SLC5A3 is important for cervical cancer cell growth.

Novel molecular targets for cervical cancer must be identified. This study examined the role of SLC5A3, a myo-inositol transporter, in the pathogenesis of cervical cancer. Through boinformatics analysis, we showed that the SLC5A3 mRNA levels were upregulated in cervical cancer tissues. The upregulated SLC5A3 mRNA levels were negatively correlated with survival and progression-free interval. Genes co-expressed with SLC5A3 were enriched in multiple signaling cascades involved in cancer progression. In primary/established cervical cancer cells, SLC5A3 shRNA/knockout (KO) exerted growth-inhibitory effects and promoted cell death/apoptosis. Furthermore, SLC5A3 knockdown or KO downregulated myo-inositol levels, induced oxidative injury, and decreased Akt-mTOR activation in cervical cancer cells. In contrast, supplementation of myo-inositol or n-acetyl-L-cysteine or transduction of a constitutively active Akt1 construct mitigated SLC5A3 KO-induced cytotoxicity in cervical cancer cells. Lentiviral SLC5A3 overexpression construct transduction upregulated the cellular myo-inositol level and promoted Akt-mTOR activation, enhancing cervical cancer cell proliferation and migration. The binding of TonEBP to the SLC5A3 promoter was upregulated in cervical cancer. In vivo studies showed that intratumoral injection of SLC5A3 shRNA-expressing virus arrested cervical cancer xenograft growth in mice. SLC5A3 KO also inhibited pCCa-1 cervical cancer xenograft growth. The SLC5A3-depleted xenograft tissues exhibited myo-inositol downregulation, Akt-mTOR inactivation, and oxidative injury. Transduction of sh-TonEBP AAV construct downregulated SLC5A3 expression and inhibited pCCa-1 cervical cancer xenograft growth. Together, overexpressed SLC5A3 promotes growth of cervical cancer cells, representing as a novel therapeutic oncotarget for the devastating disease.

A first-in-class POLRMT specific inhibitor IMT1 suppresses endometrial carcinoma cell growth.

Exploring novel molecularly-targeted therapies for endometrial carcinoma is important. The current study explored the potential anti-endometrial carcinoma activity by a first-in-class POLRMT (RNA polymerase mitochondrial) inhibitor IMT1. In patient-derived primary human endometrial carcinoma cells and established lines, treatment with IMT1 potently inhibited cell viability, proliferation, cell-cycle progression and motility, while inducing robust caspase-apoptosis activation. Treatment with the PLORMT inhibitor impaired mitochondrial functions, leading to mtDNA (mitochondrial DNA) transcription inhibition, mitochondrial membrane potential decline, reactive oxygen species formation, oxidative stress and ATP loss in the endometrial carcinoma cells. Similarly, POLRMT depletion, through shRNA-induced silencing or CRISPR/Cas9-caused knockout (KO), inhibited primary endometrial carcinoma cell proliferation and motility, and induced mitochondrial dysfunction and apoptosis. Importantly, IMT1 failed to induce further cytotoxicity in POLRMT-KO endometrial carcinoma cells. Contrarily, ectopic overexpression of POLRMT further augmented proliferation and motility of primary endometrial carcinoma cells. In vivo, oral administration of a single dose of IMT1 substantially inhibited endometrial carcinoma xenograft growth in the nude mice. mtDNA transcription inhibition, oxidative stress, ATP loss and apoptosis were detected in IMT1-treated endometrial carcinoma xenograft tissues. Together, targeting PLORMT by IMT1 inhibited endometrial carcinoma cell growth in vitro and in vivo.

Hyperthermia enhances the efficacy of chemotherapeutic drugs in heat-sensitive cells through interfering with DNA damage repair.

