[Retracted] Proteasome inhibitor sensitizes oral squamous cell carcinoma cells to TRAIL­mediated apoptosis.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that, in Fig. 4 on p. 650, the same ß­actin bands had apparently been used to show the experimental effects of the proteasome inhibitor MG­132 on c­FLIP in HSC­2 cells in Fig. 4A, and the effects of MG­132 on IAPs in HSC­3 cells in Fig. 4B. In addition, for the fourth lane in the gel showing the effects of MG­132 on c­FLIP in HSC­3 cells, this should have been labelled as '+MG­132 / +TRAIL' (not as '­/­'). Upon contacting the authors in relation to this matter, they could only admit that errors had been made in the preparation of the figure; moreover, they no longer had access to the original data owing to the time that has elapsed since the publication of the paper, and it would be impossible for them to now repeat this experiment. After having considered this matter and in conjunction with a request made by the authors, the Editor of Oncology Reports has decided that this paper should be retracted from the publication. Both the Editor and the authors apologize to the readership for any inconvenience caused. [Oncology Reports 25: 645­652, 2011; DOI: 10.3892/or.2010.1127].

Methanol and Butanol Extracts of Paeonia lutea Leaves Repress Metastasis of Squamous Cell Carcinoma.

Squamous cell carcinoma (SCC) is one of the most common cancers of the head and neck region worldwide and is generally treated surgically in combination with radiotherapy and/or chemotherapy. However, anticancer agents have numerous serious side effects, and alternative, less toxic agents that are effective as chemotherapeutics for SCC are required. The Paeoniaceae family is widely used in traditional Chinese medicine. We examined methanol and butanol extracts of Paeonia lutea (P. lutea) leaves for their potential as an anticancer agent. Both extracts decreased the proliferation of SCC cells, induced apoptotic cell death, and modulated migration, adhesion, chemotaxis, and haptotaxis in an extracellular matrix- (ECM-) dependent manner due to altered expression of several integrin subunits. Subsequently, SCC cells were subcutaneously transplanted into athymic nude mice; the extracts reduced the metastasis of SCC cells but had little effect on the volume of the primary tumor or survival or body weight of the mice. The results suggest that the extracts may hold promise for preventing cancer metastasis.

Computed Tomographic Analysis of the Mandibular Body and Ramus in Japanese Patients: Relevance to Bone Harvesting From the Mandibular Ramus.

PURPOSE: The aims of this study were to use computed tomography (CT) imaging to determine the anatomical features of the mandibular body and ramus in Japanese subjects and to relate the findings to bone harvesting from the mandibular ramus. MATERIALS AND METHODS: The mandibles of 100 patients (28 males and 72 females) under dental implant treatment plan were observed on CT imaging (slice thickness, 0.625 mm). The linear distance between the superior aspect of the inferior alveolar nerve canal and the alveolar crest (distance A), the linear distance between the buccal aspect of the inferior alveolar nerve canal and the buccal cortical bone (distance B), the thickest width of the buccal cortical bone (distance C), and the thinnest width of the buccal cortical bone (distance D) were measured in the same coronal plane at 4 specific locations (section 1: the distal aspect of the first molar, section 2: the distal aspect of the second molar, section 3: the 10 mm distal aspect of the second molar, and section 4: the 15 mm distal aspect of the second molar). RESULTS: In the measurement of distance A, the minimum section among the male subjects was section 2 (12.55 ± 3.00 mm), whereas among the females, the minimum section was section 3 (11.82 ± 2.85 mm). In the distance B measurements, the maximum value was at section 2 (males: 6.36 ± 1.33 mm, females: 6.32 ± 1.39 mm) and the minimum value was at section 4 (males: 3.85 ± 1.74 mm, females: 4.75 ± 1.47 mm). Regarding the distance C measurements, the values of all subjects ranged from 3.10 to 4.41 mm, and the distance D values were approximately 2 mm. CONCLUSION: In Japanese patients, a rectangular piece of cortical bone up to 2 mm thickness may be harvested from the ramus, the length of the rectangular graft may approach 26 mm, and the height may be 10 mm for the safest harvesting from the mandibular ramus.

A Combination of Low-Intensity Pulsed Ultrasound and Nanohydroxyapatite Concordantly Enhances Osteogenesis of Adipose-Derived Stem Cells From Buccal Fat Pad.

