Myelopreservation with Trilaciclib in recurrent advanced ovarian cancer: a case report.

Ovarian cancer is a prevalent malignant tumor of the female reproductive system, often remaining concealed until it reaches an advanced stage. The standard treatment protocol includes cytoreductive surgery for ovarian cancer plus postoperative consolidation chemotherapy and maintenance therapy, although it carries a high recurrence rate. During the treatment period, chemotherapy can lead to bone marrow suppression, a condition known as Chemotherapy-Induced Myelosuppression (CIM). This suppression may necessitate dose reduction or chemotherapy treatment cycle delay. In severe cases, CIM can result in infection, fever, and potential harm to the patient's life. Here, we report a case of a female patient with ovarian malignant tumor of biochemical recurrence who treated with chemotherapy combined with Trilaciclib, following previous perioperative chemotherapy with occurrence of severe CIM. It involves an intravenous injection of Trilaciclib before chemotherapy, which significantly abates the side effects of chemotherapy, reduces the occurrence of severe CIM, improves the patients' quality of life, and decreases the economic burden of hospitalization. We hope that this retrospective analysis of the case may serve as a reference in preventing and treating severe CIM during chemotherapy in some patients with malignant tumors, ultimately benefiting more patients with tumors.

Prognostic value of obesity in patients with cancer treated with immune checkpoint inhibitors: An updated meta­analysis and systematic review.

Accumulating interest has been surging over the past few years regarding the effects of obesity on immunotherapy. In addition to the body mass index (BMI), imaging-quantified body fat compartments have been investigated. The present study aimed to evaluate the predictive value of the BMI and computed tomography (CT)-based body fat in patients with cancer receiving immunotherapy. For this purpose, the PubMed, MEDLINE, EMBASE and Cochrane databases were searched from January 2017 to July 2022. Clinical studies evaluating the association between BMI or body fat and survival of patients with cancer treated with immune checkpoint inhibitors (ICIs) were included. In total, 15 studies reporting on the BMI were included in the meta-analysis and 16 studies evaluating body fat were included in the systematic review. According to the classification of the World Health Organization, overweight and obese patients with ICI treatment showed improved overall survival [overweight vs. normal: Hazard ratio (HR)=0.79, 95% confidence interval (CI)=0.64-0.98, P=0.03; obese vs. normal: HR=0.75, 95% CI=0.60-0.94, P=0.013] and progression-free survival (overweight vs. normal: HR=0.82, 95% CI=0.70-0.97, P=0.02; obese vs. normal: HR=0.81, 95% CI=0.65-1.02, P=0.07). Among the articles investigating the effect of body fat composition on the efficacy of immunotherapy, a number of studies included various CT analysis techniques and cutoffs to define body fat composition. Associations of body fat with survival were contradictory in different patients with cancer treated with immunotherapy. Obesity was associated with better survival in patients with cancer treated with ICIs. Further analyses are required to demonstrate the prognostic value of body fat in patients with cancer immunotherapy.

Prognostic Value of Body Composition and Systemic Inflammatory Markers in Patients with Locally Advanced Cervical Cancer Following Chemoradiotherapy.

Background: Abnormal changes in body composition and systemic inflammation response have been associated with poor survival of cancer patients. Our study was to explore the prognostic value of the association between body composition indicators and systemic inflammation markers among patients with locally advanced cervical cancer (LACC) who underwent concurrent chemoradiotherapy (CCRT). Methods: We retrospectively reviewed medical records of LACC patients treated between 2016 and 2019. Subcutaneous, visceral and intra-muscular adipose index (SAI, VAI and IMAI) and skeletal muscle index (SMI) were derived from computed tomography (CT). Kaplan-Meier analysis and Univariate and multivariate Cox analyses were used to evaluate the survival. A nomogram was constructed to assess the prognostic value. Results: The study included 196 patients treated with CCRT. According to multivariable Cox analyses, IIIC1r (P = 0.045), high systemic immune-inflammation index (SII) (P = 0.004), sarcopenia (P = 0.008), high SAI (P = 0.016) and high VAI (P = 0.001) were significantly risk factors for overall survival (OS). Kaplan-Meier analysis showed that patients with low lymphocyte-to-monocyte ratio (LMR) and sarcopenia had longer OS than those with high LMR and sarcopenia (P = 0.023). The high neutrophil-to-lymphocyte ratio (NLR) in non-sarcopenic patients showed better survival (P = 0.022). Low VAI (P = 0.019) or low IMAI (P = 0.019) combined with low SII had a favorable OS. Low LMR combined with low SAI was associated with longer OS (P = 0.022). The calibration plots of nomogram predicting the 3-year and 5-year OS rates were close to the ideal models. Conclusion: Inflammation factors were closely associated with abnormal muscle and fat distribution. The combined prognostic value of body composition indicators and systemic inflammation markers was reliable in predicting survival for LACC patients.

