HOXB2 promotes cisplatin resistance by upregulating lncRNA DANCR in ovarian cancer.

Ovarian cancer (OV) is a highly fatal malignant disease that commonly manifests at an advanced stage. Drug resistance, particularly platinum resistance, is a leading cause of treatment failure because first-line systemic chemotherapy primarily relies on platinum-based regimens. By analyzing the gene expression levels in the Cancer Genome Atlas database, Genotype-Tissue Expression database, and Gene Expression Omnibus datasets, we discerned that HOXB2 was highly expressed in OV and was associated with poor prognosis and cisplatin resistance. Immunohistochemistry and loss-of-function experiments on HOXB2 were conducted to explore its role in OV. We observed that suppressing HOXB2 could impair the growth and cisplatin resistance of OV in vivo and in vitro. Mechanical investigation and experimental validation based on RNA-Seq revealed that HOXB2 regulated ATP-binding cassette transporter members and the ERK signaling pathway. We further demonstrated that HOXB2 modulated the expression of long non-coding RNA DANCR, a differentiation antagonizing non-protein coding RNA, and thus influenced its downstream effectors ABCA1, ABCG1, and ERK signaling to boost drug resistance and cancer proliferation. These results verified that high expression of HOXB2 correlated with platinum resistance and poor prognosis of OV. Therefore, targeting HOXB2 may be a promising strategy for OV therapy.

A fNIRS investigation of menopausal-related symptoms and brain cortical activity in menopause.

BACKGROUND: This study aimed to delineate the association between menopausal-related symptoms and brain cortical hemodynamics in peri-postmenopause women. METHODS: Cross-sectional data from a total of 358 Han-Chinese women who visited the Menopause Clinic in the Shanghai Sixth People's Hospital from August 2019 to August 2022. Menopausal-related symptoms were analyzed through Kupperman index (KMI) scale and PSQI scale, while cerebral blood flow was measured using a functional near-infrared spectroscopy (fNIRS). Multiple linear regression model was used to assess the risk factors for subregions of brain hemodynamic response. RESULTS: After adjusting for confounding factors, we identified that menopausal symptom (B = -1.575, 95 % CI (-2.661, -0.488), p = 0.005) and duration of menopause (B = -14.583, 95 % CI (-26.753, -4.192), p = 0.007) were independently associated with the lower brain hemodynamic response in the prefrontal lobe, while in the temporal lobe, overweight (BMI ≥ 24 kg/m2) was negatively associated with the lower brain cortical activity (B = -36.882, 95 % CI (-72.708, -1.056), p = 0.044) after adjusting for other confounding variables. CONCLUSIONS: Our findings proposed that menopausal symptom and overweight should be attached great importance to the postmenopausal women, which provides clinical evidence for the feasible early detection and effective prevention such as menopausal hormone therapy (MHT) of brain health in postmenopausal women.

Comparison of the survival outcomes of laparoscopic, abdominal and gasless laparoscopic radical hysterectomy for early-stage cervical cancer: trial protocol of a multicenter randomized controlled trial (LAGCC trial).

Background: Radical hysterectomy (RH) is considered a cornerstone in the treatment of early-stage cervical cancer. However, the debate surrounding the optimal surgical approach, whether minimally invasive or open surgery, remains controversial. The objective of this trial is to evaluate the survival outcomes of cervical cancer patients who undergo different surgical approaches. Methods: This study is designed as a prospective, multicenter, open, parallel, and randomized controlled trial. A total of 500 patients diagnosed with stage IA1 with LVSI, IA2, IB1, or IB2 (2018 FIGO) will be recruited. Recruitment of participants started in November 2020. The participants will be randomly assigned to one of three groups: conventional laparoscopic RH, gasless laparoscopic RH, or abdominal RH. The primary endpoint of this trial is the 2-year disease-free survival (DFS) rate. The secondary endpoints will include the 2-year overall survival (OS) rate, 5-year DFS/OS, recurrence rates, operation time, intraoperative blood loss, surgery-related complications, and impact on quality of life (QoL). Discussion: We expect this trial to provide compelling and high-quality evidence to guide the selection of the most appropriate surgical approach for early-stage cervical cancer. Clinical trial registration: Chinese Clinical Trial Register, identifier ChiCTR2000035515.