The osteogenic induction of adipose-derived stem cells (ADSCs) has been regarded as an important step in bone tissue engineering. In the present study, we focused on the buccal fat pad (BFP) as a source of adipose tissue, since BFPs are encapsulated by adipose tissue and are often coextirpated during oral surgery. Low-intensity pulsed ultrasound (LIPUS) is effective in the treatment of fractures, and nanohydroxyapatite (NHA) is known as a bone substitute material. Here we investigated the synergistic effects of LIPUS and NHA in the osteogenesis of ADSCs. A combination of LIPUS irritation and NHA as a scaffold significantly increased the osteogenic differentiation of ADSCs in vitro, and in our in vivo study in which ADSCs were transplanted into calvarial bone defects of nude mice, the combinational effect greatly enhanced the new bone formation of the margin of the defects. These results demonstrate that synergistic effects of LIPUS and NHA are capable of effectively inducing the differentiation of ADSCs into osteoblasts, and they suggest a novel therapeutic strategy for bone regeneration by the autotransplantation of ADSCs.

Potential anti-osteoporotic effects of herbal extracts on osteoclasts, osteoblasts and chondrocytes in vitro.

BACKGROUND: Osteoporosis (OP) is one of the most serious diseases in the modern world, and OP patients frequently suffer from fragility fractures in the hip, spine and wrist, resulting in a limited quality of life. Although bisphosphonates (BPs) are the most effective class of anti-bone-resorptive drugs currently available and the most commonly prescribed for the clinical treatment of OP, they are known to cause serious side effects such as bisphosphonate-related osteonecrosis of the jaw. Novel therapeutic materials that can replace the use of BPs have therefore been developed. METHODS: We commenced an institutional collaborative project in which candidates of herbal extracts were selected from more than 400 bioactive herbal products for their potential therapeutic effects not only in OP, but also in oral and skeletal diseases. In the present study, we report on 3 Chinese medical herbal extracts from the root barks of Melia azedarach, Corydalis turtschaninovii, and Cynanchum atratum. RESULTS: All of these extracts inhibited osteoclast proliferation and induced apoptosis by up-regulation of caspase activity and increase of mitochondrial pro-apoptotic proteins expression. Furthermore, the extracts enhanced differentiation, but did not affect proliferation of both osteoblasts and chondrocytes. The osteo-inducible effect was also observed in cultured primary bone marrow cells. CONCLUSIONS: Although these extracts have been utilized in traditional Chinese medicine for hundreds of years, there are no reports to our knowledge, on their therapeutic effects in OP. In this study, we elucidate the potency of these herbal extracts as novel candidates for OP therapy.

Effectiveness of piezoelectric surgery in reducing surgical complications after bilateral sagittal split osteotomy.

Our aim was to investigate the effectiveness of piezoelectric surgery, where the osteotomy is made using ultrasonic vibration, in reducing surgical complications after bilateral sagittal split osteotomy (BSSO). Fifty-nine patients with skeletal mandibular prognathism who had mandibular setback with BSSO between January 2009 and April 2011 were included in the study. Piezosurgery was used in 29 cases, and the bone was split using a separator. In the remaining 30 cases, a Lindeman bur was used for the osteotomy and a chisel was used to split the bone. The amount of intraoperative bleeding and the Semmes Weinstein test scores were used as objective variables to evaluate the degree of neurosensory disturbance, and sex, age, use of piezosurgery, degree of setback, operating time, and method of fixation were used as explanatory variables. We used analysis of covariance (ANCOVA) to assess the significance of differences. Intraoperative bleeding was significantly less with age (p=0.003), and longer when operating time was prolonged (p=0.017), and was not influenced by the use of piezosurgery. The Semmes Weinstein test score significantly increased with age (p=0.01), and was significantly greater when piezoelectric surgery was used (p=0.008), and at 3 months, there were signs of more neurosensory disturbance in older patients and those who had had piezoelectric surgery. In this retrospective non-random study piezoelectric surgery reduced neither blood loss nor the incidence of neurosensory disturbance in BSSO.

Intramuscular hemangioma with phleboliths of the tongue.