Role of GPX4 inhibition-mediated ferroptosis in the chemoresistance of ovarian cancer to Taxol in vitro.

BACKGROUND: Ovarian cancer remains a common gynecological tumor and the fifth leading cause of death worldwide. Taxol-based chemotherapy is a standard approach to the treatment of ovarian cancer. Glutathione peroxidase 4 (GPX4) is the key regulator of ferroptosis, which is an important form of cell death. Here, we investigate the effect of GPX4 inhibition-mediated ferroptosis on the sensitivity of ovarian cancer cells to Taxol. METHODS AND RESULTS: A2780/PTX and OVCAR-3/PTX Taxol-resistant ovarian cancer cells were established, and stable GPX4 knockout cell lines were generated via lentivirus GPX4-sgRNA. The GPX4 expression level, the apoptosis rate and cell viability were analyzed. The levels of ferroptosis-related factor indicators such as malondialdehyde (MDA) and reactive oxygen species (ROS) were measured. The results showed that the GPX4 protein and mRNA levels were increased in the Taxol-resistant cells. Moreover, GPX4 knockout reduced cell viability and inhibited the colony formation rate. In addition, we found that GPX4 inhibition increased Taxol sensitivity by inducing ferroptosis. CONCLUSIONS: In summary, our studies reveal that GPX4 inhibition promotes ferroptosis and increases the sensitivity of ovarian cancer cells to Taxol in vitro.

The Glutaminase Inhibitor Compound 968 Exhibits Potent In vitro and In vivo Anti-tumor Effects in Endometrial Cancer.

BACKGROUND: Glutamine is one of the primary nutrients utilized by cancer cells for energy production and biosynthesis. Hence, interfering with glutamine metabolism may impose anti-tumor effects. OBJECTIVE: In this study, we assessed the anti-tumorigenic effects of glutaminase-1 enzyme (GLS1) inhibition in endometrial cancer in vitro and in vivo. METHODS: The human endometrial cancer cell lines Ishikawa and HEC-1B were used. The effects of compound 968 on cell proliferation, cell cycle, apoptosis, cellular stress, and AKT/mTOR pathway inhibition were assessed. The synergistic effects of compound 968 and paclitaxel were also analyzed. The in vivo effect of compound 968 was evaluated using tumor xenografts. RESULTS: We found that the GLS1-targeting compound 968 was able to reduce cancer cell proliferation in a dose- and time-dependent manner. Compound 968 combined with a low concentration of paclitaxel showed stronger inhibitory effects. Further analyses indicated that compound 968 induced cell cycle arrest at the G1 phase, as well as increased the production of cellular reactive oxygen species (ROS) and promoted cellular stress and cancer cell apoptosis. Additionally, the treatment of endometrial cancer with compound 968 downregulated the expression of GLS1 and cyclin D1 and upregulated the expression of P21 and E-cadherin. Moreover, the treatment of endometrial cancer cells with compound 968 significantly reduced the levels of phospho-S6 ribosomal protein and phospho-AKT (Ser473), indicative of AKT/mTOR/S6 signaling pathway inhibition. In xenograft mouse models of endometrial cancer, compound 968 significantly suppressed tumor growth. In addition, western blotting analysis indicated that GLS1 expression was upregulated in human endometrial cancer tissues. CONCLUSION: Compound 968 may be a promising approach for the management of human endometrial cancer.

Inhibition of STAT3 reverses Taxol-resistance in ovarian cancer by down-regulating G6PD expression in vitro.

