The P387 thrombospondin-4 variant promotes accumulation of macrophages in atherosclerotic lesions.

Thrombospondin-4 (TSP4) is a pro-angiogenic protein that has been implicated in tissue remodeling and local vascular inflammation. TSP4 and, in particular, its SNP variant, P387 TSP4, have been associated with cardiovascular disease. Macrophages are central to initiation and resolution of inflammation and development of atherosclerotic lesions, but the effects of the P387 TSP4 on macrophages remain essentially unknown. We examined the effects of the P387 TSP4 variant on macrophages in cell culture and in vivo in a murine model of atherosclerosis. Furthermore, the levels and distributions of the two TSP4 variants were assessed in human atherosclerotic arteries. In ApoE-/- /P387-TSP4 knock-in mice, lesions size measured by Oil Red O did not change, but the lesions accumulated more macrophages than lesions bearing A387 TSP4. The levels of inflammatory markers were increased in lesions of ApoE-/- /P387-TSP4 knock-in mice compared to ApoE-/- mice. Lesions in human arteries from individuals carrying the P387 variant had higher levels of TSP4 and higher macrophage accumulation. P387 TSP4 was more active in supporting adhesion of cultured human and mouse macrophages in experiments using recombinant TSP4 variants and in cells derived from P387-TSP4 knock-in mice. TSP4 supports the adhesion of macrophages and their accumulation in atherosclerotic lesions without changing the size of lesions. P387 TSP4 is more active in supporting these pro-inflammatory events in the vascular wall, which may contribute to the increased association of P387 TSP4 with cardiovascular disease.

Efficacy and Safety of Dual Paclitaxel and Sirolimus Nanoparticle-Coated Balloon.

We evaluated a novel dual active pharmaceutical ingredient (API) drug-coated balloon (DCB), which consists of a coating of nanoparticles encapsulating low-dose paclitaxel (PTX) in combination with sirolimus in a synergistic ratio. Compared to the PTX DCB, the dual API DCB demonstrated similar inhibition of cell proliferation in vitro but at a significantly lower total drug dose (over 13 times lower than sirolimus nanoparticles). Animal experiments demonstrated that the dual API DCB is more effective in inhibiting intimal cell proliferation with insignificant downstream embolic effects and myocardial damage compared to the PTX DCB. These findings indicate that dual API DCBs have a high potential to demonstrate improved clinical outcomes and a greater safety profile than the PTX DCBs.

Fatty acid synthase is a potential therapeutic target in estrogen receptor-/progesterone receptor-positive endometrioid endometrial cancer.

OBJECTIVE: In the current study we investigated the clinicopathological significance of fatty acid synthase (FASN) expression and its relationship with estrogen receptor (ER) and progesterone receptor (PR) in endometrioid endometrial cancer. METHODS: FASN expression in endometrioid endometrial cancer was assessed by immunohistochemistry using 108 paraffin-embedded tissue specimens and clinical data collected from a retrospective chart review. The specific FASN inhibitor C75 was used to analyze the relationship between FASN expression and cell growth as well as ER/PR expression in endometrioid endometrial cancer cell lines. RESULTS: Positive FASN immunostaining was observed in 77.8% (84/108) of the tumors analyzed. Deep myometrial invasion was significantly and inversely correlated with positive FASN expression (p = 0.024). Positive ER (p = 0.018) and PR status (p = 0.012) was significantly correlated with positive FASN expression. Patients with positive FASN expression in endometrioid endometrial cancer tissues tended to have a favorable progression-free/overall survival (p = 0.127 and p = 0.087, respectively). Ishikawa cells with high FASN expression also showed high expression of ER/PR, while HEC1B cells had low expression levels of both FASN and ER/PR. FASN inhibition by C75 (10 µM) significantly reduced ER/PR expression compared with control dimethyl sulfoxide treatment of Ishikawa cells. The growth of Ishikawa cells having positive FASN and ER/PR expression was significantly inhibited in the presence of C75 or FASN small-interfering RNA compared to HEC1B cells that lacked FASN and ER/PR expression. CONCLUSION: The current findings suggest that there may be cross talk between the ER/PR and FASN signaling pathways that modulate ER/PR activation and could play a role in endometrioid endometrial cancer pathogenesis.

