Gene Summary

Gene:KIAA1524; KIAA1524
Aliases: p90, CIP2A
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protein CIP2A
Source:NCBIAccessed: 25 June, 2015


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: KIAA1524 (cancer-related)

Wu Y, Gu TT, Zheng PS
CIP2A cooperates with H-Ras to promote epithelial-mesenchymal transition in cervical-cancer progression.
Cancer Lett. 2015; 356(2 Pt B):646-55 [PubMed] Related Publications
The oncoprotein Cancerous Inhibitor of PP2A (CIP2A) has been reported to interact with Protein phosphatase 2 (PP2A) to stabilize c-Myc and prevent its degradation, and high expression levels of CIP2A have been proved to be related to poor clinical outcomes in multiple cancers. Here, we not only proved that the expression of CIP2A is positively correlated with lymph-node metastasis and cervical-cancer progression, but also revealed a close correlation between the protein's expression and the expression levels of two core epithelial-to-mesenchymal transition (EMT) markers, Vimentin and Snail. In addition, we manipulated CIP2A expression to regulate EMT conversion and employed a pull-down assay, mass-spectrometric (MS) peptide sequencing, as well as bilateral co-immunoprecipitation to identify potentially interacting proteins in cervical-cancer cells. In this study, we proposed and successfully proved, for the first time, that CIP2A physically associates with H-Ras, which leads to the activation of the MEK/ERK signaling pathway and promotes EMT and cervical-cancer progression. Based on our observations and prior findings that CIP2A participates in c-Myc regulation, we conjecture that CIP2A may be a potentially promising molecular target for the adoptive therapy of human cancer.

Lei N, Peng B, Zhang JY
CIP2A regulates cell proliferation via the AKT signaling pathway in human lung cancer.
Oncol Rep. 2014; 32(4):1689-94 [PubMed] Free Access to Full Article Related Publications
Cancerous inhibitor of PP2A (CIP2A) is an intracellular endogenous protein phosphatase 2A (PP2A) inhibitor with oncogenic activities. Initially identified as a tumor-associated antigen (TAA) in gastric and liver cancer patients, CIP2A was overexpressed in a variety of cancer types. The overexpression of CIP2A in cancer cells is associated with increased cell proliferation. However, the mechanism of CIP2A in cancer cell proliferation remains poorly understood. In the present study, we reported that CIP2A can regulate AKT phosphorylation at S473 under growth factor stimulation and our results also showed that CIP2A may promote cell proliferation through the AKT signaling pathway. Notably, depletion of CIP2A did not induce a global change of AKT phosphatase activity, which indicated that CIP2A may recognize specific AKT targets and play certain roles in the signaling pathway. In addition, we detected that CIP2A expression was associated with mTOR phosphorylation. Our further analysis corroborated the relationship between CIP2A and AKT-mTOR signaling pathway. Therefore, our study addressed a novel role of CIP2A in mediating cancer progression through interacting with the AKT-mTOR signaling pathway.

Yu HC, Hung MH, Chen YL, et al.
Erlotinib derivative inhibits hepatocellular carcinoma by targeting CIP2A to reactivate protein phosphatase 2A.
Cell Death Dis. 2014; 5:e1359 [PubMed] Free Access to Full Article Related Publications
Protein phosphatase 2A (PP2A) is a tumor suppressor, which is functionally defective in various cancers. Previously, we found that PP2A activity determined the anticancer effect of bortezomib and erlotinib in hepatocellular carcinoma (HCC) cells. Here, we tested a novel erlotinib derivative, TD52, in four HCC cell lines, PLC5, Huh-7, Hep3B and Sk-Hep1. Using MTT and flow cytometry, we showed that TD52 had more potent apoptotic effects than erlotinib in HCC cells. TD52-induced apoptosis was associated with dose- and time- dependent reactivation of PP2A and downregulation of cancerous inhibitor of protein phosphatase 2A (CIP2A) and p-Akt. Inhibition of PP2A or ectopic expression of CIP2A or Akt in PLC5 cells abolished the effects of TD52. Furthermore, we demonstrated that TD52 affected the binding of Elk-1 to the proximal promoter of the CIP2A gene, thus downregulating transcription of CIP2A. Importantly, TD52-induced tumor inhibition was associated with reactivation of PP2A and downregulation of CIP2A and p-Akt in vivo. In conclusion, we found that enhancement of PP2A activity by inhibition of CIP2A determines the apoptotic effect induced by TD52. Our findings disclose the therapeutic mechanism of this novel targeted agent, and suggest the therapeutic potential and feasibility of developing PP2A enhancers as a novel anticancer strategy.

Wang J, Huang T, Sun J, et al.
CIP2A is overexpressed and involved in the pathogenesis of chronic myelocytic leukemia by interacting with breakpoint cluster region-Abelson leukemia virus.
Med Oncol. 2014; 31(8):112 [PubMed] Related Publications
To detect the expression of cancerous inhibitor of phosphatase 2A (CIP2A) in chronic myelocytic leukemia (CML) and investigate the mechanism underlying CIP2A knockdown-mediated cell proliferation and apoptosis as well as the interaction of CIP2A with breakpoint cluster region-Abelson leukemia virus (BCR-ABL). CIP2A mRNA and protein expression in chronic myelocytic leukemia-chronic (CML-CP) patients and healthy controls were determined by RT-PCR and Western blot. In vivo, c-Myc expression, PP2A activity, cell proliferation, and apoptosis of CML cells were detected with CIP2A depletion. In addition, the relationship among CIP2A, BCR-ABL, and tyrosine phosphatase SHP-1 was explored by depleting/overexpressing CIP2A or inhibiting BCR-ABL. The level of CIP2A mRNA was higher in CML-CP patients than healthy controls (56/74, 75.7 % vs. 1/35, 2.9 %, P < 0.001), and CIP2A protein was overexpressed in corresponding specimens. CIP2A knockdown by siRNA reduced the level of c-Myc protein and clonogenic formation, inhibited the activity of PP2A, K562 cell proliferation, and promoted cell apoptosis. Suppressing BCR-ABL by imatinib mesylate (IM) significantly decreased CIP2A expression. CIP2A knockdown decreased BCR-ABL but increased SHP-1 expression, and CIP2A overexpression had the reverse effect. CIP2A is overexpressed in CML-CP patients, and its expression may promote CML pathogenesis. CIP2A and BCR-ABL can regulate each other in a positive feedback loop. CIP2A may be a useful therapeutic target in CML-CP, particularly in patients with IM resistance. However, further studies are needed to validate the interaction between CIP2A and BCR-ABL using other tyrosine kinase inhibitors than IM.