Ovarian cancer is the eminent gynecological malignancy and chemoresistance remains a major reason for poor in ovarian cancer patients. Taxol has been proved as the most effective chemotherapeutic agent against ovarian cancer. However development of Taxol resistance remains a major problem. Here, we report that STAT3, directly activates pentose-phosphate pathway to exert pro-oncogenic effects on Taxol resistance of ovarian cancer. In addition, we found that STAT3, p-STAT3 and glucose-6-phosphate dehydrogenase (G6PD) protein levels are upregulated in Taxol resistant cell lines compared with Taxol sensitive cell lines. Furthermore, inhibition of STAT3 decreased G6PD mRNA expression level and enhanced the sensitivity of Taxol resistant cell to Taxol. Finally, we found that STAT3 directly binds to the G6PD promoter region and promotes the expression of G6PD at transcriptional level. Taken together, our data indicate that activation of STAT3 promotes ovarian cancer cell proliferation, colony formation, and Taxol resistance via augmenting G6PD expression and pentose-phosphate metabolism flux, which provides a potential therapeutic target that may improve prognosis by decreasing G6PD expression and enhancing Taxol-sensitivity.

Comparing dosimetric and cancer control outcomes after intensity-modulated radiation therapy and tomotherapy for advanced cervical cancer.

Concurrent chemoradiation therapy (CCRT) is the standard treatment for locally advanced cervical cancer. The present study aimed to compare the therapeutic responses, toxicities and dosimetric parameters between intensity-modulated radiation therapy (IMRT) and tomotherapy (TOMO) in patients with advanced cervical cancer. This retrospective study included 310 patients with stage IIB-IIIB cervical cancer who underwent CCRT, with 155 patients in each group. Intracavitary brachytherapy was performed after a course of external beam radiation therapy (EBRT), or in the last week of pelvic EBRT. The treatment planning aim at point A (defined as a reference location 2 cm above the vaginal fornix and 2 cm beside the mid axis of the uterus) was >85 Gy in an equivalent dose at 2 Gy. There was no statistical difference with regard to clinicopathological characteristics between the two groups (P>0.05). Improved dose conformity and dose homogeneity (P<0.05) were observed in TOMO planning. TOMO provided more efficacious critical organ sparing than IMRT when assessing the percentage of normal tissue receiving at least 20 Gy (V20) for the bladder, the percentage of normal tissue receiving at least 40 Gy (V40) for the femoral head, and the V40 and V20 for the rectum (P<0.05). TOMO demonstrated a greater ability to protect the ovary (P<0.05). The acute radiation toxicity of proctitis and leukopenia were significantly lower in the TOMO group (P<0.05). The chronic radiation toxicity of radiation enterocolitis and cystitis was lower in the TOMO group (P<0.05). Thus, TOMO provided better critical organ sparing than IMRT. The radiation toxicities were acceptable. Therefore, TOMO appears to be a good option for the treatment of stage IIB-IIIB cervical cancer.

Clinical Study of Sentinel Lymph Node Detection to Evaluate Pelvic Lymph Node Metastasis to Determine the Prognosis of Patients with Early Cervical Cancer.