Is ATP7B a predictive marker in patients with ovarian carcinoma treated with platinum-taxane combination chemotherapy?

OBJECTIVE: This study examined the prognostic significance of copper-transporting P-type adenosine triphosphatase (ATP7B) expression in patients with ovarian carcinoma treated with platinum-taxane combination chemotherapy. METHODS: Expression of ATP7B in ovarian carcinoma was assessed by immunohistochemistry and clinical data collected by retrospective review of medical charts. RESULTS: Overexpression of ATP7B was identified in 25 (29.1%) of 86 ovarian carcinomas. The frequency of ATP7B expression in clear cell carcinomas was significantly higher than that in serous high-grade carcinomas (P < 0.05). We observed no statistically significant correlations between high ATP7B protein expression and either disease-free survival (P = 0.722) or overall survival (P = 0.389). CONCLUSIONS: Our study is the first to demonstrate a lack of statistically significant differences between ATP7B positive and negative cases with respect to prognosis of patients with ovarian carcinoma treated with a platinum-taxane combination regimen. However, that ATP7B expression in clear cell carcinomas was significantly higher than that in serous carcinomas may partially explain the difference in chemotherapeutic response and prognosis between patients with these 2 types of carcinomas.

A Case of Stage III c Ovarian Clear Cell Carcinoma: The Role for Predictive Biomarkers and Targeted Therapies.

Ovarian cancer treatment presently does not reflect molecular differences in histologic subtype. Ovarian clear cell carcinoma (OCCC) exhibits several differences in terms of molecular pathogenesis and tumor behavior from the more common, chemosensitive, serous carcinomas, which makes OCCC a candidate for targeted therapies. A 53-year-old Japanese woman was diagnosed with stage IIIc ovarian clear cell adenocarcinoma with marked chemoresistance to conventional regimens. She demonstrated a partial response to a multikinase inhibitor. The tumor was resistant to PI3K/mTOR pathway inhibitors despite harboring a PIK3CA mutation. The present case suggests a role for targeted therapies in the treatment of OCCC and a need for the identification of biomarkers that will predict response to targeted therapies.

KRAS and MAPK1 gene amplification in type II ovarian carcinomas.

In this study, we examined the clinical significance of KRAS and MAPK1 amplification and assessed whether these amplified genes were potential therapeutic targets in type II ovarian carcinoma. Using fluorescence in situ hybridization, immunohistochemistry, and retrospectively collected clinical data, KRAS and MAPK1 amplifications were identified in 9 (13.2%) and 5 (7.4%) of 68 type II ovarian carcinoma tissue samples, respectively. Interestingly, co-amplification of KRAS and MAPK1 seemed to be absent in the type II ovarian carcinomas tested, except one case. Active phospho-ERK1/2 was identified in 26 (38.2%) out of 68 type II ovarian carcinomas and did not correlate with KRAS or MAPK1 amplification. There was no significant relationship between KRAS amplification and overall or progression-free survival in patients with type II ovarian carcinoma. However, patients with MAPK1 amplification had significantly poorer progression-free survival than patients without MAPK1 amplification. Moreover, type II ovarian carcinoma cells with concomitant KRAS amplification and mutation exhibited dramatic growth reduction following treatment with the MEK inhibitor PD0325901. These findings indicate that KRAS/MAPK1 amplification is critical for the growth of a subset of type II ovarian carcinomas. Additionally, RAS/RAF/MEK/ERK pathway-targeted therapy may benefit selected patients with type II ovarian carcinoma harboring KRAS/MAPK1 amplifications.

Nanoparticle-mediated synergistic drug combination for treating bone metastasis.