Transcriptome analyses reveal new insights on key determinants of perineural invasion in high-grade serous ovarian cancer.

Perineural invasion (PNI) is a pathological feature of many cancers associated with poor outcomes, metastases, and recurrence. In relation to ovarian cancer (OC), there is no information about PNI's role and mechanisms. Our study found that patients with PNI-positive symptoms had significantly shorter overall survival (OS) time than patients with PNI-negative symptoms. Multivariate analyses demonstrated that PNI represented a substantial independent prognostic factor in OC patients. At the transcriptome level, it is noteworthy that PNI positivity was negatively correlated with the degree of infiltration of immune killer cells in OC tumor tissues, including macrophage, central memory CD4 T-cell, natural killer cells, monocyte, and central memory CD4 T-cell. The results of this study revealed that TAS2Rs proteins were markedly upregulated in PNI-positive OC tissues and predicted poor prognoses. Moreover, Immunohistochemical analysis demonstrated that the TAS2R10 protein was associated with poor prognoses and PNI in OC. Consequently, we found for the first time that PNI was a powerful predictor of poor prognosis in OC and analyzed its expression pattern and some preliminary biochemical characterization, providing new clues for guiding clinical prevention and treatment of OC.

SORL1 stabilizes ABCB1 to promote cisplatin resistance in ovarian cancer.

Ovarian cancer (OC) has the worst prognosis among gynecological malignancies. Cisplatin (CDDP) is one of the most commonly used treatments for OC, but recurrence and metastasis are common due to endogenous or acquired resistance. High expression of ATP-binding cassette (ABC) transporters is an important mechanism of resistance to OC chemotherapy, but targeting ABC transporters in OC therapy remains a challenge. The expression of sortilin-related receptor 1 (SORL1; SorLA) in the response of OC to CDDP was determined by analysis of TCGA and GEO public datasets. Immunohistochemistry and western blotting were utilized to evaluate the expression levels of SORL1 in OC tissues and cells that were sensitive or resistant to CDDP treatment. The in vitro effect of SORL1 on OC cisplatin resistance was proven by CCK-8 and cell apoptosis assays. The subcutaneous xenotransplantation model verified the in vivo significance of SORL1 in OC. Finally, the molecular mechanism by which SORL1 regulates OC cisplatin resistance was revealed by coimmunoprecipitation, gene set enrichment analysis and immunofluorescence analysis. This study demonstrated that SORL1 is closely related to CDDP resistance and predicts a poor prognosis in OC. In vivo xenograft experiments showed that SORL1 knockdown significantly enhanced the effect of CDDP on CDDP-resistant OC cells. Mechanistically, silencing of SORL1 inhibits the early endosomal antigen 1 (EEA1) pathway, which impedes the stability of ATP-binding cassette B subfamily member 1 (ABCB1), sensitizing CDDP-resistant OC cells to CDDP. The findings of this study suggest that targeting SORL1 may represent a promising therapeutic approach for overcoming CDDP resistance in OC.

Factors influencing functional near-infrared spectroscopy in postpartum depression: A cross-sectional study.

OBJECTIVE: To explore whether functional near-infrared spectroscopy (fNIRS) can aid in the early detection and diagnosis of postpartum depression. METHODS: The study was a cross-sectional survey that invited all women who sought postpartum health examination 42 days after childbirth between August 2020 and January 2021. Personal information, Edinburgh Postnatal Depression Scale (EPDS), and well as fNIRS results were collected. RESULTS: In all, 109 individuals agreed to participate and completed the examination in its entirety. The variance in integral and centroid values was not statistically significant across different subgroups of depression (P > 0.05). The difference in diagnosis of postpartum major depression between EPDS and fNIRS was statistically significant (P < 0.001). fNIRS results in postpartum depression diagnosis were substantially associated with gestational diabetes mellitus (P = 0.027), the number of pregnancies (P = 0.001), and postpartum body mass index (P = 0.035). CONCLUSION: fNIRS can provide an objective method for early detection and diagnosis of postpartum depression. Certain clinical conditions can have an effect on brain activity, which may result in postpartum depression. Additional high-quality study is required to establish strong evidence on the subject.

