Gene Summary

Gene:CAV2; caveolin 2
Aliases: CAV
Summary:The protein encoded by this gene is a major component of the inner surface of caveolae, small invaginations of the plasma membrane, and is involved in essential cellular functions, including signal transduction, lipid metabolism, cellular growth control and apoptosis. This protein may function as a tumor suppressor. This gene and related family member (CAV1) are located next to each other on chromosome 7, and express colocalizing proteins that form a stable hetero-oligomeric complex. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. Additional isoforms resulting from the use of alternate in-frame translation initiation codons have also been described, and shown to have preferential localization in the cell (PMID:11238462). [provided by RefSeq, May 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Latest Publications: CAV2 (cancer-related)

Farago AF, Drapkin BJ, Lopez-Vilarino de Ramos JA, et al.
ATLANTIS: a Phase III study of lurbinectedin/doxorubicin versus topotecan or cyclophosphamide/doxorubicin/vincristine in patients with small-cell lung cancer who have failed one prior platinum-containing line.
Future Oncol. 2019; 15(3):231-239 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Lurbinectedin is an inhibitor of active transcription of protein-coding genes, causing DNA-break accumulation, apoptosis and modulation of the tumor microenvironment. Early-phase clinical trials indicate promising activity of lurbinectedin in small-cell lung cancer. Here, we describe the rationale and design of ATLANTIS (NCT02566993), an open-label, randomized, multicenter Phase III study to compare the efficacy of lurbinectedin and doxorubicin combination with standard-of-care chemotherapy, investigator's choice of cyclophosphamide/doxorubicin/vincristine or topotecan, in patients with small-cell lung cancer that has progressed following one line of platinum-based chemotherapy. Patients are randomized in a 1:1 ratio. The primary end point is overall survival and key secondary end points include progression-free survival, best tumor response and duration of response, each assessed by independent review committee.

Zhao Y, Lv F, Chen S, et al.
Caveolin-1 expression predicts efficacy of weekly nab-paclitaxel plus gemcitabine for metastatic breast cancer in the phase II clinical trial.
BMC Cancer. 2018; 18(1):1019 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: Nanoparticle albumin-bound (nab)-paclitaxel has better efficacy, safety profiles, and no need to use prophylactic steroids compared with solvent-based paclitaxel. We performed a single arm, phase II study to evaluate the efficacy and safety of weekly nab-paclitaxel and gemcitabine combination in patients with metastatic breast cancer (MBC) and explored role of tumor/stromal Caveolin-1 (Cav-1) as a predictive biomarker for the efficacy.
METHODS: Nab-paclitaxel (125 mg/m
RESULTS: Among 85 patients enrolled in the study, ORR was 52.4%. After a median follow-up of 17.2 months, median PFS was 7.9 months (95%CI, 6.6-9.2) and median OS was 25.8 months (95% CI, 20.4-31.1). The most common toxicities were neutropenia (75.0% for all grades; 45.2% for grade 3 or worse) and the most common non-hematologic toxicity was peripheral neuropathy (50.0% for all grades, 7.14% for grade 3 or worse). Higher tumor Cav-1 level and lower stromal Cav-1 level were significantly associated with longer PFS of nab-paclitaxel and gemcitabine.
CONCLUSIONS: The regimen had substantial antitumor activity and was well tolerated in MBC patients. Tumor/stromal Cav-1 level may be a good predictor for the efficacy of nab-paclitaxel and gemcitabine.
TRIAL REGISTRATION: NCT01550848 . Registered 12 March 2012.

Gu Y, Cai R, Zhang C, et al.
miR-132-3p boosts caveolae-mediated transcellular transport in glioma endothelial cells by targeting PTEN/PI3K/PKB/Src/Cav-1 signaling pathway.
FASEB J. 2019; 33(1):441-454 [PubMed] Related Publications
Blood-brain tumor barrier (BTB) impedes the transportation of antitumor therapeutic drugs into brain tumors. Its mechanism is still unknown, but learning how to improve the BTB permeability is critical for drug intervention. Recently, microRNAs (miRNAs) have appeared as regulation factors of numerous biologic processes and therapeutic targets of diverse diseases. In this study, we have identified that miR-132-3p is an essential miRNA by increasing the transcellular transport through the BTB. We found that miR-132-3p expression was significantly up-regulated in glioma endothelial cells (GECs). Furthermore we showed that miR132-3p

Maiuthed A, Bhummaphan N, Luanpitpong S, et al.
Nitric oxide promotes cancer cell dedifferentiation by disrupting an Oct4:caveolin-1 complex: A new regulatory mechanism for cancer stem cell formation.
J Biol Chem. 2018; 293(35):13534-13552 [PubMed] Free Access to Full Article Related Publications
Cancer stem cells (CSCs) are unique populations of cells that can self-renew and generate different cancer cell lineages. Although CSCs are believed to be a promising target for novel therapies, the specific mechanisms by which these putative therapeutics could intervene are less clear. Nitric oxide (NO) is a biological mediator frequently up-regulated in tumors and has been linked to cancer aggressiveness. Here, we search for targets of NO that could explain its activity. We find that it directly affects the stability and function of octamer-binding transcription factor 4 (Oct4), known to drive the stemness of lung cancer cells. We demonstrated that NO promotes the CSC-regulatory activity of Oct4 through a mechanism that involves complex formation between Oct4 and the scaffolding protein caveolin-1 (Cav-1). In the absence of NO, Oct4 forms a molecular complex with Cav-1, which promotes the ubiquitin-mediated proteasomal degradation of Oct4. NO promotes Akt-dependent phosphorylation of Cav-1 at tyrosine 14, disrupting the Cav-1:Oct4 complex. Site-directed mutagenesis and computational modeling studies revealed that the hydroxyl moiety at tyrosine 14 of Cav-1 is crucial for its interaction with Oct4. Both removal of the hydroxyl via mutation to phenylalanine and phosphorylation lead to an increase in binding free energy (Δ