Bone metastasis at an advanced disease stage is common in most solid tumors and is untreatable. Overexpression of receptor activator of nuclear factor κB ligand (RANKL) in tumor-bone marrow microenvironment drives a vicious cycle of tumor progression and bone resorption. Biodegradable nanoparticles (NPs), designed to localize in the tumor tissue in bone marrow, were evaluated in a prostate cancer model of bone metastasis. The combination treatment, encapsulating docetaxel, an anticancer drug (TXT-NPs), and Denosumab, a monoclonal antibody that binds to RANKL (DNmb-NPs), administered intravenously regressed the tumor completely, preventing bone resorption, without causing any mortality. With TXT-NPs alone treatment, after an initial regression, the tumor relapsed and acquired resistance, whereas DNmb-NPs alone treatment was ineffective. Only in the combination treatment, RANKL was not detected in the tumor tibia, thus negating its role in tumor progression and bone resorption. The combination treatment was determined to be safe as the vital organ tissue showed no increase in inflammatory cytokine or the liver ALT/AST levels, and animals gained weight. Overall, dual drug treatment acted synergistically to modulate the tumor-bone microenvironment with encapsulation enhancing their therapeutic potency to achieve tumor regression.

Prognostic and therapeutic impact of the chromosome 20q13.2 ZNF217 locus amplification in ovarian clear cell carcinoma.

BACKGROUND: The goal of this study was to examine the clinical significance of ZNF217 amplification and assess whether ZNF217 could be a potential therapeutic target in ovarian clear cell carcinoma (OCCC). METHODS: ZNF217 expression and amplification in OCCC was assessed by immunohistochemistry, fluorescence in situ hybridization, and clinical data collected via a retrospective chart review. ZNF217 gene knockdown using silencing RNA (siRNA) was used to assess ZNF217 functions in OCCC cell lines. RESULTS: Gene amplification was identified in 12 of 60 (20.0%) OCCCs. ZNF217 copy number correlated significantly with ZNF217 protein expression (r = 0.341; P<.01). ZNF217 amplification correlated significantly with shorter progression-free (P = .0042) and overall (P = .0199) survival. There were nonsignificant trends between high ZNF217 protein expression and poor progression-free (P = .2594) and overall (P = .2199) survival. Multivariate analysis revealed ZNF217 gene amplification to be an independent prognostic factor for progression-free and overall survival after standard platinum agent-based chemotherapy (P = .0339 and P = .031, respectively). Profound growth inhibition and apoptosis were observed in ZNF217 siRNA-treated cancer cells with gene amplification compared with cancer cells with ZNF217 moderate expression without ZNF217 gene amplification or with low ZNF217 expression. CONCLUSION: These findings indicate that ZNF217 overexpression is critical to growth and survival of OCCCs with ZNF217 gene amplification. Furthermore, they suggest that ZNF217 siRNA-induced phenotypes depend on amplification status of OCCCs. Therefore, ZNF217-targeted therapy may benefit OCCC patients with ZNF217 amplification.

Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma.

Recently, the ARID1A gene has been identified as a novel tumor suppressor in ovarian clear cell carcinoma. The prognostic significance of the loss of ARID1A expression is not known. The current study was designed to evaluate whether ARID1A was a prognostic factor for progression, survival, and chemoresistance in ovarian clear cell carcinoma. A total of 60 patients, who were surgically treated for primary ovarian clear cell adenocarcinoma, were enrolled. Surgical specimens were examined for ARID1A protein expression by immunohistochemistry. The correlations between the loss of ARID1A expression and clinicopathological characteristics, prognosis, and chemosensitivity were investigated. Loss of ARID1A expression was identified in 9 (15.0%) of 60 ovarian clear cell carcinoma samples. Loss of ARID1A staining intensity (0+) was more frequently found in cells of clear cell carcinomas than in high-grade serous carcinomas (P<0.01). Loss of ARID1A expression was significantly correlated with advanced FIGO stage and high CA125 levels (P=0.02, 0.01). There were no significant correlations between loss of ARID1A expression and patient age, status of residual tumor, Ki-67 labeling index, or the status of endometriosis. Loss of ARID1A correlated with shorter progression-free survival of patients with clear cell carcinomas treated with platinum-based chemotherapy (P<0.01). Loss of ARID1A expression tended to correlate with shorter overall survival in patients with ovarian clear cell carcinomas treated with platinum-based chemotherapy. When data were stratified for the multivariate analysis, only the loss of ARID1A expression remained a significant (P=0.03) predictor of reduced progression-free survival. Of the 60 patients with ovarian clear cell carcinomas, 14 patients had measurable residual tumor after primary cytoreductive surgery. Tumors with loss of ARID1A expression were more likely to be chemoresistant than tumors with positive ARID1A expression (100.0 vs 40.0%, P=0.04). This study demonstrates that loss of ARID1A in ovarian clear cell carcinoma is a negative prognostic factor in patients treated with platinum-based chemotherapy. Measurement of ARID1A expression may be a method to predict resistance to platinum-based chemotherapy in patients with ovarian clear cell carcinoma.