De P, Carlson J, Leyland-Jones B, Dey N
Oncogenic nexus of cancerous inhibitor of protein phosphatase 2A (CIP2A): an oncoprotein with many hands.
Oncotarget. 2014; 5(13):4581-602 [PubMed] Free Access to Full Article Related Publications
Oncoprotein CIP2A a Cancerous Inhibitor of PP2A forms an "oncogenic nexus" by virtue of its control on PP2A and MYC stabilization in cancer cells. The expression and prognostic function of CIP2A in different solid tumors including colorectal carcinoma, head and neck cancers, gastric cancers, lung carcinoma, cholangiocarcinoma, esophageal cancers, pancreatic carcinoma, brain cancers, breast carcinoma, bladder cancers, ovarian carcinoma, renal cell carcinomas, tongue cancers, cervical carcinoma, prostate cancers, and oral carcinoma as well as a number of hematological malignancies are just beginning to emerge. Herein, we reviewed the recent progress in our understanding of (1) how an "oncogenic nexus" of CIP2A participates in the tumorigenic transformation of cells and (2) how we can prospect/view the clinical relevance of CIP2A in the context of cancer therapy. The review will try to understand the role of CIP2A (a) as a biomarker in cancers and evaluate the prognostic value of CIP2A in different cancers (b) as a therapeutic target in cancers and (c) in drug response and developing chemo-resistance in cancers.

Janghorban M, Farrell AS, Allen-Petersen BL, et al.
Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer.
Proc Natl Acad Sci U S A. 2014; 111(25):9157-62 [PubMed] Free Access to Full Article Related Publications
The transcription factor c-MYC is stabilized and activated by phosphorylation at serine 62 (S62) in breast cancer. Protein phosphatase 2A (PP2A) is a critical negative regulator of c-MYC through its ability to dephosphorylate S62. By inactivating c-MYC and other key signaling pathways, PP2A plays an important tumor suppressor function. Two endogenous inhibitors of PP2A, I2PP2A, Inhibitor-2 of PP2A (SET oncoprotein) and cancerous inhibitor of PP2A (CIP2A), inactivate PP2A and are overexpressed in several tumor types. Here we show that SET is overexpressed in about 50-60% and CIP2A in about 90% of breast cancers. Knockdown of SET or CIP2A reduces the tumorigenic potential of breast cancer cell lines both in vitro and in vivo. Treatment of breast cancer cells in vitro or in vivo with OP449, a novel SET antagonist, also decreases the tumorigenic potential of breast cancer cells and induces apoptosis. We show that this is, at least in part, due to decreased S62 phosphorylation of c-MYC and reduced c-MYC activity and target gene expression. Because of the ubiquitous expression and tumor suppressor activity of PP2A in cells, as well as the critical role of c-MYC in human cancer, we propose that activation of PP2A (here accomplished through antagonizing endogenous inhibitors) could be a novel antitumor strategy to posttranslationally target c-MYC in breast cancer.

Liu N, He QM, Chen JW, et al.
Overexpression of CIP2A is an independent prognostic indicator in nasopharyngeal carcinoma and its depletion suppresses cell proliferation and tumor growth.
Mol Cancer. 2014; 13:111 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that acts as a prognostic marker for several human malignancies. In this study, we investigated the clinical significance of CIP2A and its function in nasopharyngeal carcinoma (NPC).
METHODS: Quantitative RT-PCR, western blot, and immunohistochemistry analyses were used to quantify CIP2A expression in NPC cell lines and clinical samples. Kaplan-Meier curves were used to estimate the association between CIP2A expression and patient survival. The functional role of CIP2A in NPC cell lines was evaluated by small interfering RNA-mediated depletion of the protein followed by analyses of cell proliferation and xenograft growth.
RESULTS: CIP2A levels were upregulated in NPC cell lines and clinical samples at both the mRNA and protein levels (P < 0.01). Patients with high CIP2A expression had poorer overall survival (HR, 1.98; 95% CI, 1.16-3.34; P = 0.01) and poorer disease-free survival (HR, 1.68; 95% CI, 1.07-2.62; P = 0.02) rates than patients with low CIP2A expression. In addition, CIP2A expression status was an independent prognostic indicator for NPC patients. The depletion of CIP2A expression inhibited c-Myc protein expression in NPC cell lines, suppressed cell viability, colony formation, and anchorage-independent growth in vitro, and inhibited xenograft tumor growth in vivo.
CONCLUSIONS: Our data demonstrate that high CIP2A expression in patients was associated with poor survival in NPC, and depletion of CIP2A expression inhibited NPC cell proliferation and tumor growth. Thus, these results warrant further investigation of CIP2A as a novel therapeutic target for the treatment of NPC.