Liang C, Shi S, Meng Q, et al.
MiR-29a, targeting caveolin 2 expression, is responsible for limitation of pancreatic cancer metastasis in patients with normal level of serum CA125.
Int J Cancer. 2018; 143(11):2919-2931 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive gastrointestinal tumors, with an overall 5-year survival rate less than 8%. The dismal prognosis is mainly due to aggressive potential for metastasis. Hence, there is an urgent need for a better understanding of the molecular mechanisms underlying pancreatic cancer invasion and metastasis to improve the unfavorable overall survival (OS) of PDAC patients. In this study, we identified microRNA-29a (miR-29a) as an important tumor suppressor, which was downregulated in PDAC tissues. Moreover, miR-29a counteracted MUC16-mediated migration and invasion. In the pancreatic cancer cells, MUC16 upregulated c-Myc expression, which enhanced c-Myc binding to E-box in the miR-29a promoter and inhibited miR-29a transcription. Thus, miR-29a was negatively correlated with both MUC16 expression and serum CA125 levels. Furthermore, caveolin 2 (CAV2) was demonstrated to be the target of miR-29a by bioinformatics and luciferase reporter assays, and high CAV2 expression was responsible for a poor prognosis, especially in the subgroup with normal CA125 levels. Thus, the present study explains why high levels of serum CA125 are correlated with PDAC metastasis, highlighting the predictive value of this marker in PDAC patients.

Gerstenberger W, Wrage M, Kettunen E, et al.
Stromal Caveolin-1 and Caveolin-2 Expression in Primary Tumors and Lymph Node Metastases.
Anal Cell Pathol (Amst). 2018; 2018:8651790 [PubMed] Free Access to Full Article Related Publications
The expression of caveolin-1 (CAV1) in both tumor cell and cancer-associated fibroblasts (CAFs) has been found to correlate with tumor aggressiveness in different epithelial tumor entities, whereas less is known for caveolin-2 (CAV2). The aim of this study was to investigate the clinicopathological significance and prognostic value of stromal CAV1 and CAV2 expression in lung cancer. The expression of these two genes was investigated at protein level on a tissue microarray (TMA) consisting of 161 primary tumor samples. 50.7% of squamous cell lung cancer (SCC) tumors showed strong expression of CAV1 in the tumor-associated stromal cells, whereas only 15.1% of adenocarcinomas (AC) showed a strong CAV1 expression (

Zhu Z, Yu Z, Wang J, et al.
Krüppel-Like Factor 4 Inhibits Pancreatic Cancer Epithelial-to-Mesenchymal Transition and Metastasis by Down-Regulating Caveolin-1 Expression.
Cell Physiol Biochem. 2018; 46(1):238-252 [PubMed] Related Publications
BACKGROUND/AIMS: Krüppel-like factor 4 (KLF4), a member of the KLF family of zinc finger transcription factors, has been identified as a tumor suppressor gene in a variety of tumors. However, the molecular mechanisms by which KLF4 inhibits epithelial-to-mesenchymal transition (EMT) and metastasis in pancreatic cancer remain unclear.
METHODS: KLF4 expression in pancreatic cancer was analyzed using public datasets (Oncomine and The Cancer Genome Atlas). The expression of KLF4, caveolin-1 (Cav-1), E-cadherin, and vimentin, and their correlations with clinicopathological characteristics were evaluated by immunohistochemistry in pancreatic cancer tissues. The biological functions and underlying mechanisms of KLF4 expression on EMT and metastasis were also investigated in vitro and in vivo.
RESULTS: Public datasets showed that KLF4 expression was significantly decreased in pancreatic cancer and correlated with the depth of invasion and disease stage. The expression of KLF4, Cav-1, E-cadherin, and vimentin protein in pancreatic cancer tissues was closely associated with pathological grade, disease stage, and metastasis. KLF4 expression was also positively correlated with E-cadherin expression and negatively correlated with vimentin expression, whereas Cav-1 expression was negatively associated with E-cadherin expression and positively correlated with vimentin expression. Knockdown of KLF4 expression promoted EMT and facilitated pancreatic cancer cell growth and metastasis in vitro and in vivo. In addition, immunohistochemistry (IHC) results indicated that KLF4 expression was negatively correlated with Cav-1 expression. Furthermore, down-regulating KLF4 expression increased Cav-1 and vimentin expression and decreased E-cadherin expression. Mechanistically, KLF4 could transcriptionally inhibit Cav-1 expression by binding directly to the promoter domain of Cav-1.
CONCLUSIONS: KLF4 inhibits pancreatic cancer EMT and metastasis by down-regulating Cav-1 expression, suggesting that the KLF4/Cav-1 signaling pathway may be a novel diagnostic and therapeutic target.