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to be clinically effective, but the mechanisms by which hyperthermia enhances the sensitivity of cells to chemotherapeutic drugs has not yet been elucidated. Methods: To identify the key molecules involved in thermochemotherapy, this study used mass spectrometry (MS)-based quantitative proteomics technology to analyze the effects of thermochemotherapy on the heat-sensitive ovarian cancer cell line A2780. We divided the A2780 cell line into four groups, one group served as blank control, and the other three groups were stimulated by oxaliplatin, stimulated by hyperthermia at 42 ℃, and stimulated by hyperthermia combined with oxaliplatin. Samples were then collected for tandem mass tag (TMT) labeling, high-performance liquid chromatography fractionation, and MS-based quantitative proteomics for analysis The differentially expressed proteins were quantitatively compared and identified, and Gene Ontology (GO) assessment and cluster analyses were performed. Finally, the above MS results were verified again by Western blotting experiments. Results: A total of 349 differentially expressed proteins were identified between cells treated with chemotherapy alone (group B) and cells treated with a combination of chemotherapy and hyperthermia (group D). There were 145 upregulated proteins and 204 downregulated proteins. Among the top 20 proteins with significantly different expression levels, nearly two-thirds were involved in DNA damage repair. These proteins were subsequently verified by Western blot analysis. Indeed, consistent with MS data, the expression of the RBL1 protein was significantly upregulated in cells treated with thermochemotherapy (group D) compared to cells treated with chemotherapy alone (group B). Conclusions: In heat-sensitive ovarian cancer cells, the damage repair of tumor cell DNA is disturbed by hyperthermia, making it unable to fully repair when damaged by chemotherapeutic drugs. As a result, hyperthermia enhances the efficacy of chemotherapeutic drugs. RBL1, as a tumor suppressor gene, may be associated with the repair of DNA damage, and thus it may be a key target for hyperthermia to enhance the sensitivity of thermosensitive cells to chemotherapeutic drugs.

miR­302c­3p and miR­520a­3p suppress the proliferation of cervical carcinoma cells by targeting CXCL8.

The aim of the present study was to identify the differentially expressed microRNAs (miRs) in cervical carcinoma (CC) tissues and cells and to explore the function of miR­302c­3p and miR­520a­3p in the proliferation of CC cells. Potential dysregulated miRNAs in CC tissues and tumour­adjacent tissues were detected. Reverse transcription­quantitative PCR (RT­qPCR) was performed to determine the expression of miR­302c­3p, miR­520a­3p and CXCL8 in CC tissues and cell lines. The target genes of the miRNAs were predicted using miRTarBase and verified by luciferase reporter assays. RT­qPCR and western blotting were performed to measure the expression of C­X­C motif ligand (CXCL)8 after transfection. The effect on proliferation was verified by Cell Counting Kit assay and ethynyl­2­deoxyuridine staining. Flow cytometry was utilised to assess the effect on apoptosis. In the present study, miR­302c­3p and miR­520a­3p were markedly downregulated in CC cell lines compared to the normal cervical cell line H8. Functionally, overexpression of miR­302c­3p and/or miR­520a­3p inhibited proliferation and promoted the apoptosis of CC cell lines in vitro, while the knockdown of miR­302c­3p and/or miR­520a­3p had the opposite effect. Furthermore, miR­302c­3p and miR­520a­3p could both bind to CXCL8. Inhibition of CXCL8 in combination with miR­302c­3p and/or miR­520a­3p overexpression exerted proliferation­suppressive and apoptosis­stimulating effects on CC cells, whereas restoring CXCL8 attenuated the miR­302c­3p­ and miR­520a­3p­induced anti­proliferative and pro­apoptotic effects. miR­302c­3p and miR­520a­3p suppress the proliferation of CC cells by downregulating the expression of CXCL8, which may provide a novel target for the treatment of CC.

CircATRNL1 activates Smad4 signaling to inhibit angiogenesis and ovarian cancer metastasis via miR-378.