Uterine leiomyosarcoma producing granulocyte colony stimulating factor.

Uterine leiomyosarcoma associated with the paraneoplastic production of granulocyte-colony stimulating factor (GCSF) is extremely rare. No case has been reported to date in the English literature. We describe a case of a 56-year-old female with recurrent uterin leiomyosarcoma, associated with leukocytosis (19100/mm) and an elevated serum GCSF (33.0 pg/ml). Tumore histology was consistent with a well differentiated leiomyosarcoma with marked neutrophilic infiltration of the lung and spleen metastases. tumor cells were distinctly positive for GCSF on immunohistochemistry. These findings confirmed the diagnosis of a GCSF-producting uterine leiomyosarcoma with a paraneoplastic leukocytosis.

Frequent loss of tumor suppressor ARID1A protein expression in adenocarcinomas/adenosquamous carcinomas of the uterine cervix.

OBJECTIVES: Expression of ARID1A (the adenine, thymine-rich interactive domain 1A), a putative tumor suppressor, has recently been shown to be lost in several tumor types. This study investigated whether ARID1A expression was also lost in cervical squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas. METHODS: A total of 91 patients with cervical carcinoma were enrolled. Cervical carcinoma specimens were examined for ARID1A protein expression by immunohistochemistry. The correlations between the loss of ARID1A expression and clinicopathological characteristics, and prognosis were investigated. RESULTS: Using immunohistochemistry, the frequency of loss of ARID1A expression in adenocarcinomas/adenosquamous carcinomas (31.1% [14/45]) was significantly higher than that in squamous cell carcinomas (6.5% [3/46]; P = 0.0017). There was no significant association between the loss of ARID1A expression and International Federation of Gynecology and Obstetrics staging, lymphovascular space invasion, lymph node metastasis, age, and Ki-67 LI in cervical adenocarcinomas/adenosquamous carcinomas. Loss of ARID1A expression was not correlated with shorter overall/disease-free survival in cervical adenocarcinomas/adenosquamous carcinomas. CONCLUSIONS: In conclusion, this study provides the first evidence of the frequent loss of ARID1A protein expression in cervical adenocarcinomas/adenosquamous carcinomas. No significant differences between ARID1A positive and negative cases were observed with respect to any clinicopathological features examined.

Sister Mary Joseph's nodule associated with rare endometrial squamous cell carcinoma.

BACKGROUND: Umbilical metastasis (Sister Mary Joseph's nodule) is a rare physical sign seen only in 1-3 % of patients with an intra-abdominal and/or pelvic malignancy. Here, we present a case of Sister Mary Joseph's (SMJN) nodule originating from a primary squamous cell carcinoma of the endometrium, a rare histological subtype. CASE HISTORY: SMJN was detected in a 30-year-old woman after a preoperative CT scan for a suspected umbilical hernia. Subsequent laparotomy and histopathological examination confirmed endometrial squamous cell carcinoma metastasizing to the umbilical region. CONCLUSION: The SMJN may be the first presenting sign of an intra-abdominal and/or pelvic malignancy and may co-exist with an umbilical hernia. Therefore, malignancy should be considered one of the differentials of an umbilical mass.