Intramuscular hemangioma (IMH) is relatively rare benign tumor of vascular origin. Phleboliths are calcified thrombi found in the presence of hemangioma. The main treatment of the hemangioma is a surgical extirpation based on location, accessibility, and cosmetic considerations. We herein report a rare case of IMH with phleboliths of the tongue with clinical, imaging, and histopathological findings.

Aberrant expression of EZH2 is associated with pathological findings and P53 alteration.

AIM: Enhancer of zeste homolog-2 (EZH2) and B lymphoma Mo-MLV insertion region-1 homolog (BMI1) are members of the polycomb group of proteins, which function as transcriptional repressors through chromatin modification. EZH2 forms part of the polycomb repressive complex (PRC)-2, while BMI1 is a component of PRC1. Previous studies have shown that EZH2 is highly expressed in various type of cancers. Expression of EZH2 is reported to be regulated by the P53-E2F/retinoblastoma (RB)-related pathway, and a correlation between P53 mutation and EZH2 expression was recently found in breast cancer. Here, we examined the relationship between P53 and EZH2 in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Using immunohistochemistry, we investigated the expression of EZH2 and BMI1 in 99 surgically-resected OSCC and 34 epithelial dysplasia samples. We analyzed associations between aberrant expression of EZH2 and BMI1, and clinicopathological findings and patient outcome. P53 expression was also examined and analyzed in relation to EZH2 and BMI1 expression. RESULTS: EZH2 and BMI1 protein were up-regulated in OSCC tissues compared with epithelial dysplasia and normal epithelium. Aberrant EZH2 and BMI1 protein expression was observed in 32 and 59 of the 99 OSCC samples, respectively. Aberrant EZH2 and BMI1 expression was significantly associated with mode of invasion, but not with lymph node metastasis or survival rate. Aberrant EZH2 expression was associated with P53 alteration in OSCC tissue. Expression of EZH2 mRNA in SAS/neo cells, which have wild-type P53, was significantly lower than in SAS/mp53 cells that have a mutant P53 gene. CONCLUSION: P53 alteration may be involved in dysregulated EZH2 expression, and aberrant expression of EZH2 may play a role in carcinogenesis of OSCC.

Antitumor effects of telomerase-specific replication-selective oncolytic viruses for adenoid cystic carcinoma cell lines.

We evaluated the antitumor effect of a telomerase-specific replication-selective adenovirus (Telomelysin, OBP-301) for adenoid cystic carcinoma (ACC) in vitro and in vivo. Adenovirus E1 gene expression was controlled by human telomerase reverse transcription (hTERT). Infection of ACC cells by OBP-301 induced high E1A mRNA expression and subsequent oncolytic cell death in a dose-dependent manner. Using OBP-401 (TelomeScan), a genetically engineered adenovirus that carries the GFP gene under the control of the cytomegalovirus (CMV) promoter at the deleted E3 region of OBP-301, ACC cells expressed bright GFP fluorescence as early as 12 h after OBP-401 infection. The fluorescence intensity gradually increased in a time-dependent manner, followed by rapid cell death due to the cytopathic effect of OBP-401, as evidenced by the floating, highly light-refractive cells using phase-contrast microscopy. Effects of intratumorally injected OBP-401 against established Acc2 xenograft tumors were seen in BALB/c nu/nu mice. The levels of GFP expression following ex vivo infection of OBP-401 may be of value as a positive predictive marker for the outcome of telomerase-specific virotherapy. Our data clearly indicated that telomerase-specific oncolytic adenoviruses have significant therapeutic potential against human ACC in vitro and in vivo. These results suggest that treatment with OBP-301 and OBP-401 may improve the quality of life of oral cancer patients.

Root bark extracts of Juncus effusus and Paeonia suffruticosa protect salivary gland acinar cells from apoptotic cell death induced by cis-platinum (II) diammine dichloride.