Wu J, Di D, Zhao C, et al.
Clinical Significance of Gli-1 And Caveolin-1 Expression in the Human Small Cell Lung Cancer
Asian Pac J Cancer Prev. 2018; 19(2):401-406 [PubMed] Free Access to Full Article Related Publications
Background: Lung cancer is the leading causes of cancer-related deaths around the world. Abnormal activation of the hedgehog (Hh) signaling pathway has been found to be involved in the occurrence, invasion, and metastasis of cancers. Autophagy also plays a significant role in the growth and metastasis of cancers. However, the correlation between the Hh signaling pathway and autophagy in small cell lung cancer (SCLC) is still poorly understood. This study aimed to investigate the significance of Hh signaling pathway and autophagy in SCLC. Materials and Methods: The expression of the Hh-induced transcriptional factor, glioma associated oncogene-1 (Gli-1) and the autophagy-related molecule caveolin-1 (Cav-1) and their clinical significance was performed to detect and assay by immunohistochemistry in tissue microarray including 70 patients with SCLC. Results: In our study, 47 (67.1%) patients had positive Gli-1 expression, 49 (70.0%) patients had positive Cav-1 expression, and 44 (62.9%) patients had negative fibroblastic Cav-1 expression. In SCLC, Gli-1 expression increased markedly, and was closely associated with decreased fibroblastic Cav-1 expression. Furthermore, we also found that Gli-1 expression was closely associated with increased Cav-1 expression. Conclusions: Our findings suggested that abnormal activation of the Hh signaling pathway is closely related to autophagy in SCLC. We envision that novel targets may come with the further investigation of Gli-1 and Cav-1 in carcinogenesis of SCLC.

Kopp S, Sahana J, Islam T, et al.
The role of NFκB in spheroid formation of human breast cancer cells cultured on the Random Positioning Machine.
Sci Rep. 2018; 8(1):921 [PubMed] Free Access to Full Article Related Publications
Human MCF-7 breast cancer cells were exposed to a Random Positioning Machine (RPM). After 24 hours (h) the cells grew either adherently within a monolayer (AD) or within multicellular spheroids (MCS). AD and MCS populations were separately harvested, their cellular differences were determined performing qPCR on genes, which were differently expressed in AD and MCS cells. Gene array technology was applied to detect RPM-sensitive genes in MCF-7 cells after 24 h. Furthermore, the capability to form multicellular spheroids in vitro was compared with the intracellular distribution of NF-kappaB (NFκB) p65. NFκB was equally distributed in static control cells, but predominantly localized in the cytoplasm in AD cells and nucleus in MCS cells exposed to the RPM. Gene array analyses revealed a more than 2-fold change of only 23 genes including some whose products are affected by oxygen levels or regulate glycolysis. Significant upregulations of the mRNAs of enzymes degrading heme, of ANXA1, ANXA2, CTGF, CAV2 and ICAM1, as well as of FAS, Casp8, BAX, p53, CYC1 and PARP1 were observed in MCS cells as compared with 1g-control and AD cells. An interaction analysis of 47 investigated genes suggested that HMOX-1 and NFκB variants are activated, when multicellular spheroids are formed.

Yang J, Zhu T, Zhao R, et al.
Caveolin-1 Inhibits Proliferation, Migration, and Invasion of Human Colorectal Cancer Cells by Suppressing Phosphorylation of Epidermal Growth Factor Receptor.
Med Sci Monit. 2018; 24:332-341 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Although downregulation of caveolin-1 (Cav-1), which is a key constituent of membrane caveolae and a regulator of cellular processes, is associated with colorectal cancer (CRC), its involvement in the disease progression is largely unknown. This study aimed to explore the role of Cav-1 in CRC and the associated mechanisms. MATERIAL AND METHODS Fresh tissues from patients with CRC and human CRC SW480 cells were used to evaluate Cav-1 and Ki-67 expression using immunohistochemistry and Western blotting. The MTS and Transwell assays were performed to determine the effects of Cav-1 overexpression via pcDNA3.1/Cav-1 plasmid on cell proliferation and metastasis. The effect of Cav-1 on the epidermal growth factor receptor (EGFR) activation was evaluated by Western blotting. The correlation of Cav-1 expression with clinicopathological factors was statistically analyzed. RESULTS Overexpression of Cav-1 significantly reduced proliferation, migration, and invasion of SW480 cancer cells in vitro. The EGF-induced phosphorylation of EGFR and activations of the RAF-MEK-ERK and PI3K-AKT pathways were adversely regulated by Cav-1 overexpression in vitro. In 76 cases of CRC patients with EGFR expression, a negative correlation was observed between the level of Cav-1 and tumor-node-metastasis stage, lymph node metastasis, and distant metastasis (All p<0.05). Finally, the expression level of Cav-1 was negatively correlated with that of Ki-67. CONCLUSIONS This report is the first to show that overexpression of Cav-1significantly inhibits the proliferation, migration, and invasion potential of SW480 cells, possibly through reducing EGF-induced EGFR activation. High Cav-1 expression level may be a predictor of positive outcomes in patients with colorectal cancer.

Ryu BK, Lee MG, Kim NH, et al.
Bidirectional alteration of Cav-1 expression is associated with mitogenic conversion of its function in gastric tumor progression.
BMC Cancer. 2017; 17(1):766 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Expression of caveolin-1 (Cav-1) is frequently altered in many human cancers and both tumor suppression and promotion functions of Cav-1 have been suggested based on its expression status. However, it remains unanswered how Cav-1 provokes opposite effects in different cancers or different phases of tumor progression.
METHODS: To explore the implication of Cav-1 alteration in gastric tumorigenesis, the expression and mutational status of Cav-1 and its effects on tumor cell growth were characterized.
RESULTS: A substantial fraction of primary tumors and cell lines displayed abnormally low or high Cav-1 mRNA expression, indicating the bidirectional alteration of Cav-1 in gastric cancers. While allelic imbalance and mutational alterations of the Cav-1 gene were rarely detected, aberrant promoter hyper- or hypo-methylation showed a tight correlation with bidirectional alteration of its expression. Abnormally low and high Cav-1 expression was more frequently observed in early and advanced cancers, respectively, suggesting the oncogenic switch of its function in tumor progression. Cell cycle progression, DNA synthesis, and colony forming ability were markedly decreased by Cav-1 transfection in low-expressing tumor cells but by its depletion in high-expressing cells. Interestingly, Cav-1 exerted opposite effects on MEK-ERK signaling in these two cell types through the reciprocal regulation of the RAF-ERK negative feedback loop. A feedback inhibition of RAF by ERK was stimulated by restoration of Cav-1 expression in low-expressing cells but by it depletion in high-expressing cells. As predicted, the opposite effects of Cav-1 on both tumor cell growth and inhibitory RAF phosphorylation were abolished if ERK is depleted.
CONCLUSION: Bidirectional alteration of Cav-1 is linked to its opposite effects on gastric tumor cell growth, which stem from the reciprocal control on the RAF-ERK negative feedback loop.