[A case of stage IVb cervical carcinoma in which survival was prolonged by two different chemotherapies and CCRT].

Pulmonary metastasis from primary cervical carcinoma is rare, with an incidence of 4.16-7.7%. Chemotherapy is the most common treatment; however, the overall prognosis is poor. This case report describes a complete response to CCRT and TC therapy of cervical carcinoma metastatic to the lung. The patient, a 57-year-old woman, was initially diagnosed with FIGO clinical Stage IVb cervical carcinoma with lung metastasis, after presenting with vaginal bleeding. She had a 90 pack/year smoking history. She was initially treated with systemic chemotherapy(TC therapy: PTX, CBDCA 1 course)followed by concurrent chemoradiotherapy(CCRT)with weekly CDDP2 0mg/m2. She had a complete response of her pelvic disease as well as a decrease in the size of metastatic lesions. Following CCRT, she was scheduled to continue TC therapy, but was only able to complete two courses secondary to a myocardial infarction. A lung biopsy at that time showed no evidence of malignancy, and the patient has remained without any evidence of disease for the past six years.

Loss of MKK4 expression in ovarian cancer: a potential role for the epithelial to mesenchymal transition.

In the current study, we investigated the mechanism relating downregulation of mitogen-activated protein kinase kinase 4 (MKK4) expression to development of ovarian cancer. Over-expression of the MKK4 gene in TOV-21 G cells, a line with homozygous deletion of MKK4, resulted in morphologic changes in which cells growing in a scattered, fibroblast-like pattern formed tightly packed colonies. Based on a wound healing assay and a Matrigel invasion assay, we determined that both motility and invasiveness of MKK4-transfected TOV-21G cells were significantly reduced compared to control vector-transfected cells. To confirm that MKK4 expression related to tumor invasion resulted from an epithelial to mesenchymal transition (EMT)-like morphological change, we used 2 independent but complementary approaches. MKK4 gene knockdown in MDAH 2774 cells over-expressing MKK4 increased invasion activity. Additionally, engineered expression of MKK4 in SKOV3 cells, a line with low endogenous MKK4 expression, produced a phenotype similar to that of TOVG-21G. Interestingly, we found that MKK4 upregulation caused downregulation of phosphorylated NF-κB and Twist, as well as upregulation of E-cadherin, in TOVG-21G and SKOV3 cells. Reciprocal results were obtained in MDAH 2774 cells with MKK4 knockdown. Our results suggest that MKK4 downregulation causes increased phosphorylation NF-κB. This promotes Twist over-expression, resulting in E-cadherin downregulation that induces EMT in ovarian cancer.

MKK4 acts as a potential tumor suppressor in ovarian cancer.

Our previous studies indicate that loss of MKK4 expression is associated with the progression of ovarian cancer. However, direct evidence that MKK4 inhibits the malignant phenotype of ovarian cancer cells is limited. In the current study, we investigated the mechanism relating loss of MKK4 expression to the development of ovarian cancer. Using cell growth and anchorage-independent assays, we determined that both the growth and colony-forming ability of MKK4-transfected TOV-21G cells, a line with a homozygous deletion of MKK4, were significantly reduced compared to control vector-transfected cells. Overexpression of the MKK4 gene in TOV-21G cells resulted in reduced proliferative activity and increased apoptosis. To confirm that MKK4 expression related to tumor suppress function, we used two independent but complementary approaches. MKK4 gene knockdown in OVK18#2 and MDAH2774 cells, which overexpressed MKK4, increased proliferation activity. Additionally, the engineered expression of MKK4 in SKOV3 cells, a line with low endogenous MKK4 expression, produced a phenotype similar to that of TOV-21G. Similar results were produced in tumor xenografts in nude mice. These results indicated that MKK4 acts as a tumor suppressor and may represent an important therapeutic target for the treatment of ovarian cancer.