Objective: Lymph node status is one of the most important prognostic factors for uterine cervical cancer. Sentinel lymph node (SLN) biopsy has emerged as a potential alternative to systematic lymphadenectomy for the lymph node mapping in such patients. However, the SLN metastasis detection via SLN biopsy in early-stage cervical cancer remains controversial. The current study is aimed at investigating the feasibility and accuracy of combined tracer method for localization of SLN in initial stages of cervical cancer and to evaluate the clinical value of SLN biopsy in replacing pelvic lymph node resection. Methods: We retrospectively reviewed 348 cases who were admitted to the Department of Gynecologic Oncology, Shandong Provincial Cancer Hospital, China, between February 2003 and June 2018 with FIGO stage IA2 to IIA2 cervical cancer and undergone through SLN biopsy. Methylthioninium chloride was injected in combination with 99mtechnetium-labeled sulfur colloid prior to surgery to these patients. SLNs were identified intraoperatively, excised, and subsequently submitted to fast frozen section. The detection rates, accuracy, sensitivity, coincidence rate, false negative rate, and negative predictive values of these cases were estimated, and the follow-up outcomes were carefully observed. Chi squared test or Fisher's exact test was employed for a comparison of the categorical variables. Univariate and multivariate Cox proportional hazard models were used for estimation of relationships between overall survival (OS) and disease-free survival (DFS) and prognostic factors. Results: The total detection rate of SLN was 97.1% (338/348), and identification of bilateral SLN was successful in 237 patients (70.1%). The patient's tumor size, FIGO stage, lymph node metastasis, and depth of invasion had statistically significant differences in SLN detection rates. The detection rate had inverse relation with tumors size (>4 cm), invasive depth > 2/3, lymph node positive, late staging, and preoperative radiotherapy. 117 positive SLNs were detected in 73 patients. The negative predictive value, sensitivity, false negative rate, and coincidence rate and were 97.7%, 92.4%, 7.6%, and 95.4%, respectively. In patients whose tumor size were ≦ 4 cm, the false negative rate was 4.55% (2/44), whereas it was 0 in patients with tumor size≦2 cm. The respective 1, 3, and 5-year OS was 100%, 94.8%, and 91.8%, respectively, whereas DFS rate for 1, 3, and 5 years was 96.7%, 92%, and 89.6%, respectively. The lymph node was positive, tumor size, the depth of invasion, and staging were statistically different from the recurrence rate and survival rate of patients (p < 0.05). When tumor metastasis exceeded SLN, the recurrence rate was significantly increased, and survival rate is significantly reduced (p < 0.05, p < 0.01, p < 0.05, respectively). Conclusions: The identification of SLN combined with 99mtechnetium-labeled sulfur colloid and methylthioninium chloride has a good accuracy and is safe for the assessment of the status of pelvic nodes in patients with initial stage cervical cancer. Nuclide as a tracer has low dependence on objective conditions and doctors' technology and has a good detection rate. In our study, we believe that SLN biopsy is feasible when the tumor is ≦ 4 cm. Large scale clinical trials are required in China expand the sample size and validate the results of this study.

The HOXC-AS2/miR-876-5p/HKDC1 axis regulates endometrial cancer progression in a high glucose-related tumor microenvironment.

The tumor microenvironment (TME) is related to chronic inflammation and is currently identified as a risk factor for the occurrence and development of endometrial cancer (EC). Pyroptosis is a new proinflammatory form of programmed cell death that plays a critical role in the progression of multiple diseases. However, the important role of pyroptosis in high-glucose (HG)-related EC and the underlying molecular mechanisms remain elusive. In the present study, transcriptome high-throughput sequencing revealed significantly higher hexokinase domain-containing 1 (HKDC1) expression in EC patients with diabetes than in EC patients with normal glucose. Mechanistically, HKDC1 regulates HG-induced cell pyroptosis by modulating the production of reactive oxygen species and pyroptosis-induced cytokine release in EC. In addition, HKDC1 regulates TME formation by enhancing glycolysis, promoting a metabolic advantage in lactate-rich environments to further accelerate EC progression. Subsequently, miR-876-5p was predicted to target the HKDC1 mRNA, and HOXC-AS2 was identified to potentially inhibit the miR-876-5p/HKDC1 axis in regulating cell pyroptosis in HG-related EC. Collectively, we elucidated the regulatory role of the HOXC-AS2/miR-876-5p/HKDC1 signal transduction axis in EC cell pyroptosis at the molecular level, which may provide an effective therapeutic target for patients with diabetes who are diagnosed with EC.

Wilms' Tumor 1-Associated Protein Contributes to Chemo-Resistance to Cisplatin Through the Wnt/ß-Catenin Pathway in Endometrial Cancer.