Wei L, Qu W, Sun J, et al.
Knockdown of cancerous inhibitor of protein phosphatase 2A may sensitize NSCLC cells to cisplatin.
Cancer Gene Ther. 2014; 21(5):194-9 [PubMed] Related Publications
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified human oncoprotein that can stabilize some proteins by inhibiting degradation mediated by protein phosphatase 2A (PP2A) and it increases the proliferation of several cancer cells. Recent studies have highlighted a potential role for CIP2A in promoting tumor progression and metastasis. However, whether CIP2A could increase chemoresistance of cancer cells to chemotherapeutic agent cisplatin remains unclear. To determine whether CIP2A serves as a potential therapeutic target of human non-small-cell lung cancer (NSCLC), we utilized small interference RNA (siRNA) to knock down CIP2A expression in human NSCLC cells and analyzed their phenotypic changes. The data demonstrated that CIP2A silencing led to decreased proliferation, impaired clonogenicity and enhanced chemosensitivity and apoptosis to cisplatin in human NSCLC cells, as well as reduced Akt phosphorylation. In addition, overexpression of CIP2A diminished NSCLC cell chemosensitivity to cisplatin by inducing activation of Akt pathway, suggesting critical roles of CIP2A in NSCLC cell chemoresistance to cisplatin and rasing the possibility of CIP2A inhibition as a promising approach for lung cancer therapy.

Wei Y, Du Y, Chen X, et al.
Expression patterns of microRNA-218 and its potential functions by targeting CIP2A and BMI1 genes in melanoma.
Tumour Biol. 2014; 35(8):8007-15 [PubMed] Related Publications
Melanoma is the most aggressive skin cancer, and it is typically resistant or rapidly develops resistance to a variety of chemotherapeutic agents. microRNAs (miRNAs) play a part in the occurrence and development of malignant melanoma. In this study, we analyzed the miR-218 expression level in melanoma patients and cell lines and observed alterations in proliferation, cell cycle, migration, and invasion by increasing miR-218 expression in melanoma cell lines. We also performed bioinformatic analyses using TargetScan and miRanda and cloned both the wild-type and mutant versions of the human cancerous inhibitor of protein phosphatase 2A (CIP2A) and B lymphoma Mo-MLV insertion region 1 (BMI1) 3'-UTR fragments into the pmirGLO reporter vector. We then used the Dual-Luciferase assay system, quantitative real-time RT-PCR (qRT-PCR), and Western blot analysis to determine that miR-218 targeted the 3'-UTR of the oncogenes CIP2A and BMI1 and thus regulated the biological process of melanoma. We further demonstrated that CIP2A and BMI1 knockdown phenocopies miR-218 overexpression. In conclusion, our findings have shown that miR-218 is downregulated in melanoma. By targeting CIP2A and BMI1, miR-218 regulates the proliferation, migration, and invasion of the melanoma cell lines A375 and SK-MEL-2, indicating that miR-218 plays a pivotal role in melanoma development.

Farrell AS, Allen-Petersen B, Daniel CJ, et al.
Targeting inhibitors of the tumor suppressor PP2A for the treatment of pancreatic cancer.
Mol Cancer Res. 2014; 12(6):924-39 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Pancreatic cancer is a deadly disease that is usually diagnosed in the advanced stages when few effective therapies are available. Given the aggressive clinical course of this disease and lack of good treatment options, the development of new therapeutic agents for the treatment of pancreatic cancer is of the upmost importance. Several pathways that have shown to contribute to pancreatic cancer progression are negatively regulated by the tumor suppressor protein phosphatase 2A (PP2A). Here, the endogenous inhibitors of PP2A, SET (also known as I2PP2A) and cancerous inhibitor of PP2A (CIP2A), were shown to be overexpressed in human pancreatic cancer, contributing to decreased PP2A activity and overexpression and stabilization of the oncoprotein c-Myc, a key PP2A target. Knockdown of SET or CIP2A increases PP2A activity, increases c-Myc degradation, and decreases the tumorigenic potential of pancreatic cancer cell lines both in vitro and in vivo. Moreover, treatment with a novel SET inhibitor, OP449, pharmacologically recapitulates the phenotypes and significantly reduces proliferation and tumorigenic potential of several pancreatic cancer cell lines, with an accompanying attenuation of cell growth and survival signaling. Furthermore, primary cells from patients with pancreatic cancer were sensitive to OP449 treatment, indicating that PP2A-regulated pathways are highly relevant to this deadly disease.
IMPLICATIONS: The PP2A inhibitors SET and CIP2A are overexpressed in human pancreatic cancer and are important for pancreatic cancer cell growth and transformation; thus, antagonizing SET and/or CIP2A may be an innovative approach for the treatment of human pancreatic cancer.

Wang HW, Yang SH, Huang GD, et al.
Temsirolimus enhances the efficacy of cetuximab in colon cancer through a CIP2A-dependent mechanism.
J Cancer Res Clin Oncol. 2014; 140(4):561-71 [PubMed] Related Publications
PURPOSE: A dozen clinical trials examining a combination of temsirolimus and cetuximab in treating metastatic colon cancer are currently underway. We investigated the role of cancerous inhibitor of protein phosphatase 2A (CIP2A) in the synergism between temsirolimus and cetuximab in colon cancer.
METHODS: Five colon cancer cell lines were used for in vitro studies. Signal transduction pathways were assessed by immunoblotting. The synergism between studied drugs was analyzed with combination indexes. Gene silencing was performed using small interfering RNAs. The efficacies of temsirolimus and cetuximab were tested in nude mice with colon cancer xenografts. Transcriptional activity was assessed using a reporter assay. The inhibitors leupeptin, chloroquine, and MG132 were used to assess protein degradation. The association between CIP2A, clinicopathological parameters, and survival was examined by immunohistochemical staining using a tumor tissue microarray.
RESULTS: Temsirolimus decreased the resistance of cells to cetuximab by both inhibiting transcription of CIP2A and increasing degradation of CIP2A through the lysosomal-autophagy pathway. The mammalian target of rapamycin (mTOR) protein immunoprecipitated along with CIP2A. Temsirolimus decreased expression of phosphorylated extracellular regulated protein kinase (pErk) and phosphorylated v-akt murine thymoma viral oncogene (pAKT) and decreased the interaction of CIP2A and mTOR in cell lines without the K-ras codon 12 mutation. CIP2A was a prognostic marker only in colon cancer patients with weak expression of pErk or pAKT.
CONCLUSIONS: Temsirolimus decreases cellular resistance to cetuximab by regulating CIP2A expression in colon cancer cells. Potential biomarkers for CIP2A inhibitors include pErk and pAKT.