Cui Y, Zhu T, Song X, et al.
Downregulation of caveolin-1 increased EGFR-TKIs sensitivity in lung adenocarcinoma cell line with EGFR mutation.
Biochem Biophys Res Commun. 2018; 495(1):733-739 [PubMed] Related Publications
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have shown notable effects in lung adenocarcinoma patients harboring EGFR mutations, there are significant differences between individual patients in the degree of benefits provided by EGFR-TKIs. Some evidence supports a role for caveolin-1 (Cav-1) in modulating drug sensitivity. This study aimed to investigate whether Cav-1 plays an important role in sensitivity to EGFR-TKIs in lung adenocarcinoma cells. Downregulation of Cav-1 in PC-9 cells were performed to investigate changes in sensitivity to EGFR-TKIs in vitro and in vivo. Knockdown of Cav-1 dramatically enhanced sensitivity to EGFR-TKIs by down-regulating phosphorylation of EGFR. These results suggest that Cav-1 may be a predictor of the poor efficacy of EGFR-TKIs treatment in lung adenocarcinoma with EGFR mutations.

Liu W, Yin NC, Liu H, Nan KJ
Cav-1 promote lung cancer cell proliferation and invasion through lncRNA HOTAIR.
Gene. 2018; 641:335-340 [PubMed] Related Publications
OBJECTIVES: Lung cancer is one of the most common malignant tumors worldwide, and its morbidity and mortality rates continue to rise. The role of lncRNAs in lung cancer has become an emerging area of research.
MATERIALS AND METHODS: The expression of CAV-1 and HOTAIR was determined in lung cancer tissues and cell lines by western blot and RT-qPCR. Cell proliferation, migration and invasion were analysed in lung cell following knockdown or overexpression of CAV-1 or HOTAIR by transfection with small interfering RNA (siRNA) or plasmid.
RESULTS: The expression of CAV-1 and HOTAIR in lung cancer tissues and cell lines was higher than in normal lung tissue or normal lung cell lines. We discovered that CAV-1 could regulate cell proliferation, migration and invasion. At the same time, CAV-1 could regulate the expression of HOTAIR. In addition, knockdown of the expression of HOAIR partially reverses the promotion of cell viability and invasion induced by CAV-1.
CONCLUSIONS: Our results indicated that CAV-1 coordinate the lung cancer through HOTAIR. And HOTAIR may become a novel target for lung cancer therapy.

Fourbon Y, Guéguinou M, Félix R, et al.
Sci Rep. 2017; 7(1):14199 [PubMed] Free Access to Full Article Related Publications
It is generally accepted that voltage-gated Ca

Machado I, Yoshida A, López-Guerrero JA, et al.
Immunohistochemical analysis of NKX2.2, ETV4, and BCOR in a large series of genetically confirmed Ewing sarcoma family of tumors.
Pathol Res Pract. 2017; 213(9):1048-1053 [PubMed] Related Publications
Ewing sarcoma is an aggressive neoplasm of pediatric and adolescent patients. Immunohistochemistry (IHC) can be used to support the morphologic diagnosis of Ewing sarcoma family of tumors (ESFT) in a convincing clinical/radiological context. Although neither NKX2.2 nor CD99 alone are entirely specific, when combined, the diagnostic specificity is high. The aim of the present study was to investigate the IHC expression of NKX2.2, ETV4 and BCOR in a large series of genetically confirmed ESFT. The results for CD99 and CAV-1 immunoreactivity, and the histological and fusion gene subtypes were retrieved from our previous study. NKX2.2 demonstrated moderate or strong nuclear positivity in 91.2% of the tumors. The staining intensity was heterogeneous. Many of the ESFT with negative NKX2.2 immunoreactivity were in bone. Strong/moderate ETV4 nuclear expression was detected in two small round cell tumors, both were negative for NKX2.2. No relationships could be found between expression of NKX2.2 and the histological subgroups or ESFT gene fusion subtypes. BCOR was negative in all ESFT. In conclusion, NKX2.2, ETV4 and BCOR IHC may be helpful in daily practice for distinguishing ESFT from CIC or BCOR-associated sarcomas, especially in hospitals without access to molecular assays. In addition, the combination of strong CD99 membranous positivity and nuclear NKX2.2 positivity seems to be very reliable for ESFT diagnosis in an appropriate clinicoradiological setting. So far no antibody is entirely specific for ESFT diagnosis, and the IHC or molecular results in round cell tumors of bone may be strongly influenced by decalcification processes.