BACKGROUND: Cisplatin remains the mainstay of endometrial cancer (EC) chemotherapy. Wilms' tumor 1-associated protein (WTAP), playing a critical role in transcriptional and post-transcriptional regulation, has been reported as an oncogene, and its expression is elevated in multiple types of human tumors. Recent evidence has shown that the increased expression of WTAP is also closely related to chemo-resistance. However, its specific role in the susceptibility of human EC cells to cisplatin remains largely unexplored. METHODS: WTAP over-expression and WTAP depletion cell lines as well as their corresponding controls were constructed by transfection with lentivirus. Western blotting analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to detect the expression of WTAP. Cell proliferation assay, colony formation assay, cell cycle assay, and apoptosis analysis were adopted to evaluate the effect of WTAP on the chemo-sensitivity of EC cells to cisplatin as well as its underlying mechanism. Immunofluorescence staining was used to assess the translocation of ß-catenin. Moreover, a subcutaneous xenograft tumor model was established to assess the effect of WTAP on tumor growth after cisplatin treatment. RESULTS: Depletion of WTAP in RL95-2 cells significantly enhanced the chemo-susceptibility of cells to cisplatin and increased the cell apoptosis, while WTAP over-expression in ARK-2 cells exhibited the opposite effects. Additionally, WTAP depletion significantly suppressed xenograft-tumor growth and enhanced sensitivity and apoptosis of tumor cells in vivo. Mechanistic analysis exhibited that WTAP over-expression facilitated the cytoplasm-to-nucleus translocation of ß-catenin and enhanced the GSK3ß phosphorylation at Ser9, while WTAP depletion revealed the opposite results, indicating that WTAP rendered chemo-resistance of EC cells to cisplatin by promoting the Wnt/ß-catenin pathway. CONCLUSIONS: WTAP might promote the chemo-resistance of EC cells to cisplatin through activating the Wnt/ß-catenin pathway. Collectively, our findings offered novel insights into EC treatment.

Drp1 mediates high glucose-induced mitochondrial dysfunction and epithelial-mesenchymal transition in endometrial cancer cells.

This study aims to clarify the role and molecular mechanism of dynamin-related protein 1 (Drp1)-mediated mitochondrial homeostasis in high glucose (HG)-induced endometrial cancer (EC). Normal endometrium and tumor tissues of EC patients with normal and HG levels were collected, and Drp1 and p-Drp1 expression levels were detected by immunohistochemistry. Human EC cells were cultured with different glucose concentrations, and Drp1 and p-Drp1 expression levels were evaluated by Western blotting. Cell models of control and siDrp1 groups under normal and HG conditions were established, and subsequent functional experiments were conducted. Histology and in vitro experiments showed that the HG environment increased Drp1 activation, which could lead to mitochondrial dysfunction. Moreover, the imbalance of mitochondrial homeostasis mediated by Drp1 resulted in cell dysfunction, including altered glucose metabolism and increased epithelial-mesenchymal transition (EMT), migration and invasion. All these changes caused by HG could be partially alleviated by Drp1 knockdown. This study revealed that Drp1 was involved in the progression of EC associated with HG, and Drp1 might be a new potential therapeutic target for EC patients with diabetes.

Whole-exome sequencing in cervical adenocarcinoma in mainland Chinese patients.

BACKGROUND: Cervical cancer is the most common gynecological malignancy worldwide. Adenocarcinoma is an important pathological type of cervical cancer. In recent years, the incidence of adenocarcinoma is rising in some countries and the prognosis of it remains poor. A precise description of the mutational landscape in cervical adenocarcinoma may provide insights into a better selection of treatments and improve prognosis. METHODS: In this study, we conducted whole-exome sequencing (WES) for cervical adenocarcinomas and matched blood samples from a cohort of 24 mainland Chinese patients. Additionally, the Human-Papilloma virus (HPV) infection statuses of these tumor samples were detected, and the genes that were enriched in both HPV positive and negative samples were also analyzed. RESULTS: The results of WES revealed the gene expression profile of cervical adenocarcinoma of women in mainland China and identified multiple genes/pathways, which are frequently mutated in these tumors, including the PI3K-AKT (KRAS, PIK3CA and PTEN), estrogen signaling (KRAS, PIK3CA and GNAS) and NK cell-mediated antibody-dependent cellular cytotoxicity pathways. Besides, seven patients had HPV infection, and the mutated genes in HPV-positive tumor tissues were relatively consistent, while the mutation profiles of HPV-negative tumor tissues were relatively scattered. CONCLUSIONS: Taken together, these findings provide novel insights into the pathogenesis of cervical adenocarcinomas. They suggest the potential for individualized treatment of cervical adenocarcinoma according to genomic information.