Cristóbal I, Manso R, Rincón R, et al.
PP2A inhibition is a common event in colorectal cancer and its restoration using FTY720 shows promising therapeutic potential.
Mol Cancer Ther. 2014; 13(4):938-47 [PubMed] Related Publications
Protein phosphatase 2A (PP2A) is a tumor suppressor that regulates many signaling pathways crucial for cell transformation. In fact, decreased activity of PP2A has been reported as a recurrent alteration in many types of cancer. Here, we show that PP2A is frequently inactivated in patients with colorectal cancer, indicating that PP2A represents a potential therapeutic target for this disease. We identified overexpression of the endogenous PP2A inhibitors SET and CIP2A, and downregulation of regulatory PP2A such as PPP2R2A and PPP2R5E, as contributing mechanisms to PP2A inhibition in colorectal cancer. Moreover, we observed that its restoration using FTY720 impairs proliferation and clonogenic potential of colorectal cancer cells, induces caspase-dependent apoptosis, and affects AKT and extracellular signal-regulated kinase-1/2 activation status. Interestingly, treatment with FTY720 showed an additive effect with 5-fluorouracil, SN-38, and oxaliplatin, drugs used in standard chemotherapy in patients with colorectal cancer. These results suggest that PP2A activity is commonly decreased in colorectal cancer cells, and that the use of PP2A activators, such as FTY720, might represent a potential novel therapeutic strategy in colorectal cancer.

Zhao Y, Li Y, Han J, et al.
Helicobacter pylori enhances CIP2A expression and cell proliferation via JNK2/ATF2 signaling in human gastric cancer cells.
Int J Mol Med. 2014; 33(3):703-10 [PubMed] Related Publications
Helicobacter pylori (H. pylori) infection plays an important role in the development of gastric carcinomas. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a novel human oncoprotein that functions as an important regulator of cell growth and malignant transformation. In the present study, we aimed to investigate the potential mechanisms by which H. pylori upregulates the expression of CIP2A and the functional impact of H. pylori-induced CIP2A in gastric cancer cells. We demonstrated that infection of MKN-45 cells with H. pylori led to a marked increase in the expression of CIP2A at the mRNA and protein levels. H. pylori-induced CIP2A was associated with increased cell proliferation. In addition, H. pylori was found to activate the JNK2 pathway. Importantly, both H. pylori-induced CIP2A production and cell proliferation were partially reversed by inhibition of JNK2 signaling. Similarly, the blockade of H. pylori-induced CIP2A expression by siRNA against CIP2A also inhibited cell proliferation. Thus, H. pylori appears to stimulate the expression of CIP2A and proliferation of gastric cancer cells via JNK2 signaling. These findings suggest that H. pylori-induced upregulation of CIP2A contributes to the development and progression of gastric cancer. Further in vivo studies are warranted to explore the biological role of CIP2A and its interaction with JNK2 signaling in gastric cancer.

Shi F, Ding Y, Ju S, et al.
Expression and prognostic significance of CIP2A in cutaneous malignant melanoma.
Biomarkers. 2014; 19(1):70-6 [PubMed] Related Publications
OBJECTIVE: We investigated the expression and clinical significance of Cancerous inhibitor of protein phosphatase 2A (CIP2A) in Cutaneous malignant melanoma (CMM).
METHODS: CIP2A expression was analyzed by immunohistochemistry and western blot. We tested the invasion and migration capability of A375 cells with Matrigel invasion assay, Scratch migration assay and Matrigel migration assay after down-regulating CIP2A expression using siRNA.
RESULTS: CIP2A immunostaining level was correlated with Breslow thickness, Clark's Level and lymphovascular invasion. High-CIP2A expression implied poor survival for patients. Downregulation of CIP2A attenuated metastasis of CMM cells.
CONCLUSIONS: CIP2A may serve as a novel marker to predict the prognosis for CMM patients.

Hou DR, Huang AC, Shiau CW, et al.
Bortezomib congeners induce apoptosis of hepatocellular carcinoma via CIP2A inhibition.
Molecules. 2013; 18(12):15398-411 [PubMed] Related Publications
CIP2A is an oncoprotein that upregulates p-Akt and promotes cancer cell proliferation and survival. The proteasome inhibitor bortezomib has been shown to reduce CIP2A and lead to cell apoptosis. Here; we modified the functional group of bortezomib to generate a series of novel compounds and conducted a structure-activity relationship (SAR) study. The results showed that compound 1 was able to repress CIP2A expression and cell apoptosis in the same manner as bortezomib, but with less potency in inhibition of proteasome activity. This finding provides a new direction for the design of CIP2A inhibitors.

Srivastava P, Mangal M, Agarwal SM
Understanding the transcriptional regulation of cervix cancer using microarray gene expression data and promoter sequence analysis of a curated gene set.
Gene. 2014; 535(2):233-8 [PubMed] Related Publications
Cervical cancer, the malignant neoplasm of the cervix uteri is the second most common cancer among women worldwide and the top-most cancer in India. Several factors are responsible for causing cervical cancer, which alter the expression of oncogenic genes resulting in up or down-regulation of gene expression and inactivation of tumor-suppressor genes/gene products. Gene expression is regulated by interactions between transcription factors (TFs) and specific regulatory elements in the promoter regions of target genes. Thus, it is important to decipher and analyze TFs that bind to regulatory regions of diseased genes and regulate their expression. In the present study, computational methods involving the combination of gene expression data from microarray experiments and promoter sequence analysis of a curated gene set involved in the cervical cancer causation have been utilized for identifying potential regulatory elements. Consensus predictions of two approaches led to the identification of twelve TFs that might be crucial to the regulation of cervical cancer progression. Subsequently, TF enrichment and oncomine expression analysis suggested that the transcription factor family E2F played an important role for the regulation of genes involve in cervical carcinogenesis. Our results suggest that E2F possesses diagnostic/prognostic value and can act as a potential drug target in cervical cancer.