Cis-platinum (II) diammine dichloride (CDDP) is a platinum-based anticancer agent, and is often used for chemotherapy for malignant tumors, albeit CDDP has serious side-effects, including xerostomia (dry mouth). Since patients with xerostomia have reduced quality of life, it is urgent and important to identify nontoxic and natural agents capable of reducing the adverse effect of chemotherapy on salivary gland function. Therefore, we commenced an institutional collaborative project in which candidates of herbal extracts were selected from more than 400 bioactive herbal products for their potential therapeutic effects not only on xerostomia, but also on oral diseases. In the present study, we report on two Chinese medical herbal extracts from the root barks of Juncus effusus and Paeonia suffruticosa. The two extracts showed a protective effect in NS-SV-Ac cells from the cytotoxicity and apoptosis caused by CDDP. The effect was dependent on the p53 pathway, protein kinase B/Akt 1 and mitochondrial apoptosis-related proteins (i.e. Bcl-2 and Bax), but was not dependent on nuclear factor κB. Notably, the apoptosis-protective effect of the extracts was not observed in adenocystic carcinoma cell lines. Although these extracts have been utilized in traditional Chinese medicine for hundreds of years, there are no reports to our knowledge, on their therapeutic effects on xerostomia. Thus, in the present study, we elucidated the potency of these herbal extracts as novel candidates for xerostomia to improve the quality of life of patients undergoing chemotherapy.

microRNA expression profiles in oral squamous cell carcinoma.

microRNAs (miRNAs) are involved in cancer pathogenesis, apoptosis and cell growth, thereby functioning as both tumor suppressors and oncogenes. However, the expression patterns and roles of miRNAs in oral squamous cell carcinoma (OSCC) remain largely unknown. We hypothesized that oral cancer may have a unique miRNA profile, which in turn may play a critical role in oral cancer development, progression, diagnosis and prognosis. We, therefore, investigated the expression profiles of 29 OSCC tumors and 7 normal oral mucosal samples. The miRNA expression patterns in OSCC were examined by TaqMan-based microRNA assays. We were subsequently able to identify the candidates of cancer-related miRNAs through analysis of the miRNA expression profiles. In conclusion, OSCC tissues were shown to have a unique miRNA profile pattern when compared with that in normal tissues. The present study may provide useful information for further investigation of the functional roles of miRNAs in OSCC development, progression, diagnosis and prognosis.

Tumor protein D54 is a negative regulator of extracellular matrix-dependent migration and attachment in oral squamous cell carcinoma-derived cell lines.

PURPOSE: Tumor protein D54 (TPD54) belongs to the TPD52 family of proteins and is expressed in several types of cancer, including oral squamous cell carcinoma (OSCC). Here, we investigated relationships between various OSCC-related characteristics and TPD54 expression in vitro. METHODS: The expression of TPD54 in several OSCC-derived cell lines and normal, non-malignant, cells was assessed. Based on the results obtained, OSCC-derived SAS cells were subsequently subjected to exogenous over-expression of alternative splice variants (ASVs) of TPD54 and to TPD54 knock-down, mediated by siRNA. Next, the role of TPD54 in cellular growth, apoptosis, invasion, migration and extracellular-matrix (ECM)-dependent migration and attachment was investigated, as also the concomitant expression of integrins and integrin-related proteins by the OSCC-derived cells. RESULTS: Western blot analysis and RT-PCR revealed that several TPD54 ASVs were expressed in the OSCC-derived cell lines tested. Neither exogenous ASV over-expression nor TPD54 knock-down modulated the proliferation or invasion of SAS cells in a monolayer culture assay. However, exogenous ASV over-expression did decrease anchorage-independent growth and TPD54 knock-down did increase anchorage-independent growth, irrespective of caspase activities. The same effects were observed on ECM-dependent cellular migration and cell attachment to the ECM. The expression levels of the major α and ß integrin subunits, and of E-cadherin, were found to be similar to those observed in the non-transfected control cells, whereas talin1 expression was found to be increased after TPD54 knock-down. Also Akt was found to be activated after TPD54 knock-down, even in the absence of serum stimulation. Very similar effects were observed in the OSCC-derived cell lines HSC 2 and HSC 3. CONCLUSIONS: Our results show that TPD54 affects OSCC cell attachment to the ECM, OSCC cell migration, and Akt/PKB activation by modulating integrin activation via a talin1-mediated inside-out signal of the ECM. Based on these results, we suggest that TPD54 may serve as a novel biomarker for OSCC and as a putative target for OSCC therapy.

Multicenter phase II trial of preoperative chemoradiotherapy with S-1 for locally advanced oral squamous cell carcinoma.