Intraoperative frozen pathology exam of Common iliac lymph nodes and Para-Aortic lymphadenectomy on the prognosis and quality of life for patients with IB2-IIA2 Cervical Cancer: trial protocol for a randomized controlled trial (C-PACC trial).

BACKGROUND: The impact of para-aortic lymphadenectomy (PALD) on prognosis and quality of life (QoL) for IB2-IIA2 cervical cancer patients remain controversial. And whether intraoperative frozen pathology exam on common iliac lymph nodes could help predict para-aortic lymph node (PALN) metastasis was unanswered with high-level evidence. METHODS: A multi-center, randomized controlled study is intended to investigate the effect of PALD on the prognosis and QoL in cervical cancer patients and to assess the value of intraoperative frozen pathological evaluation of common iliac nodes metastasis for the prediction of PALN metastasis. After choosing whether to receive intraoperative frozen pathological examination of bilateral common iliac lymph nodes, eligible patients will be randomly assigned (1:1) to receive PALD or not. The primary end point is 2-year progression-free survival (PFS). The secondary end points include 5-year PFS, 2-year overall survival (OS), 5-year OS, adverse events (AEs) caused by PALD, AEs caused by radiotherapy and QoL. A total of 728 patients will be enrolled from 8 hospitals in China within 3-year period and followed up for 5 years. TRIAL REGISTRATION: Chinese Clinical Trial Register Identifier: ChiCTR2000035668.

Effects of 5-aminolevulinic acid photodynamic therapy for cervical low-grade squamous intraepithelial lesions with HR-HPV infections.

Objective: To determine the effectiveness and safety of 5-aminolevulinic acid mediated photodynamic therapy (5-ALA PDT) in HR-HPV infected patients with cervical low-grade squamous intraepithelial lesions (LSIL) and to explore possible factors affecting treatment outcomes. Methods: This retrospective study included 96 patients with histologically confirmed cervical LSIL and high-risk human papillomavirus (HR-HPV) infection. They received 5-ALA PDT treatment once a week for a total of 3 courses. All patients were evaluated by cytology tests, HPV DNA assay, colposcopy, and biopsy at 2 weeks, 3 months, and 6 months checkpoint. The chi-square test were used to evaluate the differences in various clinical data, and a p value <0.05 was considered statistically significant. Results: At 2 weeks, 3 months, and 6 months checkpoint, colposcopies showed that the cervical iodine-unstained area under VILI (visual inspection with Lugol's iodine) significantly reduced (p < 0.01) with no structure changes. At 3 months and 6 months checkpoint, the pathological regression rate reached 87.5% (84/96) and 94.79% (91/96), while the HR-HPV clearance rates reached 80.21% (77/96) and 93.75% (90/96) respectively. We also examined the efficacy in the HPV 16/18-related group and non-HPV 16/18-related group. The HR-HPV clearance rate in the HPV16/18 group [94.87% (37/39)] was significantly higher than that of the non-HPV 16/18 group [70.17% (40/57)]. However, at 6 months after treatment, the clearance rate of the HPV 16/18 group [94.87% (37/39)] showed no statistical difference from the non-HPV 16/18 group [92.30% (53/57)]. Conclusion: Topical 5-ALA PDT can effectively eliminate HR-HPV infection and treat low-grade cervical squamous intraepithelial lesions, it offers an alternative treatment option for patients with LSIL, especially for those with fertility requirements and who wish to preserve cervical structure or function.