Khanna A, Pimanda JE, Westermarck J
Cancerous inhibitor of protein phosphatase 2A, an emerging human oncoprotein and a potential cancer therapy target.
Cancer Res. 2013; 73(22):6548-53 [PubMed] Related Publications
Protein phosphatase 2A (PP2A) complexes function as tumor suppressors by inhibiting the activity of several critical oncogenic signaling pathways. Consequently, inhibition of the PP2A phosphatase activity is one of many prerequisites for the transformation of normal human cells into cancerous cells. However, mechanisms for PP2A inactivation in human cancers are poorly understood. The aberrant expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), a recently identified endogenous PP2A inhibitor in malignant cells, is one such mechanism. Various independent studies have validated CIP2A's role in promoting tumor growth and resistance to apoptosis and senescence-inducing therapies. Notably, high CIP2A expression predicts poor patient prognosis in several human cancer types. Among the oncogenic proteins dephosphorylated by PP2A, the MYC oncoprotein, which is phosphorylated at serine 62, has surfaced as a marker for the oncogenic activity of CIP2A. The positive-feedback loop between CIP2A and MYC augments the activity of MYC in cancer cells. In addition, CIP2A promotes the phosphorylation and activity of additional oncoproteins, including E2F1 and AKT. However, CIP2A is not essential for normal mouse growth and development. These findings indicate that CIP2A is a novel anticancer target based on PP2A reactivation and inhibition of the oncogenic activity of its downstream effectors. The potential approaches and feasibility of targeting CIP2A are discussed here.

Wiegering A, Pfann C, Uthe FW, et al.
CIP2A influences survival in colon cancer and is critical for maintaining Myc expression.
PLoS One. 2013; 8(10):e75292 [PubMed] Free Access to Full Article Related Publications
The cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogenic factor that stabilises the c-Myc protein. CIP2A is overexpressed in several tumours, and expression levels are an independent marker for long-term outcome. To determine whether CIP2A expression is elevated in colon cancer and whether it might serve as a prognostic marker for survival, we analysed CIP2A mRNA expression by real-time PCR in 104 colon cancer samples. CIP2A mRNA was overexpressed in colon cancer samples and CIP2A expression levels correlated significantly with tumour stage. We found that CIP2A serves as an independent prognostic marker for disease-free and overall survival. Further, we investigated CIP2A-dependent effects on levels of c-Myc, Akt and on cell proliferation in three colon cancer cell lines by silencing CIP2A using small interfering (si) and short hairpin (sh) RNAs. Depletion of CIP2A substantially inhibited growth of colon cell lines and reduced c-Myc levels without affecting expression or function of the upstream regulatory kinase, Akt. Expression of CIP2A was found to be dependent on MAPK activity, linking elevated c-Myc expression to deregulated signal transduction in colon cancer.

Li D, Jin L, Alesi GN, et al.
The prometastatic ribosomal S6 kinase 2-cAMP response element-binding protein (RSK2-CREB) signaling pathway up-regulates the actin-binding protein fascin-1 to promote tumor metastasis.
J Biol Chem. 2013; 288(45):32528-38 [PubMed] Free Access to Full Article Related Publications
Metastasis is the leading cause of death in patients with breast, lung, and head and neck cancers. However, the molecular mechanisms underlying metastases in these cancers remain unclear. We found that the p90 ribosomal S6 kinase 2 (RSK2)-cAMP response element-binding protein (CREB) pathway is commonly activated in diverse metastatic human cancer cells, leading to up-regulation of a CREB transcription target Fascin-1. We also observed that the protein expression patterns of RSK2 and Fascin-1 correlate in primary human tumor tissue samples from head and neck squamous cell carcinoma patients. Moreover, knockdown of RSK2 disrupts filopodia formation and bundling in highly invasive cancer cells, leading to attenuated cancer cell invasion in vitro and tumor metastasis in vivo, whereas expression of Fascin-1 significantly rescues these phenotypes. Furthermore, targeting RSK2 with the small molecule RSK inhibitor FMK-MEA effectively attenuated the invasive and metastatic potential of cancer cells in vitro and in vivo, respectively. Taken together, our findings for the first time link RSK2-CREB signaling to filopodia formation and bundling through the up-regulation of Fascin-1, providing a proinvasive and prometastatic advantage to human cancers. Therefore, protein effectors of the RSK2-CREB-Fascin-1 pathway represent promising biomarkers and therapeutic targets in the clinical prognosis and treatment of metastatic human cancers.

Khanna A, Kauko O, Böckelman C, et al.
Chk1 targeting reactivates PP2A tumor suppressor activity in cancer cells.
Cancer Res. 2013; 73(22):6757-69 [PubMed] Free Access to Full Article Related Publications
Checkpoint kinase Chk1 is constitutively active in many cancer cell types and new generation Chk1 inhibitors show marked antitumor activity as single agents. Here we present a hitherto unrecognized mechanism that contributes to the response of cancer cells to Chk1-targeted therapy. Inhibiting chronic Chk1 activity in cancer cells induced the tumor suppressor activity of protein phosphatase protein phosphatase 2A (PP2A), which by dephosphorylating MYC serine 62, inhibited MYC activity and impaired cancer cell survival. Mechanistic investigations revealed that Chk1 inhibition activated PP2A by decreasing the transcription of cancerous inhibitor of PP2A (CIP2A), a chief inhibitor of PP2A activity. Inhibition of cancer cell clonogenicity by Chk1 inhibition could be rescued in vitro either by exogenous expression of CIP2A or by blocking the CIP2A-regulated PP2A complex. Chk1-mediated CIP2A regulation was extended in tumor models dependent on either Chk1 or CIP2A. The clinical relevance of CIP2A as a Chk1 effector protein was validated in several human cancer types, including neuroblastoma, where CIP2A was identified as an NMYC-independent prognostic factor. Because the Chk1-CIP2A-PP2A pathway is driven by DNA-PK activity, functioning regardless of p53 or ATM/ATR status, our results offer explanative power for understanding how Chk1 inhibitors mediate single-agent anticancer efficacy. Furthermore, they define CIP2A-PP2A status in cancer cells as a pharmacodynamic marker for their response to Chk1-targeted therapy.