Microwave endometrial ablation is a highly efficacious way to emergently control life-threatening uterine hemorrhage.

OBJECTIVE: To asses the effectiveness of microwave endometrial ablation (MEA) using a new curved applicator for the emergent control of uterine hemorrhage. STUDY DESIGN: Seven patients received emergency MEA. Three out of seven patients were treated with MEA as their primary procedure, and four out of seven patients were treated for an intraoperative hemorrhage. RESULTS: In all three patients treated preoperatively, MEA was highly effective and successfully controlled acute uterine hemorrhage. Four out of seven patients were treated with MEA for a hemorrhage following resection of a submucosal myoma or polyp. MEA successfully controlled bleeding in all four patients, thereby preventing them from undergoing hysterectomy. CONCLUSION: Our results suggest that emergency MEA is a promising way to control a life-threatening uterine hemorrhage.

[A case of postoperative rapid brain metastasis originating from stage II a cervical adenosquamous cell carcinoma].

Cerebralmetastases from primary cervical carcinomas are very rare with a repeated incidence of 0. 5-1. 2% in various studies. A 46-year-old woman was initially diagnosed and treated for FIGO clinical stage II a cervical carcinoma. She was two gravid, two para. When 40 years old, she had a right hemicolectomy and chemotherapy, due to colon cancer. Her mother also had colon cancer, cervical cancer, and stomach cancer. She had habitually smoked ten/day for 26 years. First, she went to the outpatient clinic, due to abnormal vaginal bleeding. She had a biopsy of her cervix and was diagnosed with cervical cancer. She underwent a radical hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy. Pathological diagnosis was adenosquamous cell carcinoma of uterine cervix with extensive LVSI and pelvic lymph node metastasis (right internalil iac LN), myometrial invasion (depth 10 mm), anterior vaginal wall metastasis, but no metastasis of vaginal stump. She came to our hospital for radiotherapy. The woman received concurrent chemoradiotherapy(CCRT)with weekly CDDP 30 mg/m² as adjuvant therapy. Shortly after CCRT, she was diagnosed with multiple metastases to the bone, liver, lung, and brain. She received palliative radiotherapy and eventually died four months after being diagnosed. The extremely rapid progression of this patient's disease is unusual. To our knowledge, this is one of the most aggressive cases of cervical adenosquamous cell carcinoma documented.

Functional and clinicopathological analysis of loss of MKK4 expression in endometrial cancer.

OBJECTIVE: In the current study, we investigated the mechanism relating downregulation of mitogen-activated protein kinase kinase-4 (MKK4) expression to the development of endometrial cancer. METHODS: MKK4 expression in endometrial cancer was assessed by immunohistochemistry using 87 paraffin-embedded tissue specimens, and clinical data was collected via a retrospective chart review. MKK4 gene knockdown using silencing RNA and an MKK4 gene transfection system was used to assess MKK4 function in tissue samples of endometrial cancer. RESULTS: Lower expression of MKK4 immunointensity was observed in 63.2% (55/87) of the analyzed tumors. High-grade endometrioid adenocarcinoma (G2 and G3) (p = 0.024), postmenopausal status (p = 0.018), and patient age (≥ 60) (p = 0.012) were significantly correlated with lower MKK4 expression. Patients with lower MKK4 expression in endometrial cancer tissues tended to have a shorter overall survival (p = 0.197). Using cell growth and anchorage-independent assays, we determined that both the growth and colony-forming ability of MKK4-transfected HEC1B cells, a line with a low endogenous expression of MKK4, were significantly reduced compared to control vector-transfected cells. Overexpression of the MKK4 gene in HEC1B cells resulted in reduced cell migration activity in a simulated wound healing assay. To confirm that MKK4 expression is related to tumor suppressor function, we used 2 independent but complementary approaches. MKK4 gene knockdown in JHEM1 cells, which overexpressed MKK4, increased proliferation activity. Additionally, the engineered expression of MKK4 in Ishikawa cells, a line with low endogenous MKK4 expression, produced a phenotype similar to that of HEC1B. Similar results were produced in tumor xenografts in nude mice. CONCLUSION: These results indicate that MKK4 acts as a tumor suppressor, and reduced expression of MKK4 may contribute to the development of endometrial cancer.