Ariana M, Arabi N, Pornour M, et al.
The diversity in the expression profile of caveolin II transcripts, considering its new transcript in breast cancer.
J Cell Biochem. 2018; 119(2):2168-2178 [PubMed] Related Publications
Most studies have revealed the effects of caveolins in cancer inhibition. However, due to a lack of reports about their new transcripts, their presence and their effects on different cancers are unclear. This study was conducted to evaluate the cavolin-2 (cav-2) transcripts expression changes in tumoral and corresponding tissues and in contralateral breast, to investigate their variation associated with the variation of caveolin-1 (cav-1) expression in breast cancer. There were 40 breast-derived tumoral, corresponding, and contralateral tissues obtained from the patients with breast cancer. The RNA and proteins were extracted from these samples. So, cav-1 and cav-2 transcripts' variation were assessed in whole tumoral, corresponding, and contralateral breast. Also, their expression modifications were evaluated via the Western blotting technique. The results derived from this study verified the presence of transcript III of cav-2 for the first time, which was reported only in the gene bank, but we could not detect and validate any protein associated with these transcripts. Also, the decreasing trend of cav-1 and the cav-2 (transcripts I and II) were observed in tumoral tissues compared to unaffected tissues especially in stages I and II. It seems that the descending expression levels of cav-1 and cav-2 (transcript I, II) besides the lasting expression of cav-2 (transcript III) are associated with the incidence and promotion of breast cancer, especially in the initial stages of breast cancer. So, this may show a potential in determining the patients who can undergo the prophylactic mastectomy. Moreover, the results of the study demonstrated that transcript III may be a candidate as a non-coding RNA.

Gandla J, Lomada SK, Lu J, et al.
miR-34c-5p functions as pronociceptive microRNA in cancer pain by targeting Cav2.3 containing calcium channels.
Pain. 2017; 158(9):1765-1779 [PubMed] Free Access to Full Article Related Publications
Pathophysiological mechanisms underlying pain associated with cancer are poorly understood. microRNAs (miRNAs) are a class of noncoding RNAs with emerging functional importance in chronic pain. In a genome-wide screen for miRNAs regulated in dorsal root ganglia (DRG) neurons in a mouse model of bone metastatic pain, we identified miR-34c-5p as a functionally important pronociceptive miRNA. Despite these functional insights and therapeutic potential for miR-34c-5p, its molecular mechanism of action in peripheral sensory neurons remains unknown. Here, we report the identification and validation of key target transcripts of miRNA-34c-5p. In-depth bioinformatics analyses revealed Cav2.3, P2rx6, Oprd1, and Oprm1 as high confidence putative targets for miRNA-34c-5p. Of these, canonical and reciprocal regulation of miR-34c-5p and Cav2.3 was observed in cultured sensory neurons as well as in DRG in vivo in mice with cancer pain. Coexpression of miR-34c-5p and Cav2.3 was observed in peptidergic and nonpeptidergic nociceptors, and luciferase reporter assays confirmed functional binding of miR-34c-5p to the 3' UTR of Cav2.3 transcripts. Importantly, knocking down the expression of Cav2.3 specifically in DRG neurons led to hypersensitivity in mice. In summary, these results show that Cav2.3 is a novel mechanistic target for a key pronociceptive miRNA, miR-34c-5p, in the context of cancer pain and indicate an antinociceptive role for Cav2.3 in peripheral sensory neurons. The current study facilitates a deeper understanding of molecular mechanisms underlying cancer pain and suggests a potential for novel therapeutic strategies targeting miR-34c-5p and Cav2.3 in cancer pain.

Fu SJ, Jeng CJ, Ma CH, et al.
Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Ca
J Neurosci. 2017; 37(9):2485-2503 [PubMed] Free Access to Full Article Related Publications
Voltage-gated Ca

Lázaro-Ibáñez E, Lunavat TR, Jang SC, et al.
Distinct prostate cancer-related mRNA cargo in extracellular vesicle subsets from prostate cell lines.
BMC Cancer. 2017; 17(1):92 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Multiple types of extracellular vesicles (EVs), including microvesicles (MVs) and exosomes (EXOs), are released by all cells constituting part of the cellular EV secretome. The bioactive cargo of EVs can be shuffled between cells and consists of lipids, metabolites, proteins, and nucleic acids, including multiple RNA species from non-coding RNAs to messenger RNAs (mRNAs). In this study, we hypothesized that the mRNA cargo of EVs could differ based on the EV cellular origin and subpopulation analyzed.
METHODS: We isolated MVs and EXOs from PC-3 and LNCaP prostate cancer cells by differential centrifugation and compared them to EVs derived from the benign PNT2 prostate cells. The relative mRNA levels of 84 prostate cancer-related genes were investigated and validated using quantitative reverse transcription PCR arrays.
RESULTS: Based on the mRNA abundance, MVs rather than EXOs were enriched in the analyzed transcripts, providing a snapshot of the tumor transcriptome. LNCaP MVs specifically contained significantly increased mRNA levels of NK3 Homeobox 1 (NKX3-1), transmembrane protease serine 2 (TMPRSS2), and tumor protein 53 (TP53) genes, whereas PC-3 MVs carried increased mRNA levels of several genes including, caveolin-2 (CAV2), glutathione S-transferase pi 1 (GSTP1), pescadillo ribosomal biogenesis factor 1 (PES1), calmodulin regulated spectrin associated protein 1 (CAMSAP1), zinc-finger protein 185 (ZNF185), and others compared to PNT2 MVs. Additionally, ETS variant 1 (ETV1) and fatty acid synthase (FASN) mRNAs identified in LNCaP- and PC-3- derived MVs highly correlated with prostate cancer progression.
CONCLUSIONS: Our study provides new understandings of the variability of the mRNA cargo of MVs and EXOs from different cell lines despite same cancer origin, which is essential to better understand the the proportion of the cell transcriptome that can be detected within EVs and to evaluate their role in disease diagnosis.