Cantini L, Attaway CC, Butler B, et al.
Fusogenic-oligoarginine peptide-mediated delivery of siRNAs targeting the CIP2A oncogene into oral cancer cells.
PLoS One. 2013; 8(9):e73348 [PubMed] Free Access to Full Article Related Publications
Despite a better understanding of the pathogenesis of oral cancer, its treatment outcome remains poor. Thus, there is a need for new therapeutic strategies to improve the prognosis of this disease. RNA interference (RNAi) appears to be a promising therapeutic tool for the treatment of many diseases, including oral cancer. However, an obstacle for RNAi-mediated therapies has been delivery, in particular, the retention of small interfering RNAs (siRNAs) in endosomes and their subsequent degradation in lysosomes, resulting in inefficient gene silencing. Thus, the current study examined the feasibility of designing and utilizing a peptide, termed 599, consisting of a synthetic influenza virus-derived endosome-disruptive fusogenic peptide sequence and a stretch of cationic cell-penetrating nona(D-arginine) residues, to deliver siRNAs into oral cancer cells and induce silencing of the therapeutic target, CIP2A, an oncoprotein overexpressed in various human malignancies including oral cancer. Increasing the 599 peptide-to-siRNA molar ratio demonstrated a higher binding capacity for siRNA molecules and enhanced siRNA delivery into the cytoplasm of oral cancer cells. In fact, quantitative measurements of siRNA delivery into cells demonstrated that a 50∶1 peptide-to-siRNA molar ratio could deliver 18-fold higher amounts of siRNAs compared to cells treated with siRNA alone with no significant long-term cytotoxic effects. Most importantly, the 599 peptide-mediated siRNA delivery promoted significant CIP2A mRNA and protein silencing which resulted in decreased oral cancer cell invasiveness and anchorage-independent growth. Together, these data demonstrate that a chimeric peptide consisting of a fusogenic sequence, in combination with cell-penetrating residues, can be used to effectively deliver siRNAs into oral cancer cells and induce the silencing of its target gene, potentially offering a new therapeutic strategy in combating oral cancer.

Zhai M, Cong L, Han Y, Tu G
CIP2A is overexpressed in osteosarcoma and regulates cell proliferation and invasion.
Tumour Biol. 2014; 35(2):1123-8 [PubMed] Related Publications
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a newly characterized oncoprotein involved in a variety of malignant tumors. However, its expression pattern and biological functions in osteosarcoma remain unclear. In the present study, CIP2A expression was analyzed in 51 human osteosarcoma specimens using immunohistochemistry. CIP2A siRNA was used in the MG-63 cell line, and the effect of CIP2A depletion on cell proliferation and invasion was evaluated. We found that CIP2A was overexpressed in 76.5 % (39/51) of osteosarcoma tissues, while normal bone tissues showed negative CIP2A expression. In addition, the positive rate of CIP2A expression was higher in stage IIB osteosarcoma than stage IIA cases. Knockdown of the CIP2A expression significantly reduced osteosarcoma cell proliferation and invasion, with decreased c-Myc expression and p-AKT expression. CIP2A depletion also facilitated apoptosis and inhibited MMP9 mRNA expression. Taken together, our data identified CIP2A as a critical oncoprotein involved in cell proliferation and invasion, which could serve as a therapeutic target in osteosarcoma.

Kim JS, Kim EJ, Oh JS, et al.
CIP2A modulates cell-cycle progression in human cancer cells by regulating the stability and activity of Plk1.
Cancer Res. 2013; 73(22):6667-78 [PubMed] Related Publications
Abnormal cell-cycle control can lead to aberrant cell proliferation and cancer. The oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) is an inhibitor of protein phosphatase 2A (PP2A) that stabilizes c-Myc. However, the precise role of CIP2A in cell division is not understood. Herein, we show that CIP2A is required for mitotic progression by regulating the polo-like kinase (Plk1). With mitotic entry, CIP2A translocated from the cytoplasm to the nucleus, where it was enriched at spindle poles. CIP2A depletion delayed mitotic progression, resulting in mitotic abnormalities independent of PP2A activity. Unexpectedly, CIP2A interacted directly with the polo-box domain of Plk1 during mitosis. This interaction was required to maintain Plk1 stability by blocking APC/C-Cdh1-dependent proteolysis, thereby enhancing the kinase activity of Plk1 during mitosis. We observed strong correlation and in vivo interactions between these two proteins in multiple human cancer specimens. Overall, our results established a novel function for CIP2A in facilitating the stability and activity of the pivotal mitotic kinase Plk1 in cell-cycle progression and tumor development.