Postoperative adjuvant chemotherapy combined with intracavitary brachytherapy achieved the equivalent survival compared with concurrent chemoradiotherapy in cervical cancer patients with intermediate-risk.

OBJECTIVES: The current study was aimed to evaluate the efficacy and toxicity of postoperative adjuvant chemotherapy (CT) combined with intracavitary brachytherapy (ICRT) in cervical cancer patients with intermediate-risk. METHODS: We analyzed the medical records of 558 patients who were submitted to radical surgery for Stage IB-IIA cervical cancer. A total of 172 of those 558 patients were considered intermediate-risk according to the GOG criteria. Among those 172 patients, 102 were subjected to CT combined with ICRT (CT+ICRT) and the remaining 70 patients were treated with concurrent chemoradiation (CCRT). The 3-year disease free survival (DFS), overall survival (OS), and complications of each group were evaluated and analyzed. RESULTS: No significant difference was observed in 3-year DFS or OS of the patients submitted to CT+ICRT and CCRT. Importantly, the frequencies of grade III to IV acute complications were significantly higher in patients submitted to CCRT than in those treated with CT+ICRT (Hematologic, P = 0.016; Gastrointestinal, P = 0.041; Genitourinary, P = 0.019). Moreover, the frequencies of grade III-IV late complications in patients treated with CCRT were significantly higher compared with CT+ICRT-treated patients (Gastrointestinal, P = 0.026; Genitourinary, P = 0.026; Lower extremity edema, P = 0.008). CONCLUSIONS: Postoperative adjuvant CT+ICRT treatment achieved equivalent 3-year DFS and OS but low complication rate compared to CCRT treatment in early stage cervical cancer patients with intermediate-risk.

SOX11 hypermethylation as a tumor biomarker in endometrial cancer.

We previously reported that SOX4 is overexpressed in endometrial cancer and that it partially contributes to hypermethylation of miR-129-2 and miR-203. The current study seeks to identify methylation and expression levels of the SOX gene family in endometrial carcinomas. Methylation levels of the 16 SOX gene family members were measured by combining bisulfite restriction analysis (COBRA), MassARRAY, and pyrosequencing assays of cell lines and endometrial cancer samples. Gene expression was determined by RT-qPCR. The methylation level of the SOX11 locus was correlated with clinicopathologic factors in primary endometrial tumors and in TCGA endometrial cohort. It was also examined in DNA of serum and endometrial specimens from a longitudinal cohort of early stage endometrial cancer patients. COBRA assays indicated that hypermethylation of SOX1, SOX2, SOX11, SOX14, SOX15, SOX17, and SOX18 was present in endometrial cancer cell lines and not in the normal control. SOX11 expression was reactivated only by a DNA methylation inhibitor. Moreover, aberrant DNA methylation of SOX11 was detected in the majority of endometrioid endometrial carcinomas (n=114) and none of the 22 adjacent normal endometrial samples (P<0.0001). The methylation status of SOX11 associated significantly with microsatellite instability and MLH1 methylation in endometrial tumors (P<0.0001), and this finding was validated in TCGA endometrial cohort. Furthermore, SOX11 was not hypermethylated in serum DNA from early stage endometrial cancer patients. This study found that hypermethylation of SOX11 is common in endometrial carcinomas and strongly associates with microsatellite instability and MLH1 methylation.

Physiological functions of Wilms' tumor 1-associating protein and its role in tumourigenesis.

The Wilms' tumor-associated gene WT1 encodes a tumor suppressor gene, which is implicated in renal differentiation and development of adult urogenital system. Wilms' tumor 1-associating protein (WTAP) is initially identified as a nuclear protein that specifically interacts with WT1 in both in vitro and in vivo assays. WTAP is ubiquitously expressed in different tissues and various growth periods, and its expression is involved in cell cycle, RNA splicing and stabilization, N6-methyladenosine RNA modification, cell proliferation, and apoptosis as well as embryonic development. In the present review, we aimed to summarize the functions of WTAP in various physiological and pathological processes, in particular with regard to the current knowledge about the role of WTAP in tumorigenesis of different cancers.