Ovarian cancer is one of the most frequent carcinomas in females, and the occurrence rate is still rising despite many advances made. The pathogenesis of ovarian cancer remains greatly unclear. Here, we investigated the mechanisms of ovarian cancer, with the focus on circATRNL1. Human ovarian cancer tissues and cell lines were used to examine levels of circATRNL1, miR-378, Smad4, AKT, and other proliferation-related and migration-related proteins. Cellular assays were used to determine cancer cell proliferation, invasion, migration, apoptosis, and angiogenesis. We validated the interactions of circATRNL1/miR-378 and miR-378/Smad4, and a mouse tumor xenograft model was employed to assess the effect of circATRNL1 on tumor growth and metastasis in vivo. We found that circATRNL1 was decreased while miR-378 was increased in human ovarian cancer tissues and cells. circATRNL1 bound to miR-378 while miR-378 directly targeted Smad4. Overexpression of circATRNL1 or knockdown of miR-378 suppressed angiogenesis and ovarian cancer cell proliferation, invasion, and migration via decreasing proliferation- and migration-related proteins via miR-378 or Smad4, respectively. Overexpression of circATRNL1 restrained ovarian cancer growth and abdominal metastasis in vivo. Our findings indicate that circATRNL1 acts as a miR-378 sponge to active Smad4 signaling and suppresses angiogenesis and ovarian cancer metastasis.

Expression of the lncRNA ZFAS1 in cervical cancer and its correlation with prognosis and chemosensitivity.

OBJECTIVE: To investigate the expression of the lncRNA ZFAS1 in cervical cancer and its relationship with patient prognosis and cervical cancer cell chemosensitivity. METHODS: The expression of ZFAS1 in cervical cancer tissues and cell lines was detected by qRT-PCR. The cervical cancer CaSki and the HeLa cell lines were transfected to be divided into Blank, siR-Control, and siR-ZFAS1 groups. MTT, wound-healing, and transwell assays were used to evaluate cell biological function. Cisplatin with different concentrations was used to treat cells in different transfection groups, and MTT assays were used to detect the cell growth inhibition rate and the half-inhibitory concentration (IC50) of cisplatin was measured. Cell apoptosis was determined by flow cytometry. A xenograft mouse model was used to investigate the effects of siR-ZFAS1 on the chemosensitivity to cisplatin. RESULTS: ZFAS1 was significantly upregulated in cervical cancer tissues and cell lines, and increased ZFAS1 levels led to poor prognoses in patients. In addition, cells in the siR-ZFAS1 group showed remarkably reduced ZFAS1 expression as well as cell proliferation, invasion and migration. After being treated with cisplatin at different concentrations, cells in the siR-ZFAS1 group had dramatically increased cell growth inhibition and apoptosis but lower cisplatin IC50s. In addition, siR-ZFAS1 reduced the volumes and weights of tumors in nude mice treated with cisplatin and enhanced the chemosensitivity of cervical cancer cells to cisplatin. CONCLUSION: The lncRNA ZFAS1 was upregulated in cervical cancer tissues, and its high expression indicated a poor prognosis. Silencing ZFAS1 may inhibit cell proliferation, migration and invasion and enhance cisplatin chemosensitivity.

Expression Levels of Myostatin and Matrix Metalloproteinase 14 mRNAs in Uterine Leiomyoma are Correlated With Dysmenorrhea.

Uterine leiomyoma is the most common benign neoplasm of female reproductive system, found in about 50% of women in reproductive age. The mechanisms of leiomyoma growth include cell proliferation, which is modulated by growth factors, and deposition of extracellular matrix (ECM). Activin A and myostatin are growth factors that play a role in proliferation of leiomyoma cells. Matrix metalloproteinases (MMPs) are known for their ability to remodel the ECM in different biological systems. The aim of this study was to evaluate the expression levels of activin ßA-subunit, myostatin, and MMP14 messenger RNAs (mRNAs) in uterine leiomyomas and the possible correlation of these factors with clinical features of the disease. Matrix metalloproteinase 14 was highly expressed in uterine leiomyoma and correlated with myostatin and activin A mRNA expression. Moreover, MMP14 and myostatin mRNA expression correlated significantly and directly with the intensity of dysmenorrhea. Overall, the present findings showed that MMP14 mRNA is highly expressed in uterine leiomyoma, where it correlates with the molecular expression of growth factors and is further increased in cases of intense dysmenorrhea.

Increased progesterone receptor expression in uterine leiomyoma: correlation with age, number of leiomyomas, and clinical symptoms.