Insulin sensitivity, ß cell function, and adverse pregnancy outcomes in women with gestational diabetes.

BACKGROUND: The potential impact of ß cell function and insulin sensitivity on adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM) remains uncertain. We aimed to investigate the association between ß cell dysfunction, insulin resistance, and the composite adverse pregnancy outcomes. METHODS: This observational study included 482 women diagnosed with GDM during pregnancy. Quantitative metrics on ß cell function and insulin sensitivity during pregnancy were calculated using traditional equations. The association of ß cell dysfunction and insulin resistance with the risk of the composite adverse pregnancy outcomes was investigated using multivariable-adjusted logistic regression models. RESULTS: Multivariable-adjusted odds ratios (ORs) of adverse pregnancy outcomes across quartiles of homeostatic model assessment for insulin resistance (HOMA-IR) were 1.00, 0.95, 1.34, and 2.25, respectively (P for trend = 0.011). When HOMA-IR was considered as a continuous variable, the multivariable-adjusted OR of adverse pregnancy outcomes was 1.34 (95% confidence interval 1.16-1.56) for each 1-unit increase in HOMA-IR. Multivariable-adjusted ORs of adverse pregnancy outcomes across quartiles of homeostatic model assessment for ß cell function (HOMA-ß) were 1.00, 0.51, 0.60, and 0.53, respectively (P for trend = 0.068). When HOMA-ß was considered as a continuous variable, the multivariable-adjusted OR of adverse pregnancy outcomes was 0.57 (95% CI 0.24-0.90) for each 1-unit increase in HOMA-ß. However, other quantitative metrics were not associated with the composite adverse pregnancy outcomes. CONCLUSIONS: We demonstrated a significant association of ß cell function and insulin sensitivity with the risk of adverse pregnancy outcomes. We have provided additional evidence on the early identification of adverse pregnancy outcomes besides the glycemic values.

Association of sleep characteristics with renal function in menopausal women without recognized chronic kidney disease.

Objective: To delineate the association between sleep characteristics and renal function in peri-post menopause free of Chronic kidney disease (CKD) as well as cardiometabolic and hormone indicators. Methods: Cross-sectional data from a total of 823 Han-Chinese women aged 40-67 years who visited the Menopause Clinic in the Shanghai Sixth People's Hospital from November 2011 to November 2020 were analyzed through the Pittsburgh Sleep Quality Index (PSQI) and serum cystatin C (Cys-C). Logistic regression models were used to assess the association between cumulative/each sleep parameter and renal function after adjusting for cardiometabolic variables. Results: After confounding factors, we identified that poor perceived sleep quality, shorter sleep duration (<6 h), low sleep efficiency (<75%), delayed sleep latency and worse sleep disturbance elevated more than doubled the odds ratio for declining renal function (≥0.91 mg/dL, the highest Cys-C) in postmenopause in a graded fashion. Meanwhile, multiple logistic regression analysis revealed that sleep disorder (PSQI ≥ 8), late postmenopause, highest quartile independently increased the odds ratio for declining renal function (OR 2.007, 95% CI: 1.408-2.861, OR = 3.287, 95%CI: 3.425-8.889, OR = 2.345, 95% CI: 1.310-4.199, respectively), while participants with menopausal hormone replacement (MHT) lower the odds of declining renal function (OR = 0.486, 95% CI: 0.324-0.728). Conclusion: The findings proposed that maintaining good sleep quality should be attached great importance to postmenopausal women, which provides clinical evidence for the feasible early detection and effective prevention such as MHT of renal disease progression in postmenopausal women.

Chinese expert consensus on the clinical applications of aminolevulinic acid-based photodynamic therapy in female lower genital tract diseases (2022).