PURPOSE: We evaluated whether preoperative chemotherapy with S-1 and concurrent radiotherapy is feasible and efficacious in the treatment of advanced oral squamous cell carcinoma. METHODS: Participants comprised 39 patients with oral carcinoma (stage III, n = 15; stage IVA, n = 24). All patients received a total radiation dose of 40 Gy, in once-daily 2-Gy fractions, and received S-1 at 65 mg/m(2)/day for 5 consecutive days, over 4 consecutive weeks with concurrent radiotherapy. RESULTS: Hematological toxicity was mild and reversible. The most common non-hematological toxicity was grade 3 mucositis, but this was transient and tolerable. Radical surgery was performed for 37 patients, with the remaining 2 patients declining the surgery. Postoperatively, local failure developed in 1 patient, and neck failure in 2 patients. Distant metastases were identified in 4 patients. At a median follow-up of 38.0 months (range 23-88 months), locoregional control, disease-specific survival, and overall survival rates at 3 years were 91.5, 83.8, and 83.8 %, respectively. CONCLUSION: Concurrent administration of S-1 and radiotherapy combined with surgery offers a well-tolerated method of successfully treating advanced oral squamous cell carcinoma. The locoregional control rate remains high even at 3 years of follow-up, and no serious adverse effects have been encountered.

The potential anticancer activity of extracts derived from the roots of Scutellaria baicalensis on human oral squamous cell carcinoma cells.

Various herb products derived from plants have potent biological effects including anticancer activity. In the present study, the antitumor activity of a herbal product derived from the Scutellaria baicalensis (S. baicalensis) was examined, using in vitro assays in a human oral squamous cell carcinoma (OSCC) cell line. Results showed that S. baicalensis root extract at the concentration of 100 µg/ml inhibited monolayer- and anchorage-independent growth in human OSCC cell lines, while not affecting the adhering abilities of cells. This suggested that it did not alter the expression of any of the adhesion receptors that mediate cell-extracellular matrix (ECM) interactions. The S. baicalensis root extract demonstrated potent cytostatic and apoptotic effects due to the downregulation of the cyclin-dependent kinase 4 expression and its partner cyclin D1, resulting in G1 arrest and poly (ADP-ribose) polymerase (PARP) cleavage. Additionally, the S. baicalensis root extract was found to have blocked vascular endothelial growth factor (VEGF)-induced migration and tube formation in human endothelial cells. Taken together, these results demonstrate that as a herbal product, the S. baicalensis root extract is a potential inhibitor of tumori- and angiogenesis and may be valuable in the development of pharmaceutical medications for the treatment of oral squamous cell carcinoma.

General rules for clinical and pathological studies on oral cancer: a synopsis.

For the doctors and other medical staff treating oral cancers, it is necessary to standardize basic concepts and rules on oral cancers to progress in the treatment, research and diagnosis. Oral cancers are integrated in head and neck cancers and are applied to the general rules on head and neck cancer, but it is considered that more detailed rules based on the characteristics of oral cancers are essential. The objectives of this 'General Rules for Clinical and Pathological Studies on Oral Cancer' are to contribute to the development of the diagnosis, treatment and research of oral cancers based on the correct and useful medical information of clinical, surgical, pathological and image findings accumulated from individual patients at various institutions.

The root bark of Paeonia moutan is a potential anticancer agent in human oral squamous cell carcinoma cells.

Currently there is growing use of complementary and alternative anticancer medicines worldwide, and considerable interest in finding anticancer drugs among Chinese medicinal herbs. The aim of this study was to determine the antitumor activity of the root bark of Paeonia moutan (RBPM) in human squamous cell carcinoma (OSCC) cells. Cell lines derived from human oral squamous cell carcinoma (HSC2, 3, 4, SAS) were tested with different concentrations of RBPM (1-100 µg/ml) using a series of in vitro assay systems. RBPM at a concentration of 100 µg/ml inhibited monolayer and anchorage-independent growth, and interrupted coordinated migration. RBPM activated the phosphorylation of extracellular signal-regulated kinase (ERK) and serine/threonine kinase AKT in 30 min; then, at a later stage (after 6 hours) exhibited potent cytostatic, pro-apoptotic effects through the down-regulation of the expression of cyclin-dependent kinase 4 and its partner cyclin D1, and poly(ADP-ribose) polymerase cleavage. We found direct evidence that RBPM induces apoptotic cell death via DNA fragmentation. Taken together, the antitumor activity of RBPM was demonstrated through antiproliferative and apoptotic effects.