Kim ES, Kwon JH, Shin JH, et al.
Identification of Caveolin-1 as an Invasion-Associated Gene in Liver Cancer Cells Using Dendron-Coated DNA Microarrays.
Appl Biochem Biotechnol. 2017; 182(4):1276-1289 [PubMed] Related Publications
The conventional gene expression profiling approaches have been replaced with DNA microarrays with exhibiting a powerful high-throughput capacity. Most solid surfaces of DNA microarrays contain such a high area density of functional groups to immobilize capture DNAs to the surface that the hybridization of capture DNAs with cDNA can be hindered, resulting in low intensity and reproducibility. Since our previous works showed that the 9-acid dendron was able to increase the hybridization efficiency, we aimed to demonstrate the feasibility of 9-acid dendron-coated glass slides as an advanced microarray platform for gene expression profiling. The 9-acid dendron-coated DNA microarray could reproducibly obtain the expression levels of 2800 human cancer-associated genes in the two liver cancer lines: Hep3B and SK-Hep1. Among the differentially expressed genes, Caveolin-1 (Cav-1) was identified as the most highly up-regulated gene in invasive SK-Hep1 in comparison to non-motile Hep3B. The overexpression of Cav-1 in Hep3B promoted the cell invasion, whereas its knockdown in SK-Hep1 suppressed the invasive feature, which confirms that the overexpression of Cav-1 is closely associated with cell invasion of liver carcinoma. Collectively, the 9-acid dendron-coated surface could successfully detect the transcript levels of cells, demonstrating its feasible potential to identify the candidate genes for further functional studies or diagnosis of diseases.

Uehiro N, Sato F, Pu F, et al.
Circulating cell-free DNA-based epigenetic assay can detect early breast cancer.
Breast Cancer Res. 2016; 18(1):129 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Circulating cell-free DNA (cfDNA) has recently been recognized as a resource for biomarkers of cancer progression, treatment response, and drug resistance. However, few have demonstrated the usefulness of cfDNA for early detection of cancer. Although aberrant DNA methylation in cfDNA has been reported for more than a decade, its diagnostic accuracy remains unsatisfactory for cancer screening. Thus, the aim of the present study was to develop a highly sensitive cfDNA-based system for detection of primary breast cancer (BC) using epigenetic biomarkers and digital PCR technology.
METHODS: Array-based genome-wide DNA methylation analysis was performed using 56 microdissected breast tissue specimens, 34 cell lines, and 29 blood samples from healthy volunteers (HVs). Epigenetic markers for BC detection were selected, and a droplet digital methylation-specific PCR (ddMSP) panel with the selected markers was established. The detection model was constructed by support vector machine and evaluated using cfDNA samples.
RESULTS: The methylation array analysis identified 12 novel epigenetic markers (JAK3, RASGRF1, CPXM1, SHF, DNM3, CAV2, HOXA10, B3GNT5, ST3GAL6, DACH1, P2RX3, and chr8:23572595) for detecting BC. We also selected four internal control markers (CREM, GLYATL3, ELMOD3, and KLF9) that were identified as infrequently altered genes using a public database. A ddMSP panel using these 16 markers was developed and detection models were constructed with a training dataset containing cfDNA samples from 80 HVs and 87 cancer patients. The best detection model adopted four methylation markers (RASGRF1, CPXM1, HOXA10, and DACH1) and two parameters (cfDNA concentration and the mean of 12 methylation markers), and, and was validated in an independent dataset of 53 HVs and 58 BC patients. The area under the receiver operating characteristic curve for cancer-normal discrimination was 0.916 and 0.876 in the training and validation dataset, respectively. The sensitivity and the specificity of the model was 0.862 (stages 0-I 0.846, IIA 0.862, IIB-III 0.818, metastatic BC 0.935) and 0.827, respectively.
CONCLUSION: Our epigenetic-marker-based system distinguished BC patients from HVs with high accuracy. As detection of early BC using this system was comparable with that of mammography screening, this system would be beneficial as an optional method of screening for BC.

Shi D, Liu Y, Xi R, et al.
Caveolin-1 contributes to realgar nanoparticle therapy in human chronic myelogenous leukemia K562 cells.
Int J Nanomedicine. 2016; 11:5823-5835 [PubMed] Free Access to Full Article Related Publications
Chronic myelogenous leukemia (CML) is characterized by the t(9;22) (q34;q11)-associated

Yuan S, Wang L, Chen X, et al.
Triptolide inhibits the migration and invasion of human prostate cancer cells via Caveolin-1/CD147/MMPs pathway.
Biomed Pharmacother. 2016; 84:1776-1782 [PubMed] Related Publications
Prostate cancer (PCa) is the second most common type of carcinoma and the 5th leading cause of cancer-related death in males. Triptolide, is a main and effective component of Tripterygium wilfordii Hook F, which exerts an broad-spectrum anti-malignant tumor function. However, the effect of triptolide on migration and invasion of human prostate cancer cells is still poorly understood. In this study, we demonstrated that triptolide significantly inhibited the proliferation, migration and invasion of prostate cancer cells in a time- and dose-dependent manner. Caveolin-1 (Cav-1) is regarded as a major structural protein of caveolae and participated in lipid transport, signal transduction and tumor progression. Triptolide treatment inhibited the expression of tumor promoter Cav-1 and reduced CD147 and MMPs activities at both mRNA and protein levels. Meanwhile, triptolide treatment combined with Cav-1 knockdown in PCa cells enhanced the effects of anti-migration and anti-invasion, and those effects were restored following Cav-1-rescued. Together, our research indicates that triptolide represses the migration and invasion through Cav-1/CD147/MMPs pathway in PCa cells, which gives a better understanding of triptolide in clinical aggressive prostate cancer therapy.