Sung WW, Wang YC, Lin PL, et al.
IL-10 promotes tumor aggressiveness via upregulation of CIP2A transcription in lung adenocarcinoma.
Clin Cancer Res. 2013; 19(15):4092-103 [PubMed] Related Publications
PURPOSE: Interleukin-10 (IL-10) determines virus persistent infection and promotes viral-associated tumor progression via tumor immune escape. However, the role of IL-10 in tumor progression and prognosis in lung adenocarcinoma remains controversial.
EXPERIMENTAL DESIGN: To investigate how IL-10 is regulated by HPV E6, IL-10 promoter was constructed to understand which transcriptional factor could be responsible for its transcription. To verify which molecule could be responsible for IL-10-mediated soft agar growth and invasion capability, PCR array and mechanistic strategies were conducted. IL-10 and CIP2A mRNA levels in lung tumors from patients with lung cancer were determined by real-time reverse transcription PCR. The prognostic value of both molecules on survival was estimated by Cox regression model.
RESULTS: Mechanistic studies showed that IL-10 protein and mRNA expression was decreased in E6 knockdown TL1 cells and increased in E6- overexpressing TL4 cells. In addition, IL-10 transcription was predominantly regulated by E6-mediated phosphorylation of cAMP response element-binding protein (CREB) and C/enhancer-binding protein β (C/EBPβ) via phosphoinositide 3-kinase (PI3K) signaling pathway. IL-10-mediated tumor aggressiveness in vitro and in vivo occurs through increased CIP2A expression via PI3K signaling pathway. Among patients, IL-10 mRNA expression in lung tumors was positively correlated with CIP2A mRNA expression. Cox-regression analysis showed that IL-10 and CIP2A mRNA levels may independently predict survival in patients with lung adenocarcinoma, especially in patients with E6-positive tumors.
CONCLUSION: IL-10 production from lung tumors and immune cells promotes lung adenocarcinoma aggressiveness and patients with poor survival. We thus suggest that PI3K inhibitor combined with chemotherapy may potentially enhance tumor regression and improve patients' outcome and life quality.

Jung HM, Patel RS, Phillips BL, et al.
Tumor suppressor miR-375 regulates MYC expression via repression of CIP2A coding sequence through multiple miRNA-mRNA interactions.
Mol Biol Cell. 2013; 24(11):1638-48, S1-7 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) are small, noncoding RNAs involved in posttranscriptional regulation of protein-coding genes in various biological processes. In our preliminary miRNA microarray analysis, miR-375 was identified as the most underexpressed in human oral tumor versus controls. The purpose of the present study is to examine the function of miR-375 as a candidate tumor suppressor miRNA in oral cancer. Cancerous inhibitor of PP2A (CIP2A), a guardian of oncoprotein MYC, is identified as a candidate miR-375 target based on bioinformatics. Luciferase assay accompanied by target sequence mutagenesis elucidates five functional miR-375-binding sites clustered in the CIP2A coding sequence close to the C-terminal domain. Overexpression of CIP2A is clearly demonstrated in oral cancers, and inverse correlation between miR-375 and CIP2A is observed in the tumors, as well as in NCI-60 cell lines, indicating the potential generalized involvement of the miR-375-CIP2A relationship in many other cancers. Transient transfection of miR-375 in oral cancer cells reduces the expression of CIP2A, resulting in decrease of MYC protein levels and leading to reduced proliferation, colony formation, migration, and invasion. Therefore this study shows that underexpression of tumor suppressor miR-375 could lead to uncontrolled CIP2A expression and extended stability of MYC, which contributes to promoting cancerous phenotypes.

Yu G, Liu G, Dong J, Jin Y
Clinical implications of CIP2A protein expression in breast cancer.
Med Oncol. 2013; 30(2):524 [PubMed] Related Publications
The aim of this work is to study the expression and regulatory effects of CIP2A protein in breast cancer and the correlation between CIP2A protein expression and the prognosis of breast cancer. The CIP2A protein level was detected by immunohistochemistry staining. The relationship between CIP2A protein and clinicopathological parameters of breast cancer was determined. It was observed that 448 (35.00 %) of the 1,280 cases positively expressed CIP2A protein. Univariate analysis indicated that CIP2A expression was related to histological grade, lymph node metastasis, distant metastasis, and triple-negative breast cancer (P = 0.001, 0.001, 0.001, and 0.001, respectively). Spearman correlation analysis showed that CIP2A expression has line correlation with histological grade, lymph node metastasis, distant metastasis, triple-negative breast cancer, and TNM stage (P = 0.03, 0.001, 0.008, 0.001, and 0.001, respectively). After multivariate analysis, tumor size, histological grade, lymph node metastasis, triple-negative breast cancer, distant metastasis, and TNM stage were related to CIP2A expression (P = 0.035, 0.001, 0.028, 0.001, 0.001, and 0.001, respectively). CIP2A expression also significantly related to chemotherapeutic sensitivity of breast cancer in the neoadjuvant chemotherapy. In the Cox regression test, histological grade, lymph node metastasis, triple-negative breast cancer, and TNM stage were detected as the independent prognostic factors (P = 0.001, 0.006, 0.01, 0.011, and 0.001, respectively). CIP2A expression may be a potential biomarker for chemotherapeutic sensitivity and prognosis of breast cancer.

Yi F, Ni W, Liu W, et al.
Expression and biological role of CIP2A in human astrocytoma.
Mol Med Rep. 2013; 7(5):1376-80 [PubMed] Related Publications
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently characterized oncoprotein involved in the progression of several human malignancies. The present study aimed to investigate the clinical significance and biological function of CIP2A in astrocytoma. CIP2A expression was analyzed in 135 archived astrocytoma specimens using immunohistochemistry. Of these specimens, 75 cases (55.6%) overexpressed CIP2A. The CIP2A overexpression was observed to be positively correlated with advanced tumor grade (P<0.001). siRNA-mediated knockdown of CIP2A was performed in A172 and U87 cell lines. MTT, colony formation and soft agar colony formation assays and Annexin V/propidium iodide analysis were performed to assess the role of CIP2A in cell proliferation and apoptosis. CIP2A depletion in the astrocytoma cell lines inhibited cell growth, reduced anchorage‑independent cell growth and increased apoptosis. In addition, CIP2A depletion increased caspase‑3 cleavage and downregulated c‑Myc, Bcl‑2 and phospho‑Akt expression. These results validate the role of CIP2A as a clinically relevant oncoprotein and establish CIP2A as a promising therapeutic target of astrocytoma.