Evaluation of anticancer activities of benzo[c]phenanthridine alkaloid sanguinarine in oral squamous cell carcinoma cell line.

While the effects of benzo[c]phenanthridine alkaloids (QBA), known mainly as sanguinarine and chelerythrine, on the inhibition of some kinds of cancer cell proliferation have been established, the effect on oral squamous cell is not known. Here, the antitumor activity of sanguinarine was demonstrated using in vitro assay systems in SAS, a human oral squamous cell carcinoma (OSCC) cell line. The anti-proliferative and -invasive effects were confirmed with IC50 values in the concentration range of 0.75-1.0 µM by MTT assay and invasive assay, respectively. Sanguinarine was also able to suppress cell anchorage-independent growth, whereas it did not affect the cells' adhering capabilities. Finally, sanguinarine induced apoptotic cell death by activating caspase and altering the Bcl-2/Bax ratio. Taken together, these results indicate that sanguinarine is a potential inhibitor of tumorigenesis and suggest that it may be valuable in the development of new anticancer drugs for the treatment of OSCC.

Anti-tumor activity of dehydroxymethylepoxyquinomicin against human oral squamous cell carcinoma cell lines in vitro and in vivo.

Several reports have indicated that nuclear factor-kappa B (NF-κB) is constitutively activated in a variety of cancer cells including human oral squamous carcinoma cells, and play a key role in their growth and survival. Recent studies report that NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), inhibits proliferation and induces apoptosis in prostate cancer cell lines. However this anti-tumor effects are still unknown in end human oral squamous carcinoma cells. In the present study, we investigated the effects of DHMEQ on oral squamous carcinoma cell (OSCC) lines in vitro and in vivo. Human OSCC cell lines (HSC-3, SAS) were treated with DHMEQ and examined for cell viability by MTT assay, cell cycle distribution by flow-cytometry, apoptosis by TUNEL assay, and protein expression by western blotting, respectively. In vivo activities were also investigated in a mouse xenograft model. DHMEQ inhibited growth of two OSCC cell lines in a dose-dependent manner measured by MTT assay. A flow cytometric analysis demonstrated that treatment with DHMEQ induced accumulation in sub-G1 phase. TUNEL assay showed that DHMEQ induced DNA fragmentation. Protein expression by western blotting analysis revealed that DHMEQ induced nuclear down regulation of Survivin, cIAP-1, and cIAP-2. In nude mice, DHMEQ inhibited growth of OSCC without major toxic side effects. The present results demonstrated that administration of DHMEQ is suggested to be a novel anti-tumor approach to the treatment of OSCC.

Binding of glyceraldehyde-3-phosphate dehydrogenase to the cis-acting element of structure-anchored repression in ccn2 mRNA.

CCN2/connective tissue growth factor (CTGF) can be induced by hypoxia and promotes tumor angiogenesis. Our previous studies revealed that hypoxia-induced gene expression of human ccn2 mRNA is regulated post-transcriptionally in human chondrosarcoma-derived cell line, HCS-2/8, in which a minimal cis-element, entitled CAESAR, in the 3'-untranslated region (UTR) of ccn2 mRNA and a 35-kDa protein counterpart play an important role by determining the stability of ccn2 mRNA. In the present study, we identified this corresponding protein as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by utilizing RNA affinity chromatography combined with mass spectrometry. The results of an RNA binding assay revealed the specific binding of GAPDH to this cis-element. To further characterize the interaction between GAPDH and ccn2 mRNA, we examined the roles of redox conditions and glycolytic coenzyme in the binding of GAPDH to the ccn2 mRNA. An oxidizing agent, diamide, abolished the GAPDH-RNA interaction in a concentration-dependent manner; whereas this effect could be reversed by subsequent treatment with 2-mercaptoethanol (2-ME). In addition, nicotinamide-adenine dinucleotide (NAD), a coenzyme of GAPDH, inhibited the GAPDH-RNA binding. Taken together, these findings suggest that the glycolytic enzyme GAPDH regulates the gene expression of ccn2 mRNA in trans by acting as a sensor of oxidative stress and redox signals, leading to CCN2 overexpression under the condition of hypoxia and promotion of angiogenesis.