Derlin1 functions as an oncogene in cervical cancer via AKT/mTOR signaling pathway.

BACKGROUND: Cervical cancer (CC) ranks third in the morbidity and mortality of female cancer around the world. Derlin1 has been found to be overexpressed in several human cancers. However, it is still unclear about its roles in CC. The research aims to explore the relationship between Derlin1 and CC. METHODS: We purchased a human CC tissues microarray, which contained CC tissues and corresponding para-cancerous tissues from 93 patients with primary cervical squamous cell carcinoma. Immunohistochemical staining was used to confirm the expression of Derlin1 in these tissues. And we detected the differential expression of Derlin1 in cervical cancer cell lines and normal cervical epithelial cells (H8). Further, the cervical cancer cell lines SiHa and C33A were used as an in vitro model, which was down-regulated the expression of Derlin1 using siRNA interference technology. The effects of Derlin1 down-regulating in CC cell lines on cell proliferation and migration were detected by CCK8 assay and transwell assay, respectively. The effect of Derlin1 down-regulating on apoptosis was analyzed by flow cytometry, and apoptosis-related proteins were detected using western blotting. In-depth mechanisms were studied using western blotting. In addition, the effects of Derlin1 up-regulating in normal cervical epithelial cells also were exposed. RESULTS: Derlin1 was significantly elevated in CC tissues (81.7%, 76/93), and the expression of Derlin1 was positively correlated with the tumor size, pathological grade, and lymph node metastasis in CC patients. And Derlin1 was high expressed in cervical cancer cell lines compared to H8 cells. Knockdown of Derlin1 in cervical cancer cell lines inhibited cell proliferation and migration. Moreover, knockdown of Derlin1 induced apoptosis and affected the expression of apoptosis-related proteins, including Bcl-2, Bax, Bim, caspase3 and caspase9. Further experiments showed that AKT/mTOR signal pathway might be involve in this processes that knockdown of Derlin1 inhibited the expression of p-AKT and p-mTOR. Over-expression of Derlin1 in H8 cells promoted cell proliferation and migration via up-regulated the expression of p-AKT and p-mTOR. CONCLUSION: Derlin1 is an oncogene in CC via AKT/mTOR pathway. It might be a potential therapeutic target for CC.

Upregulation of miR­33b promotes endometriosis via inhibition of Wnt/ß­catenin signaling and ZEB1 expression.

The present study aimed to investigate the role and mechanisms of microRNA (miR)­33b in endometriosis (Ems). Reverse transcription­quantitative polymerase chain reaction (RT­qPCR), MTT assays, flow cytometry, caspase­3/9 activity assays and western blotting were performed in the present study. Initially, miR­33b expression in an Ems rat model was investigated by RT­qPCR and was demonstrated to be upregulated in Ems tissue samples of rats compared with the control group. In addition, miR­33b upregulation inhibited cell growth and enhanced apoptosis in an Ems model (primary cell cultures) compared with the control group. In addition, miR­33b up­regulation reduced Wnt/ß­catenin signaling pathway and suppressed zinc finger E­box­binding homeobox 1 (ZEB1) protein expression in the in vitro Ems model (primary cell cultures) compared with the control group. Furthermore, small interfering­ZEB1 ameliorated the effects of miR­33b downregulation on Ems cell growth in the in vitro Ems model. Additionally, a Wnt agonist reduced the effects of miR­33b upregulation on Ems cell growth in the in vitro Ems model. In conclusion, the present study demonstrated that upregulation of miR­33b may promote Ems through Wnt/ß­catenin by ZEB1 expression.

MicroRNA-152 Acts as a Tumor Suppressor MicroRNA by Inhibiting Krüppel-Like Factor 5 in Human Cervical Cancer.

