High Cancerous Inhibitor Of Protein Phosphatase 2A Expression Research Articles

Cancerous inhibitor of protein phosphatase 2A (CIP2A) modifies energy metabolism via 5' AMP-activated protein kinase signalling in malignant cells.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an adverse biomarker across many malignancies. Using K562 cells engineered to have high or low CIP2A expression, we show that high CIP2A levels significantly bias cellular energy production towards oxidative phosphorylation (OXPHOS) rather than glycolysis. Mass spectrometric analysis of CIP2A interactors and isobaric tagging for relative and absolute protein quantitation (ITRAQ) experiments identified many associated proteins, several of which co-vary with CIP2A level. Many of these CIP2A associating and co-varying proteins are involved in energy metabolism including OXPHOS, or in 5' AMP-activated protein kinase (AMPK) signalling, and manipulating AMPK activity mimics the effects of low/high CIP2A on OXPHOS. These effects are dependent on the availability of nutrients, driven by metabolic changes caused by CIP2A. CIP2A level did not affect starvation-induced AMPK phosphorylation of Unc-51 autophagy activating kinase 1 (ULK-1) at Ser555, but autophagy activity correlated with an increase in AMPK activity, to suggest that some AMPK processes are uncoupled by CIP2A, likely via its inhibition of protein phosphatase 2A (PP2A). The data demonstrate that AMPK mediates this novel CIP2A effect on energy generation in malignant cells.

CIP2A overexpression in Taiwanese oral cancer patients.

Introduction: Oral cancer is a prevalent form of cancer worldwide, particularly in Taiwan, and mechanisms involved in oral squamous cell carcinoma (OSCC) progression remain relatively unknown. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an oncoprotein, is aberrantly expressed in many human malignant tumors including oral cancer. However, the expression and role played by CIP2A in oral cancer pathogenesis remain obscure.Methods: In this study, immunohistochemistry was used to analyze CIP2A expression between OSCC tissues and their adjacent noncancerous tissues. Furthermore, associations between CIP2A expression and histopathological parameters were investigated.Results: In this study, we showed that CIP2A was overexpressed in most of the OSCC tissues. High CIP2A expression was significantly associated with moderate/poor tumor differentiation (P=0.02). No significant association was found between CIP2A expression and other clinical parameters. Kaplan–Meier analysis revealed that high CIP2A expression showed poorer survival rates than those with low CIP2A expression (P=0.047). Multivariate Cox regression analysis indicated that CIP2A expression, N stage, American Joint Committee on Cancer stage and clinical therapy were independent prognostic factors for survival.Conclusion: Thus, our study suggests that CIP2A is an independent prognostic marker for OSCC and a novel target for OSCC treatment.

Protein phosphatase 2A (PP2A) inhibitor CIP2A indicates resistance to radiotherapy in rectal cancer.

Preoperative (chemo)radiotherapy, (C)RT, is an essential part of the treatment of rectal cancer patients, but tumor response to this therapy among patients is variable. Thus far, there are no clinical biomarkers that could be used to predict response to (C)RT or to stratify patients into different preoperative treatment groups according to their prognosis. Overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) has been demonstrated in several cancers and is frequently associated with reduced survival. Recently, high CIP2A expression has also been indicated to contribute to radioresistance in head and neck squamous cell carcinoma, but few studies have examined the connection between CIP2A and radiation response regarding other malignancies. We have evaluated CIP2A protein expression levels in relation to tumor regression after preoperative (C)RT and survival of rectal adenocarcinoma patients. The effects of CIP2A knockdown by siRNA on cell survival were further investigated in colorectal cancer cells exposed to radiation. Patients with low‐CIP2A‐expressing tumors had more frequently moderate or excellent response to long‐course (C)RT than patients with high‐CIP2A‐expressing tumors. They also had higher 36‐month disease‐specific survival (DSS) rate in categorical analysis. In the multivariate analysis, low CIP2A expression level remained as an independent predictive factor for increased DSS. Suppression of CIP2A transcription by siRNA was found to sensitize colorectal cancer cells to irradiation and decrease their survival in vitro. In conclusion, these results suggest that by contributing to radiosensitivity of cancer cells, low CIP2A protein expression level associates with a favorable response to long‐course (C)RT in rectal cancer patients.

Increase in CIP2A expression is associated with cisplatin chemoresistance in gastric cancer.

The cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein which involves in the progression of several human malignancies. Development of cisplatin (DDP) resistance is the obstacle to an effective control of gastric cancer (GC) clinically. We thus assessed whether CIP2A expression is associated with sensitivity of GC to DDP. Real-time quantitative PCR, immunohistochemical analysis, or western blotting was performed to detect CIP2A expression in GC patients' tissues. SGC7901/DDP cells were transfected with CIP2A siRNA. MTT assay was used to determine the DDP-sensitivity of cells. Flow cytometry was used to measure cell apoptosis. CIP2A has higher expression in DDP-resistant GC patients. DDP-resistant GC patients with high CIP2A expression presented with poorer overall survival rates than those with low CIP2A expression. CIP2A knockdown in DDP-resistant GC cells resulted in attenuated proliferative abilities and increased apoptosis level. CIP2A depletion sensitizes DDP-resistant cells to DDP and CIP2A overexpression antagonizes DDP-sensitive cells to DDP. CIP2A influences the expression of multidrug resistance-related proteins in GC cells. Our results suggested that CIP2A oncoprotein plays an important role in DDP resistance of GC and could serve as a novel therapeutic target for the treatment of GC patients with DDP resistance.

High expression of CIP2A protein is associated with tumor aggressiveness in stage I-III NSCLC and correlates with poor prognosis.

The aim of this work was to examine the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A) in non-small cell lung cancer (NSCLC) and analyze its correlation with clinical outcomes. CIP2A protein levels were detected by immunohistochemistry (IHC). One hundred and eighty-four of 209 (88.3%) primary stage I–III NSCLC specimens and 4 of 38 (10.5%) adjacent normal lung tissue specimens expressed CIP2A protein. High expression of CIP2A was detected in 38.8% (81/209) of the NSCLC specimens. Patients diagnosed histologically with late-stage NSCLC (p<0.001) and malignant nodes (p=0.001) exhibited high CIP2A expression. Univariate analysis using the log-rank test identified CIP2A expression as a prognostic predictor for overall survival (p=0.005). In multivariate analyses using the Cox regression test, CIP2A expression, T stage, N stage, histological type, and chemotherapy were identified as independent prognostic factors (p=0.007, 0.001, 0.003, <0.001, and <0.001, respectively). Furthermore, Kaplan–Meier survival curves demonstrated that high CIP2A expression indicated poor prognosis in the subgroup of patients with squamous cell carcinoma (p=0.008). Similar results were noted in the subgroup of patients with adenocarcinoma, but the results did not reach statistical significance (p=0.084). We also used univariate analysis and multivariate analysis to assess the prognostic factors for overall survival in the subgroup of patients who received postoperative chemotherapy. CIP2A expression was also an independent prognostic factor in NSCLC patients who received postoperative chemotherapy (p=0.009), along with histological type (p=0.001) and N stage (p=0.034). In conclusion, adding to the accumulating evidence, our research suggested that the CIP2A expression is associated with aggressiveness and correlates with poor prognosis in NSCLC. Our findings also indicated that CIP2A might be a potential therapeutic target against NSCLC.

Overexpression of CIP2A is associated with poor prognosis in multiple myeloma

Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous protein phosphatase 2A (PP2A) inhibitor, has been identified as an oncoprotein in promoting cancer initiation and progression of several types of cancer. However, the expression and the role played by CIP2A in the pathogenesis of multiple myeloma (MM) remain unclear. In this study, we showed that CIP2A was overexpressed in human MM cell lines and MM patients’ bone marrow tissues. Clinicopathologic analysis showed that CIP2A expression was significantly correlated with clinical stage and percent of plasma cells in bone marrow. Kaplan–Meier analysis revealed that patients with high CIP2A expression presented with poorer overall survival rates than those with low CIP2A expression. Moreover, CIP2A knockdown in MM cells resulted in attenuated proliferative abilities. In addition, CIP2A depletion sensitizes dexamethasone (Dex)-resistant cells to Dex. The effect of CIP2A on proliferation and Dex therapy was mediated by the inhibition of PP2A, which in turn activated Akt. In vivo studies confirmed that CIP2A regulated MM tumorigenesis and the phosphorylation of Akt. Taken together, our results suggest that CIP2A oncoprotein plays an important role in MM progression and could serve as a prognosis marker and a novel therapeutic target for the treatment of patients with MM.