Kucharski TJ, Ng TF, Sharon DM, et al.
Activation of the Chicken Anemia Virus Apoptin Protein by Chk1/2 Phosphorylation Is Required for Apoptotic Activity and Efficient Viral Replication.
J Virol. 2016; 90(20):9433-45 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Chicken anemia virus (CAV) is a single-stranded circular DNA virus that carries 3 genes, the most studied of which is the gene encoding VP3, also known as apoptin. This protein has been demonstrated to specifically kill transformed cells while leaving normal cells unharmed in a manner that is independent of p53 status. Although the mechanistic basis for this differential activity is unclear, it is evident that the subcellular localization of the protein is important for the difference. In normal cells, apoptin exists in filamentous networks in the cytoplasm, whereas in transformed cells, apoptin is present in the nucleus and appears as distinct foci. We have previously demonstrated that DNA damage signaling through the ataxia telangiectasia mutated (ATM) pathway induces the translocation of apoptin from the cytoplasm to the nucleus, where it induces apoptosis. We found that apoptin contains four checkpoint kinase consensus sites and that mutation of either threonine 56 or 61 to alanine restricts apoptin to the cytoplasm. Furthermore, treatment of tumor cells expressing apoptin with inhibitors of checkpoint kinase 1 (Chk1) and Chk2 causes apoptin to localize to the cytoplasm. Importantly, silencing of Chk2 rescues cancer cells from the cytotoxic effects of apoptin. Finally, treatment of virus-producing cells with Chk inhibitor protects them from virus-mediated toxicity and reduces the titer of progeny virus. Taken together, our results indicate that apoptin is a sensor of DNA damage signaling through the ATM-Chk2 pathway, which induces it to migrate to the nucleus during viral replication.
IMPORTANCE: The chicken anemia virus (CAV) protein apoptin is known to induce tumor cell-specific death when expressed. Therefore, understanding its regulation and mechanism of action could provide new insights into tumor cell biology. We have determined that checkpoint kinase 1 and 2 signaling is important for apoptin regulation and is a likely feature of both tumor cells and host cells producing virus progeny. Inhibition of checkpoint signaling prevents apoptin toxicity in tumor cells and attenuates CAV replication, suggesting it may be a future target for antiviral therapy.

Buchanan PJ, McCloskey KD
Eur Biophys J. 2016; 45(7):621-633 [PubMed] Free Access to Full Article Related Publications
The importance of ion channels in the hallmarks of many cancers is increasingly recognised. This article reviews current knowledge of the expression of members of the voltage-gated calcium channel family (Ca

Karantanos T, Karanika S, Wang J, et al.
Caveolin-1 regulates hormone resistance through lipid synthesis, creating novel therapeutic opportunities for castration-resistant prostate cancer.
Oncotarget. 2016; 7(29):46321-46334 [PubMed] Free Access to Full Article Related Publications
Caveolin-1 (Cav-1) is overexpressed in aggressive and metastatic prostate cancer (PCa) and induces PCa cell proliferation. Androgens mediate lipid synthesis through acetyl-CoA carboxylase-1 (ACC1) and fatty acid synthase (FASN). We investigated the Cav-1-mediated lipid synthesis in the development of castration resistance, and identified novel therapeutic opportunities. Using the PBCre+;Ptenloxp/loxp;PBCav-1+ mouse model we found that Cav-1 induction increased cancer incidence and growth, and ACC1-FASN expression in intact and castrated mice. We demonstrated that Cav-1 regulated ACC1 and FASN expression in an AR-independent way and increased palmitate synthesis using western blot analysis, qRT-PCR and mass spectrometry in vitro. By using FASN siRNA and C-75, we found that FASN inhibition was more effective in Cav-1-overexpressing cells. This inhibition was abrogated by ACC1si RNA, revealing the role of malonyl-CoA, an ACC1 product, as a mediator of cytotoxicity. Cav-1 was associated with ACC1 in human tumors and ACC1, FASN, and Cav-1 expression were increased in metastatic PCa compared to primary tumors and normal prostate epithelium. Palmitoleate and oleate levels were higher in BMA from patients with metastatic PCa who responded poorly to abiraterone acetate. Our findings suggest that Cav-1 promotes hormone resistance through the upregulation of ACC1-FASN and lipid synthesis under androgen deprivation, suggesting that FASN inhibition could be used to treat PCa that demonstrates Cav-1 overexpression.

Kowalska K, Nowakowska M, Domińska K, Piastowska-Ciesielska AW
Coexpression of CAV-1, AT1-R and FOXM1 in prostate and breast cancer and normal cell lines and their influence on metastatic properties.
Acta Biochim Pol. 2016; 63(3):493-9 [PubMed] Related Publications
The aim of this study was to evaluate the coexpression of caveolin-1 (CAV-1), angiotensin II type 1 receptor (AT1-R) and forkhead box Ml (FOXM1) in prostate and breast cancer cell lines, in comparison with normal cell lines. CAV-1, AT1-R and FOXM1 expression was determined by reverse transcription-quantitative polymerase chain reaction and western blot analysis in the prostate cancer cell lines PC3, DU145 and LNCaP; prostate normal cell line PNT1A; breast cancer cell lines MCF-7 and MDA-MB-231; and the normal breast cell line 184A1. A correlation between the expression levels of the investigated genes and their metastatic properties was determined by the Spearman's rank test (P<0.05) and Aspin-Welsch t-test, respectively. In prostate cell lines, a significant correlation was noted between CAV-1 and AT1-R expression and between FOXM1 and CAV-1 expression. A correlation between the expression levels of the investigated genes and their metastatic potential was also observed, with relatively high expression of all the investigated genes in the normal prostate cell line PNT1A. In comparison to prostate cancer cell lines, an adverse dependency between CAV-1, AT1-R, FOXM1 expression and metastatic potential was observed in the breast cancer cell lines. Relatively high expression of all tested genes was observed in the normal breast cell line 184A1, which was decreasing respectively with increasing metastatic potential of breast cancer cell lines. The results obtained here indicate that CAV-1, FOXM1 and AT1-R may be potential markers of tumorigenesis in certain types of cancer in vitro.