OBJECTIVE: To investigate the possible correlation between progesterone receptor (PR) expression in uterine leiomyoma or adjacent myometrium and patient's age, size/number of leiomyomas, or clinical symptoms such as dysmenorrhea, acyclic pelvic pain, or menstrual and intermenstrual uterine bleeding. DESIGN: Cross-sectional study. SETTING: Referral center. PATIENT(S): Sixty-two Chinese women undergoing elective hysterectomy for uterine leiomyomata. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Evaluation of PR-total and PR-B mRNA with real-time polymerase chain reaction; PR-A and PR-B proteins quantified by Western blot in leiomyoma tissue and myometrium; symptoms rated by the patients using visual analog scores. RESULT(S): The PR-B mRNA and PR-A and PR-B proteins were more concentrated in leiomyomas than in matched myometrium. A direct correlation between PR-B mRNA levels in leiomyoma and age (r = 0.347) and number of tumors (r = 0.295) was found. Conversely, there was an inverse correlation between PR-B mRNA levels in leiomyoma and dysmenorrhea (r = -0.260) and intermenstrual bleeding (r = -0.266). Multiple regression analysis indicated that age (ß = 0.363) and the number of myomas (ß = 0.296) were independently associated with PR-B mRNA levels in leiomyoma tissue. CONCLUSION(S): The levels of PR-B mRNA in leiomyoma tissue are directly associated with the number of tumors and inversely correlated with the intensity of intermenstrual bleeding and dysmenorrhea, suggesting that PR signaling may favor leiomyoma growth while attenuating clinical symptoms. This duality should be taken into account in the clinical management of patients with symptomatic uterine leiomyoma.

Factors associated with maternal near-miss morbidity and mortality in Kowloon Hospital, Suzhou, China.

OBJECTIVE: To investigate factors associated with acute maternal morbidity and mortality in Kowloon Hospital, Suzhou, China. METHODS: Data from cases of near-miss and maternal death between January 2008 and December 2012 were reviewed retrospectively. Maternal characteristics and related factors were identified, and multiple regression analysis was used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: During the study period, there were 18 104 deliveries, 69 near-miss cases, and 3 maternal deaths. Women who had no health insurance (aOR, 4.55; 95% CI, 0.87-21.8), had fewer than 6 prenatal consultations (aOR, 6.76; 95% CI, 0.76-45.8), were part of a migrant population (aOR, 2.34; 95% CI, 0.45-24.9), or delayed seeking healthcare (aOR, 4.76; 95% CI, 0.89-13.6) had a greater risk of near-miss morbidity or death. Admission to intensive care (aOR, 6.75; 95% CI, 0.89-34.6) and blood transfusion within 30 min (aOR, 3.79; 95% CI, 0.65-8.67) were protective factors in disease progression. CONCLUSION: The factors associated with maternal near-miss morbidity and mortality were closely related to health insurance and socioeconomic status, suggesting that the government should take an active role in the community in preventing morbidity and mortality in pregnancy.

Health-related quality of life among breast cancer patients and its influencing factor in a Chinese population.

AIM: The aim of this study was to investigate the quality of life (QOL) of breast cancer patients by using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaires. METHODS: A total of 522 adult patients who were admitted to our hospital with breast cancer were collected during the period of Jun. 2007 to Dec. 2009. RESULTS: Our FACT-B questionnaire study suggested that women below 50 years old, employed, higher education and annual income, lower TNM stage and receiving modified radical mastectomy manifested significantly better QOL using the assessment tool of the FACT-B subscale. Moreover, regression analysis indicated patients with young age, low stage cancer, high education and income were more likely to have high score of QOL, with ORs (95% CI) of 2.8 (1.52-4.56), 2.1 (1.15-3.95), 3.1 (1.45-5.12) and 3.54 (1.54-5.43), respectively. CONCLUSION: Our study showed younger age, lower stage of cancer, higher education and income could influence the QOL of breast cancer patients in our Chinese population. Further large sample studies are still needed for confirmation.