Overexpression of CIP2A in clear cell renal cell carcinoma promotes cellular epithelial-mesenchymal transition and is associated with poor prognosis

Cancerous inhibitor of protein phosphatase2A (CIP2A) is a newly characterized oncoprotein involved in a variety of malignant tumors. However, its expression pattern and biological functions in clear cell renal cell carcinoma (ccRCC) remain unclear. In the present study, our findings demonstrated that expressions of CIP2A mRNA and protein in ccRCC tissues and cell lines were significantly higher than those in paired normal renal tissues or normal renal tubular epithelial cells (P<0.05). High CIP2A level was closely correlated with Tstage (P=0.001), tumor size (P=0.009), lymph node metastasis (P=0.014), vascular invasion (P=0.018) and high Snail expression (P<0.001). Additionally, ccRCC patients with high CIP2A expression had significantly shorter overall survival (OS, P<0.001) and disease-free survival (DFS, P<0.001) when compared with patients with the low expression of CIP2A. On Cox multivariate analysis, CIP2A overexpression was an independent and significant prognostic factor for OS (P=0.010) and DFS (P=0.004). Furthermore, knockdown of the CIP2A expression significantly reduced ccRCC cell invasion, with decreased Snail and Vimentin expression, and increased E-cadherin expression. Taken together, our data identified CIP2A as a critical oncoprotein involved in cell invasion and epithelial mesenchymal transition (EMT), which could serve as a therapeutic target in ccRCC.

Cellular localization of CIP2A determines its prognostic impact in superficial spreading and nodular melanoma.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an important oncogene contributing to cancer progression partially by regulating cMYC and AKT. We examined CIP2A expression in cutaneous melanomas, its association with clinicopathological parameters and mapped molecular mechanisms regulated by CIP2A in vitro. CIP2A expression was analyzed by immunohistochemistry in 17 nevi, 132 primary melanomas and 49 metastases. Effects of siRNA-mediated down-regulation on proliferation, apoptosis and signaling pathways were assessed in melanoma cell lines. In superficial spreading melanomas (SSM), high nuclear CIP2A expression was associated with poor overall survival (OS) (P = 0.0018). Surprisingly, high cytoplasmic expression was related to improved relapse-free (P = 0.031) and OS (P = 0.014) in nodular melanomas (NM). In vitro experiments revealed that CIP2A can regulate proliferation and/or apoptosis partially through the PI3K/AKT pathway but also independently. In summary, CIP2A could represent a potential therapeutic target in SSM. However, in NM cytoplasmic CIP2A is associated with improved prognosis indicating that CIP2A has distinct, complex functions dependent on the molecular context and histological subtype. As seen in other cancer types, CIP2A can influence cMYC and AKT, but our data also suggest that in melanoma it has additional targets which need to be identified.

Clinical significance of cancerous inhibitor of protein phosphatase 2A in human cancers.

Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A), a recently identified oncogene, has emerged as a potential drug target for a range of different tumor types. High CIP2A expression has been reported in almost all solid organ cancers and in some hematological tumors and is associated with high grade and poor prognosis. Notably, high CIP2A expression is determined in over 70% of tumor patient samples in the majority of human cancers. High expression of CIP2A has also been proposed as a useful biomarker that predicts therapeutic response to chemotherapeutics such as Bortezomib, Erlotinib, Checkpoint Kinase 1 inhibitors and pro-senescence based therapies. In this review, we highlight, critically evaluate and discuss the ambiguity in CIP2A's prognostic role in different human cancers and its role in modulating response and resistance to chemotherapeutics.

Overexpression of CIP2A is an independent prognostic indicator in nasopharyngeal carcinoma and its depletion suppresses cell proliferation and tumor growth.

BackgroundCancerous 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).MethodsQuantitative 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.ResultsCIP2A 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.ConclusionsOur 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.

Cancerous Inhibitor of Protein Phosphatase 2A, an Emerging Human Oncoprotein and a Potential Cancer Therapy Target

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.