Tenzer S, Leidinger P, Backes C, et al.
Integrated quantitative proteomic and transcriptomic analysis of lung tumor and control tissue: a lung cancer showcase.
Oncotarget. 2016; 7(12):14857-70 [PubMed] Free Access to Full Article Related Publications
Proteomics analysis of paired cancer and control tissue can be applied to investigate pathological processes in tumors. Advancements in data-independent acquisition mass spectrometry allow for highly reproducible quantitative analysis of complex proteomic patterns. Optimized sample preparation workflows enable integrative multi-omics studies from the same tissue specimens.We performed ion mobility enhanced, data-independent acquisition MS to characterize the proteome of 21 lung tumor tissues including adenocarcinoma and squamous cell carcinoma (SCC) as compared to control lung tissues of the same patient each. Transcriptomic data were generated for the same specimens. The quantitative proteomic patterns and mRNA abundances were subsequently analyzed using systems biology approaches.We report a significantly (p = 0.0001) larger repertoire of proteins in cancer tissues. 12 proteins were higher in all tumor tissues as compared to matching control tissues. Three proteins, CAV1, CAV2, and RAGE, were vice versa higher in all controls. We also identified characteristic SCC and adenocarcinoma protein patterns. Principal Component Analysis provided evidence that not only cancer from control tissue but also tissue from adenocarcinoma and SCC can be differentiated. Transcriptomic levels of key proteins measured from the same matched tissue samples correlated with the observed protein patterns.The applied study set-up with paired lung tissue specimens of which different omics are measured, is generally suited for an integrated multi-omics analysis.

Lee EJ, Park MK, Kim HJ, et al.
Epithelial membrane protein 2 regulates sphingosylphosphorylcholine-induced keratin 8 phosphorylation and reorganization: Changes of PP2A expression by interaction with alpha4 and caveolin-1 in lung cancer cells.
Biochim Biophys Acta. 2016; 1863(6 Pt A):1157-69 [PubMed] Related Publications
Sphingosylphosphorylcholine (SPC) is found at increased in the malignant ascites of tumor patients and induces perinuclear reorganization of keratin 8 (K8) filaments that contribute to the viscoelasticity of metastatic cancer cells. However, the detailed mechanism of SPC-induced K8 phosphorylation and reorganization is not clear. We observed that SPC dose-dependently reduced the expression of epithelial membrane protein 2 (EMP2) in lung cancer cells. Then, we examined the role of EMP2 in SPC-induced phosphorylation and reorganization of K8 in lung cancer cells. We found that SPC concentration-dependently reduced EMP2 in A549, H1299, and other lung cancer cells. This was verified at the mRNA level by RT-PCR and real-time PCR (qPCR), and intracellular variation through confocal microscopy. EMP2 gene silencing and stable lung cancer cell lines established using EMP2 lentiviral shRNA induced K8 phosphorylation and reorganization. EMP2 overexpression reduced K8 phosphorylation and reorganization. We also observed that SPC-induced loss of EMP2 induces phosphorylation of JNK and ERK via reduced expression of protein phosphatase 2A (PP2A). Loss of EMP2 induces ubiquitination of protein phosphatase 2A (PP2A). SPC induced caveolin-1 (cav-1) expression and EEA1 endosome marker protein but not cav-2. SPC treatment enhanced the binding of cav-1 and PP2A and lowered binding of PP2A and alpha4. Gene silencing of EMP2 increased and gene silencing of cav-1 reduced migration of A549 lung cancer cells. Overall, these results suggest that SPC induces EMP2 down-regulation which reduces the PP2A via ubiquitination induced by cav-1, which sequestered alpha4, leading to the activation of ERK and JNK.

Zhang K, Yang G, Wu W, et al.
Decreased Expression of Caveolin-1 and E-Cadherin Correlates with the Clinicopathologic Features of Gastric Cancer and the EMT Process.
Recent Pat Anticancer Drug Discov. 2016; 11(2):236-44 [PubMed] Related Publications
BACKGROUND: Recent researches and relevant patents have been reported to prove the significant value of Caveolin-1 (Cav-1) in cancer diagnosis and treatment.
OBJECTIVE: Our study aimed to study the role of Cav-1 in gastric cancer progression and investigate the relationship between Cav-1/E-cadherin expression and the clinical status of gastric cancer.
METHOD: Immunohistochemistry was applied to detect the expression of Cav-1 and E-cadherin in gastric cancer in a tissue microarray. Real-time PCR was used to further detect the mRNA expression of Cav-1 and E-cadherin in tumor-derived and peritumoral tissues and in different gastric cancer cell lines. The expression of E-cadherin was analyzed by Western Blot and the cell migration ability was examined by Transwell migration assays after downregulation of Cav-1 using siRNA.
RESULTS: The staining of Cav-1 and E-cadherin were both strong in all 5 of the normal gastric tissues, while in gastric cancer tissues the staining of Cav-1 and E-cadherin were downregulated (44&33 negative, 21&22weak and 5&15 strong). And their level was correlated with tumor clinical stage, pathological grade, and metastasis status. Moreover, there was a positive correlation between Cav-1 expression and E-cadherin expression in gastric cancer tissues(r = 0.42, P < 0.05). Knockdown of Cav-1 resulted in decreased expression of E-cadherin, cell morphology changes and elevated migration ability of gastric cancer cells.
CONCLUSION: Decreased expression of Cav-1 and E-cadherin may play an important role in the progression of gastric cancer; Knockdown of Cav-1 may promote EMT of gastric cancer by targeting E-cadherin.

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