Yu HC, Hou DR, Liu CY, et al.
Cancerous inhibitor of protein phosphatase 2A mediates bortezomib-induced autophagy in hepatocellular carcinoma independent of proteasome.
PLoS One. 2013; 8(2):e55705 [PubMed] Free Access to Full Article Related Publications
Previously, we reported that cancerous inhibitor of protein phosphatase 2A (CIP2A) mediates the apoptotic effect of bortezomib in hepatocellular carcinoma (HCC). Here, we report a proteasome-independent mechanism by which bortezomib induces autophagy in HCC. Our data indicate that bortezomib activated autophagy in a dose- and time- dependent manner in HCC cell lines including Huh-7, Sk-Hep1, and Hep3B. Bortezomib downregulated CIP2A, phospho-Akt (P-Akt) and phospho-4EBP1 (P-4EBP1) in a dose- and time-dependent manner in all tested HCC cells. Ectopic expression of CIP2A abolished the effect of bortezomib on autophagy. Co-treatment of bortezomib and calyculin A, a PP2A inhibitor, reduced the effect of bortezomib on P-Akt, P-4EBP1, and autophagy. Increased phosphorylation of either Akt or 4EBP1 by ectopic overexpression protected cells from bortezomib-induced autophagy. Furthermore, we examined the effect of ΔBtz, a bortezomib derivative that closely resembles bortezomib structurally but has no proteasome activity, in HCC. Interestingly, ΔBtz demonstrated similar effects to bortezomib on autophagy, CIP2A, P-Akt and P-4EBP1, suggesting that the effect of bortezomib on autophagy is independent of proteasome inhibition. Moreover, our in vivo data showed that both bortezomib and ΔBtz inhibited tumor growth, downregulated CIP2A, P-Akt and induced autophagy in Huh-7 tumors. In conclusion, bortezomib induces autophagy in HCC through a CIP2A-PP2A-Akt-4EBP1 pathway.

Huang LP, Savoly D, Sidi AA, et al.
CIP2A protein expression in high-grade, high-stage bladder cancer.
Cancer Med. 2012; 1(1):76-81 [PubMed] Free Access to Full Article Related Publications
Bladder cancer is one of the most common cancers in the United States. Numerous markers have been evaluated for suitability of bladder cancer detection and surveillance. However, few of them are acceptable as a routine tool. Therefore, there exists a continuing need for an assay that detects the presence of bladder cancer in humans. It would be advantageous to develop an assay with a protein that is associated with the development of bladder cancer. We have identified the cancerous inhibitor of PP2A (CIP2A) protein as a novel bladder cancer biomarker. In this study, Western blot analysis was used to assess the expression level of CIP2A protein in bladder cancer cell lines and bladder cancer patient tissues (n = 43). Our studies indicated CIP2A protein was abundantly expressed in bladder cancer cell lines but not in nontumor epithelial cell lines. Furthermore, CIP2A was specifically expressed in transitional cell carcinoma (TCC) of the bladder tumor tissues but not in adjacent nontumor bladder tissue. Our data showed that CIP2A protein detection in high-grade TCC tissues had a sensitivity of 65%, which is 3.4-fold higher than that seen in low-grade TCC tissues (19%). The level of CIP2A protein expression increased with the stage of disease (12%, 27%, 67%, and 100% for pTa, pT1, pT2, and pT3 tumor, respectively). In conclusion, our studies suggest that CIP2A protein is specifically expressed in human bladder tumors. CIP2A is preferentially expressed in high-grade and high-stage TCC tumors, which are high-risk and invasive tumors. Our studies reported here support the role of CIP2A in bladder cancer progression and its usefulness for the surveillance of recurrence or progression of human bladder cancer.

Yu HC, Chen HJ, Chang YL, et al.
Inhibition of CIP2A determines erlotinib-induced apoptosis in hepatocellular carcinoma.
Biochem Pharmacol. 2013; 85(3):356-66 [PubMed] Related Publications
Erlotinib is a small-molecular inhibitor of epidermal growth factor receptor (EGFR). Here, we identify that cancerous inhibitor of protein phosphatase 2A (CIP2A) is a major determinant mediating erlotinib-induced apoptosis in hepatocellular carcinoma (HCC). Erlotinib showed differential effects on apoptosis in 4 human HCC cell lines. Erlotinib induced significant apoptosis in Hep3B and PLC5 cell lines; however, Huh-7 and HA59T cell lines showed resistance to erlotinib-induced apoptosis at all tested doses. Down-regulation of CIP2A, a cellular inhibitor of protein phosphatase 2A (PP2A), mediated the apoptotic effect of erlotinib in HCC. Erlotinib inhibited CIP2A in a dose- and time-dependent manner in all sensitive HCC cells whereas no alterations in CIP2A were found in resistant cells. Overexpression of CIP2A upregulated phospho-Akt and protected Hep3B cells from erlotinib-induced apoptosis. In addition, silencing CIP2A by siRNA restored the effects of erlotinib in Huh-7 cells. Moreover, adding okadaic acid, a PP2A inhibitor, abolished the effects of erlotinib on apoptosis in Hep3B cells; and forskolin, a PP2A agonist enhanced the effect of erlotinib in resistant HA59T cells. Combining Akt inhibitor MK-2206 with erlotinib restored the sensitivity of HA59T cells to erlotinib. Furthermore, in vivo xenograft data showed that erlotinib inhibited the growth of PLC5 tumor but had no effect on Huh-7 tumor. Erlotinib downregulated CIP2A and upregulated PP2A activity in PLC5 tumors, but not in Huh-7 tumors. In conclusion, inhibition of CIP2A determines the effects of erlotinib on apoptosis in HCC. CIP2A may be useful as a therapeutic biomarker for predicting clinical response to erlotinib in HCC treatment.

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