INTRODUCTION: With the younger onset age of female lower genital tract diseases, there are increasing demands for protecting organ and tissue structures to preserve fertility and, therefore, effective fertility-sparing treatments that cause minimal normal tissue damage and less adverse reactions are urgently needed. OBJECTIVE: This study is aimed at reviewing information and achieving consensus on recommendations on the clinical applications of aminolevulinic acid-based photodynamic therapy (ALA-PDT) in female lower genital tract diseases. METHODS: Members of the expert panel held online and in-person meetings to discuss and revise drafts created by the steering committee based on the literature review and the clinical experiences of the expert panel. Opinions of the experts were transcribed and discussed in detail to ensure that the consensus statement best reflects the current advances in the field and the experts' view. RESULTS: After numerous rounds of meetings, experts unanimously agreed on the importance of ALA-PDT in the treatment of cervical squamous intraepithelial lesions (SIL), vaginal SIL, vulvar SIL, vulvar lichen sclerosus (VLS), and condyloma acuminatumon (CA). Experts also reached consensus on the recommended treatment regimen and treatment methods. CONCLUSION: This consensus aimed to provide practical basis and guidance for the clinical applications of ALA-PDT in female lower genital tract diseases in China. Of note, this is the only expert consensus prepared by board-certified specialists in gynecology and obstetrics in China. More evidence-based clinical studies should be made to update and expand the current recommendations.

Topical 5-aminolevulinic acid photodynamic therapy for cervical high-grade squamous intraepithelial lesions.

OBJECTIVE: To evaluate the efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) in the treatment of high-grade squamous intraepithelial lesions of the cervix (HSIL). METHODS: This retrospective study included 22 female patients with histologically confirmed HSIL and high-risk human papillomavirus (HR-HPV) infections. Patients were treated with ALA-PDT once a week for a total of 6 times. All patients had a follow-up period of 3 months and 6 months. The assessment of effectiveness of ALA-PDT was performed by ThinPrep cytology test (TCT), HPV DNA assay, HPV E6/E7 mRNA examination, colposcopy, biopsy, and immunohistochemistry detection. RESULTS: Three months after 5-ALA PDT, the histologic disappearance rate was 81.82% (18/22), while the HPV clearance rate was 54.55% (12/22). At the 6 months checkpoint, the HSIL disappearance rate was 90.91% (20/22) and the HPV clearance rate was 86.36% (19/22). Before PDT, 68.18% of patients (15/22) were confirmed with TCT abnormalities, while only one patient (1/22, 4.55%) was abnormal in the TCT test at 6 months checkpoint. All participants were found HPV E6/E7 mRNA positive initially, while the HPV E6/E7 mRNA negative rate was 90.91% (20/22) at 6 months checkpoint. Additionally, we found a significant difference of the expression of CD4+ and CD8+ T cells and HPV E6 and E7 proteins before ALA-PDT and at 3 months follow-up (P < 0.01). No severe side effects were seen. CONCLUSIONS: Topical 5-ALA PDT is an effective treatment for cervical HSIL with HR-HPV infection.

Noninvasive isolation of transcervical trophoblast cells for fetal identification.

OBJECTIVE: To identify trophoblastic cells retrieved from the cervix at a gestational age (GA) of 5-9 weeks by a noninvasive modality in fetuses. METHOD: Transcervical cells (TCCs) were noninvasively extracted by a cytobrush using the Papanicolaou sampling method. TCCs were immunostained with antihuman leukocyte antigen (HLA)-G and anticytokeratin (CK)-7 antibodies to identify trophoblastic cells. Maternal finger blood, gestational sacs, and 20 trophoblastic cells collected by a laser-guided microscopic single-cell capture system were examined and compared by short tandem repeat (STR) genotyping. RESULTS: Forty-nine pregnant women with GA of 5-9 weeks and six nonpregnant healthy women were included in the study. Trophoblastic cells were identified in 37 (75.5%) TCC samples, among which 34 (69.4%) were eligible for STR genotyping analysis. No trophoblastic cells were identified in nonpregnant healthy women. The STR genotyping analyses revealed 24 female and 10 male fetuses. TCC trophoblastic cells exhibited the same STR profiles as gestational sac and maternal blood in all samples, which indicated that the TCC trophoblastic cells originated from fetuses. CONCLUSION: This primary study validated that trophoblastic cells from TCCs at GA 5-9 weeks originated from the fetus. Further studies are needed to verify whether this method can be used for early noninvasive prenatal diagnosis and paternity testing.