Aberrant expression of microRNA-152 (miR-152) is frequently observed in human cancers including ovarian cancer, breast cancer, prostate cancer, and gastric cancer. However, its expression and functional role in cervical cancer (CC) are poorly understood. Also, the association between miR-152 and Krüppel-like factor 5 (KLF5) expression in CC remains unclear. In this study, analyzing the expression of miR-152 by quantitative real-time PCR (qRT-PCR) revealed it was sharply reduced in CC tissues and cell lines. In addition, the negative correlation of miR-152 expression and KLF5 expression was observed. The dual-luciferase reporter assay validated that KLF5 was a target of miR-152. In vitro functional assays revealed that miR-152 could inhibit cell proliferation and cell cycle progression through regulating the expression of KLF5. Taken together, our study suggested that miR-152 functions as a tumor suppressor in CC, and the miR-152/KLF5 axis may provide novel therapeutic targets for CC treatment.

Surgical and Oncologic Outcomes of Radical Abdominal Trachelectomy Versus Hysterectomy for Stage IA2-IB1 Cervical Cancer.

STUDY OBJECTIVE: To compare the surgical and oncologic outcomes between abdominal radical trachelectomy (ART) and radical hysterectomy (RH) for stage IA2-IB1 cervical cancer. DESIGN: A retrospective cohort study (Canadian Task Force classification II-2). SETTING: Shandong Cancer Hospital, Shandong, China. PATIENTS: Three hundred twenty-nine patients with IA2-IB1 cervical cancer. INTERVENTIONS: All patients underwent ART or RH. MEASUREMENTS AND MAIN RESULTS: All patients were divided into ART (n = 143) and RH (n = 186) groups according to the surgical approach. Additionally, oncologic and fertility outcomes were compared for different tumor pathologies and sizes in ART patients. The ART group had similar case characteristics as the RH group, except that the ART group had a longer surgical time. During a similar follow-up period, there were 4 (2.9%) recurrences and 3 (2.2%) patients who died from recurrence in the ART group compared with 8 (4.6%) recurrences and 4 (2.3%) patients who died from recurrence in the RH group (p = .444 and p = .999, respectively). In the ART group, squamous cell carcinoma (SCC) patients had a 5-year overall survival and pregnancy rate similar to those of non-SCC patients (98.1% vs 96.8%, p = .999; 33.3% vs 26.7%, p = .873), and patients with tumors ≤2 cm and 2 to 4 cm experienced a similar 5-year overall survival rate (97.0% vs 98.6%, p = .999), except patients with tumors ≤2 cm had a higher pregnancy rate (45.2% vs 17.2%, p = .020). CONCLUSION: ART seems to have similar surgical and oncologic outcomes to RH, except ART has a longer surgical time. Both non-SCC patients and stage IA2-IB1 patients with 2- to 4-cm tumors can undergo ART safely. Patients with tumors ≤2 cm have a higher pregnancy rate than patients with 2- to 4-cm tumors.

Tetrandrine suppresses cervical cancer growth by inducing apoptosis in vitro and in vivo.

INTRODUCTION AND AIM: Cervical cancers are the most common forms of cancer that occur in women globally and are difficult to be cured in their terminal stages. Tetrandrine (TET), a monomeric compound isolated from a traditional Chinese medicine, Radix Stephania tetrandrae, exhibits anticancer effects on different tumor types. However, the mechanisms by which TET regulates the proliferation, apoptosis, migration, and invasion in cervical cancer remain unclear. Thus, this study aimed to investigate the therapeutic effects of TET on cervical cancer in vitro and in vivo. METHODS: Cell Counting Kit-8, immunofluorescence, flow cytometry, wound healing, and transwell migration assays were used to detect cell proliferation, apoptosis, and migration and invasion, respectively, in vitro. In addition, immunohistochemical assays were performed to evaluate tumor growth and apoptosis in vivo. Moreover, Western blotting was used to examine active caspase 3, matrix metalloproteinase (MMP)2, and MMP9 protein levels in vitro and in vivo. RESULTS: The results revealed that TET significantly inhibited SiHa cell proliferation in vitro and suppressed tumor growth in vivo. Meanwhile, TET was revealed to induce cervical cancer cell apoptosis by upregulating active caspase 3 in vitro and in vivo. Furthermore, the migration and invasion of SiHa cells were inhibited by TET accompanied with MMP2 and MMP9 downregulation. CONCLUSION: We have shown that TET inhibited cervical tumor growth and migration in vitro and in vivo for the first time. The accumulating evidence suggests that TET could be a potential therapeutic agent for the treatment of cervical cancer.