog for highly selective and efficient detection of H2S in aqueous and in living cells

Hydrogen sulphide is a gaseous neurotransmitter responsible for neuronal function and controls vast range of physiological functions. Herein, we report the synthesis and evaluation of novel Green Fluorescent Protein (GFP) chromophore analog, acryloyl-4-(p-hydroxybenzylidene)-5-imidazolidinone (AHBI) for turn-on fluorescent detection of H2S over wide range of anions and various biologically important competitive thiols. AHBI probe exhibited high selectivity and sensitivity, high fluorescence stability, large stokes shift and lower detection limit (15.85 ppb) for H2S in complete water medium. Cell imaging studies in human colon cancer cells (HCT116) and normal human dermal fibroblasts (HDF) confirmed the compatibility and versatility of AHBI probe at micromolar level. Overall, we believe the AHBI, as an optical probe will be useful to investigate the role of H2S in various physiological processes, regulation of cancer cell growth, and in pathogenic events.

OBG-like ATPase 1 inhibition attenuates angiotensin II-induced hypertrophic response in human ventricular myocytes via GSK-3beta/beta-catenin signalling.

Obg-like ATPase 1 (OLA1) that possesses both GTP and ATP hydrolyzing activities has been shown to be involved in translational regulation of cancer cell growth and survival. Also, GSK3β signalling has been implicated in cardiac development and disease. However, the role of OLA1 in pathological cardiac hypertrophy is unknown. We sought to understand the mechanism by which OLA1 regulates GSK3β-β-Catenin signalling and its functional significance in angiotensin-II (ANG II)-induced cardiac hypertrophic response. OLA1 function and its endogenous interaction with GSK3β/β-catenin signalling in cultured human ventricular cardiomyocytes (AC16 cells) and mouse hearts (in vivo) was evaluated with/without ANG II-stimulated hypertrophic response. ANG II administration in mice increases myocardial OLA1 protein expression with a corresponding increase in GSK3β phosphorylation and decrease in β-Catenin phosphorylation. Cultured cardiomyocytes treated with ANG II show endogenous interaction between OLA1 and GSK3β, nuclear accumulation of β-Catenin and significant increase in cell size and expression of hypertrophic marker genes such as atrial natriuretic factor (ANF; NPPA) and β-myosin heavy chain (MYH7). Intriguingly, OLA1 inhibition attenuates the above hypertrophic response in cardiomyocytes. Taken together, our data suggest that OLA1 plays a detrimental role in hypertrophic response via GSK3β/β-catenin signalling. Translation strategies to target OLA1 might potentially limit the underlying molecular derangements leading to left ventricular dysfunction in patients with maladaptive cardiac hypertrophy.

AMP-activated protein kinase regulates cancer cell growth and metabolism via nuclear and mitochondria events.

Adenine monophosphate‐activated protein kinase (AMPK) is a fuel sensing enzyme that is activated in shortage of energy and inhibited in its surplus. Cancer is a metabolic disease characteristic of aerobic glycolysis, namely Warburg effect, and possesses heterogeneity featured by spatiotemporal hypoxia and normoxia, where AMPK is deeply implicated. The present study delineates the regulation of mitochondrial functions by AMPK in cancer cells. On the one hand, AMPKα subunit binds to mitochondria independently of β subunit and targeting AMPK to mitochondria facilitates oxidative phosphorylation and fatty acid oxidation, and inhibits glycolysis. As such, mitochondrial AMPK inhibits the growth of cancer cells and tumorigenesis. On the other hand, ablation of the β subunits completely abolishes AMPK activity and simultaneously leads to decreases in mitochondria DNA and protein contents. The effect of the β deletion is rescued by overexpression of the active mutant of bulky AMPKα1 subunit. In conjunction, the transcriptional factors PGC1α and Nrf‐1 are up‐regulated by LKB1/AMPK, an event that is abolished in the absence of the β subunits. Intriguingly, the stimulation of mitochondria biogenesis is not achieved by mitochondria‐targeted AMPK. Therefore, our study suggests that AMPK inhibits cancer cell growth and tumorigenesis via regulation of mitochondria‐mediated metabolism.

Crucial role of the pentose phosphate pathway in malignant tumors.

Interest in cancer metabolism has increased in recent years. The pentose phosphate pathway (PPP) is a major glucose catabolism pathway that directs glucose flux to its oxidative branch and leads to the production of a reduced form of nicotinamide adenine dinucleotide phosphate and nucleic acid. The PPP serves a vital role in regulating cancer cell growth and involves many enzymes. The aim of the present review was to describe the recent discoveries associated with the deregulatory mechanisms of the PPP and glycolysis in malignant tumors, particularly in hepatocellular carcinoma, breast and lung cancer.

The therapeutic efficacy for targeting the PI3K signaling pathway for fighting breast, prostate and multiple myeloma cancer cells

The PI3K signaling pathway is involved in the regulation of cancer cell growth, motility, survival and metabolism. This pathway is frequently active in many different types of cancer as breast, prostate and multiple myeloma. Targetable genetic aberrations in this pathway give the researchers many opportunities for the development of targeted therapies for different types of cancer. The high frequency of mutations in this pathway in multiple types of cancer has led to the development of small-molecule inhibitors of PI3K, several of which are currently in clinical trials. However, several feedback mechanisms either within the PI3K pathway or in compensatory pathways can render tumor cells resistant to therapy. Here, we give insight into the importance of the PI3K pathway as a target for cancer therapy and discuss the potential clinical efficacy of PI3K inhibitors. We mainly focused on the roles of PI3K signaling pathway in three cancer cell types including breast cancer, prostate cancer and multiple myeloma cancer.