Expression of nuclear Notch3 in cervical squamous cell carcinomas and its association with adverse clinical outcomes.

OBJECTIVE: The aim of this study was to clarify the functional role of Notch3 in human cervical carcinomas. METHODS: Notch3 expression in cervical cancer was assessed by immunohistochemistry, and data on clinical variables were collected by retrospective chart review. We used dual-color fluorescence in situ hybridization (FISH) to analyze DNA copy number alterations in cervical cancer. Inactivation of Notch3 and knocking down Notch3 gene were done using gamma-secretase inhibitor and Notch 3 specific SiRNA to asses Notch3 function in cervical cancer either in vivo or in vitro. RESULTS: Immunohistochemical analysis revealed that Notch3 was significantly overexpressed in cervical squamous cell carcinomas compared with adenocarcinomas. In contrast to normal cervical tissue and cervical intraepithelial neoplasms [CINs], squamous cell carcinomas demonstrated higher nuclear Notch3 immunoreactivity. Notch3 amplification was not found in any cervical carcinomas using FISH analysis. Notch3 nuclear expression was significantly correlated with Jagged-1, a putative Notch3 ligand, and Pbx1b, a potential Notch3 downstream target (P<0.05).Patients with cervical carcinomas positive for nuclear Notch3 expression had significantly shorter overall survival than their peers whose tumors did not express nuclear Notch3. Inactivation of Notch3 decreased cell proliferation and induced apoptosis in ME180 and SKGIIIb cell lines that overexpressed Notch3. Injection of a gamma-secretase inhibitor into ME180 cell tumors established on mice, demonstrated a reduction in tumor growth. CONCLUSION: Our findings suggest that Notch3 might play important role for the proliferation and survival of Notch3 overexpressing tumors and that inactivation of Notch3 may represent a new therapeutic avenue for cervical squamous cell carcinomas.

Biological role and prognostic significance of NAC1 in ovarian cancer.

OBJECTIVE: This study examined the biological and clinical significance of NAC1 expression in ovarian cancer and assessed whether NAC1 has the potential to be a therapeutic target. METHODS: NAC1 expression and gene amplification were assessed in ovarian cancers by immunohistochemistry, fluorescence in situ hybridization, and clinical data collected by a retrospective chart review. NAC1 gene knockdown using silencing RNA and a NAC1 gene transfection system were used to assess NAC1 function in ovarian cancer tissue samples. RESULTS: The frequency of positive NAC1 expression in serous adenocarcinomas (50.0%:22/44) was significantly higher than that in the other histological subtypes (33.3%: 10/30). NAC1 gene amplification was identified in seven (9.5%) of 74 ovarian carcinomas. Positive NAC1 expression significantly correlated with shorter disease-free and overall survival (P = 0.002, P = 0.0048). A multivariate analysis showed that positive NAC1 expression was an independent prognostic factor for disease-free and overall survival after standard platinum-taxane chemotherapy (P = 0.0027, P = 0.0302). Profound growth inhibition, increased apoptosis, decreased cell proliferation, and decreased cell migration and invasion were observed in silencing RNA-treated cancer cells with NAC1 overexpression compared with cancer cells without NAC1 expression. NAC1 overexpression stimulated proliferation, migration, and invasion in ovarian cancer cell lines KF28 and TOV-21G, which normally lacked NAC1 expression. CONCLUSION: These findings indicate that NAC1 over-expression is critical to the growth and survival of ovarian cancers. Furthermore, they suggest that NAC1 silencing RNA-induced phenotypes depend on the expression status of the targeted cell line. Therefore, NAC1-targeted therapy may benefit ovarian cancer patients with NAC1 expression.