Expression of cancerous inhibitor of protein phosphatase 2A in tissue microarray of colorectal cancer and its clinical significance

To investigate the expression of cancerous inhibitor of protein phosphatase 2A(CIP2A) in human colorectal cancer, and to examine the association of CIP2A expression with clinicopathology and prognosis. CIP2A expression in colorectal cancer tissue microarray of 92 cases was detected by immunohistochemistry method. Up-regulated CIP2A expression was closely related with TNM staging, histological type, peritoneal seeding and liver metastasis (all P<0.05), but not related with gender, age, tumor location, CEA, family history and grade of differentiation. Overall survival rates of 1-, 3-, 5-, and 10-year in high CIP2A expression group were 97.1%, 71.4%, 59.2%, and 44.4% respectively, significantly lower than 98.2%, 85.7%, 80.3%, and 74.9% in low CIP2A expression group(P=0.021). Multivariate analysis showed that CIP2A was not an independent factor associated with prognosis(P=0.099, HR=1.982, 95%CI:0.879 to 4.469). Up-regulated CIP2A expression is closely related to clinicopathology of colorectal cancer. CIP2A may be used as a potential predictive marker of metastasis, prognosis and therapeutic target in colorectal cancer.

CIP2A Is Highly Expressed in Hepatocellular Carcinoma and Predicts Poor Prognosis

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is highly expressed in hepatocellular carcinoma (HCC) and promotes cell proliferation, cell invasion, and aggressive tumor behavior. However, there have been few studies on the usefulness of CIP2A as an independent prognostic index of HCC. In the current study, the aim was to explore the association between CIP2A expression and prognosis in HCC. The expression of CIP2A and c-MYC was examined by immunohistochemistry in 136 HCC specimens. CIP2A mRNA expression in 27 HCC tissues was also analyzed using quantitative reverse-transcription polymerase chain reaction. The prognostic significance was analyzed by the Kaplan-Meier survival method and log-rank test. Cox regression was adopted for univariate and multivariate analysis of prognostic factors. CIP2A protein was found to be highly expressed in human liver cancer samples (85/136, 62.5%) and correlated with poor survival (P<0.05). The liver cancer tissues examined exhibited much higher levels of CIP2A mRNA compared with their corresponding normal tissues (19/27, 70.3%). Furthermore, CIP2A mRNA levels were correlated with c-MYC mRNA levels. In addition, the highly expressed CIP2A was associated with recurrence (P=0.014) and invasion (P=0.017) of HCC. Patients with high CIP2A expression had both poorer overall survival (OS) and disease-free survival (DFS). On multivariate analysis, the CIP2A status was a significant prognostic factor for OS and DFS (P=0.017, P=0.026, respectively). CIP2A overexpression may be useful as an independent prognostic biomarker for OS and DFS of HCC.

ETS1 Mediates MEK1/2-Dependent Overexpression of Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) in Human Cancer Cells

EGFR-MEK-ERK signaling pathway has an established role in promoting malignant growth and disease progression in human cancers. Therefore identification of transcriptional targets mediating the oncogenic effects of the EGFR-MEK-ERK pathway would be highly relevant. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently characterized human oncoprotein. CIP2A promotes malignant cell growth and is over expressed at high frequency (40–80%) in most of the human cancer types. However, the mechanisms inducing its expression in cancer still remain largely unexplored. Here we present systematic analysis of contribution of potential gene regulatory mechanisms for high CIP2A expression in cancer. Our data shows that evolutionary conserved CpG islands at the proximal CIP2A promoter are not methylated both in normal and cancer cells. Furthermore, sequencing of the active CIP2A promoter region from altogether seven normal and malignant cell types did not reveal any sequence alterations that would increase CIP2A expression specifically in cancer cells. However, treatment of cancer cells with various signaling pathway inhibitors revealed that CIP2A mRNA expression was sensitive to inhibition of EGFR activity as well as inhibition or activation of MEK-ERK pathway. Moreover, MEK1/2-specific siRNAs decreased CIP2A protein expression. Series of CIP2A promoter-luciferase constructs were created to identify proximal −27 to −107 promoter region responsible for MEK-dependent stimulation of CIP2A expression. Additional mutagenesis and chromatin immunoprecipitation experiments revealed ETS1 as the transcription factor mediating stimulation of CIP2A expression through EGFR-MEK pathway. Thus, ETS1 is probably mediating high CIP2A expression in human cancers with increased EGFR-MEK1/2-ERK pathway activity. These results also suggest that in addition to its established role in invasion and angiogenesis, ETS1 may support malignant cellular growth via regulation of CIP2A expression and protein phosphatase 2A inhibition.