THE DEPENDENCE OF MALIGNANT CELLS' GROWTH RATE ON THE CHARACTERISTICS OF THE STATIC MAGNETIC FIELD

We identified patterns of K562 cell line of human erythroleukemia growth speed change depending on such magnetic field characteristics as magnetic field strength, direction and time of exposure. We identified presence of growth speed extremum in the function of magnetic field exposure time. Based on the generally accepted assumption that main biochemical reactions of energy carriers’ synthesis in biological objects have spin-spin relationships between chemical elements participating in chemical reactions, they depend on magnetic field and electromagnetic microwave field. Hopefully, clarification of energy carriers’ synthesis mechanism in cancer cells will allow us to evaluate the probability of decrease of its effectiveness in terms of proliferation and probably establish examples of magnetobiological effects practical use for cancer cell growth regulation.

Biochemical and Pharmacological Applications of Essential Oils in Human Health Especially in Cancer Prevention.

Essential oils (EOs) are aromatic, volatile and concentrated hydrophobic liquids extracted from plant material. EOs are also called as ethereal oils, volatile oils or aetherolea. EOs also play a crucial role in plant defence and signalling processes. They are mostly used in perfumes, cosmetics, soaps and other products for flavouring food, drinks, adding scents to incense and household cleaning products. EOs have a long medicinal history. Reported research literature and online contents related to the use of EOs for their biochemical pharmacological applications in cancer prevention therapy were reviewed. The most relevant and updated citations were included in this review. This review elaborates the various types of EOs, their biochemical characteristics, and pharmacology. Medicinal benefits of essential oil products range from various skin treatments to different types of therapies for cancer and are dependent entirely on historical backgrounds of use of EOs for these properties. EOs have antimicrobial, anticancer, antioxidant, antiparasitical, insecticidal, anti-inflammatory, viricidal, fungicidal, wound healing, antihypertensive, analgesic properties and other medicinal properties. The efficiency of EOs in medical treatments and treatment of cancers are these days a subject of interest in most countries. This review elaborated the potentials of EOs in regulating cancer cell growth and have explored the probable EOs that can be used in drug development.

The oncogenic roles of TRPM ion channels in cancer.

Transient receptor potential (TRP) proteins are a diverse family of ion channels present in multiple types of tissues. They function as gatekeepers for responses to sensory stimuli including temperature, vision, taste, and pain through their activities in conducting ion fluxes. The TRPM (melastatin) subfamily consists of eight members (i.e., TRPM1-8), which collectively regulate fluxes of various types of cations such as K+ , Na+ , Ca2+ , and Mg2+ . Growing evidence in the past two decades indicates that TRPM ion channels, their isoforms, or long noncoding RNAs encoded within the locus may be oncogenes involved in the regulation of cancer cell growth, proliferation, autophagy, invasion, and epithelial-mesenchymal transition, and their significant association with poor clinical outcomes of cancer patients. In this review, we describe and discuss recent findings implicating TRPM channels in different malignancies, their functions, mechanisms, and signaling pathways involved in cancers, as well as summarizing their normal physiological functions and the availability of ion channel pharmacological inhibitors.

The interaction of p130Cas with PKN3 promotes malignant growth.

Protein p130Cas constitutes an adaptor protein mainly involved in integrin signaling downstream of Src kinase. Owing to its modular structure, p130Cas acts as a general regulator of cancer cell growth and invasiveness induced by different oncogenes. However, other mechanisms of p130Cas signaling leading to malignant progression are poorly understood. Here, we show a novel interaction of p130Cas with Ser/Thr kinase PKN3, which is implicated in prostate and breast cancer growth downstream of phosphoinositide 3‐kinase. This direct interaction is mediated by the p130Cas SH3 domain and the centrally located PKN3 polyproline sequence. PKN3 is the first identified Ser/Thr kinase to bind and phosphorylate p130Cas and to colocalize with p130Cas in cell structures that have a pro‐invasive function. Moreover, the PKN3–p130Cas interaction is important for mouse embryonic fibroblast growth and invasiveness independent of Src transformation, indicating a mechanism distinct from that previously characterized for p130Cas. Together, our results suggest that the PKN3–p130Cas complex represents an attractive therapeutic target in late‐stage malignancies.

CCNA2 acts as a novel biomarker in regulating the growth and apoptosis of colorectal cancer.

ObjectiveColorectal cancer (CRC) is considered to be the most prevalent malignant tumors that contribute to high cancer-related mortality. However, the signaling pathways involved in CRC and CRC-driven genes are largely unknown. We seek to discover a novel biomarker in CRC.Materials and methodsAll clinical CRC samples (n=33) were from Xiangya Hospital. We first selected CCNA2 by integrated bioinformatics analysis of four GSE databases. Next, the expression of CCNA2 in tissues and cell lines was verified by quantitative real-time PCR. The effects of CCNA2 on cell growth, proliferation, cell cycle, and apoptosis were examined by in vitro assays.ResultsWe identified 498 shared DEGs (294 upregulated and 204 downregulated), and the top ten hub genes were selected by integrated analysis. These hub genes were significantly overexpressed in CRC samples and were positively correlated. Our data revealed that the expression of CCNA2 in CRC tissues is higher than that in normal tissues. The CCNA2 knockdown could significantly suppress CRC cell growth by impairing cell cycle progression and inducing cell apoptosis.ConclusionCCNA2, as a novel oncogenic gene, plays a role in regulating cancer cell growth and apoptosis. It could be used as a new biomarker for diagnosis and therapy in CRC.