Increased Nuclear Transporter Importin 7 Contributes to the Tumor Growth and Correlates With CD8 T Cell Infiltration in Cervical Cancer.

Background: Importin 7 (IPO7), a karyopherin-ß protein, is involved in various tumorigenesis and progression abilities by mediating the nuclear import of oncoproteins. However, the exact biological functions of IPO7 remain to be further elucidated. Materials and Methods: TCGA and GEO datasets were used to identify dysregulated expression of IPO7 in various cancers. Gain-of-function and loss-of-function analyses were used to identify the oncogenic functions of IPO7 in vitro and in vivo. Moreover, LC-MS/MS and parallel reaction monitoring analysis were used to comparatively profiled IPO7-related proteomics and potential molecular machinery. Results: Our works demonstrated that the expression of IPO7 was upregulated and was correlated with a poor prognosis in cervical cancer. In vitro and in vivo experiments demonstrated that knockdown of IPO7 inhibited the proliferation of HeLa and C-4 I cells. LC-MS/MS analysis showed that IPO7-related cargo proteins mainly were enriched in gene transcription regulation. Then independent PRM analysis for the first time demonstrated that 32 novel IPO7 cargo proteins, such as GTF2I, RORC1, PSPC1, and RBM25. Moreover, IPO7 contributed to activating the PI3K/AKT-mTOR pathway by mediating the nuclear import of GTF2I in cervical cancer cells. Intriguingly, we found that the IPO7 expression was negatively correlated with CD8 T cell infiltration via regulating the expression of CD276 in cervical cancer. Conclusion: This study enhances our understanding of IPO7 nuclear-cytoplasmic translocation and might reveal novel potential therapeutic targets. The results of a negative correlation between the IPO7 and CD8 T cell infiltration indicate that the IPO7 might play an important impact on the immune microenvironment of cervical cancer.

A study on the timing of uterine artery embolization followed by pregnancy excision for cesarean scar pregnancy: a prospective study in China.

BACKGROUND: Cesarean scar pregnancy (CSP) remains a sporadic and special form of ectopic pregnancy in which the fertilized ovum is implanted on a previous cesarean scar within 12 weeks. This study aims to evaluate the optimal time interval between uterine artery embolization (UAE) and curettage modalities in order to provide the best clinical outcomes. METHODS: From January 2018 to December 2020, we recruited 61 patients with CSP. They were randomly divided into two groups depending on whether the time interval between UAE and dilatation and curettage (D&C) requires additional hospitalization: 31 patients received prophylactic UAE followed by D&C on the same day (0-12 h; group A) and 30 patients need hospitalization (12-72 h; group B). The clinical characteristics, diagnostic data, and outcomes of the two groups were compared and analyzed. RESULTS: A total of 59 (96.72%) cases had responded well to the first treatment. One patient in each arm undergone retreatment, but none of the 61 patients needed additional hysterectomy. There was no considerable relationship between the two groups with respect to the intraoperative hemorrhage during D&C, serum index (containing ß-hCG, hemoglobin, CRP, and D-dimer) on the first day after D&C, side effects (containing fever and abdominal pain), renal, hepatic, and coagulation function, time of CSP residual mass disappearance, and hospitalization cost. The time of serum ß-hCG resolution after surgery was 41.22 ± 14.97 days in group A and 66.67 ± 36.64 days in group B (P = 0.027), and group A treatment resulted in a shorten hospital stay as compared with group B (4.81 ± 2.74 days vs. 6.80 ± 2.14 days, P <  0.001). However, the average hourly serum ß-hCG decrease rate within 24 h and the leukocytes on the first day after D&C in group B were superior than in group A (P <  0.050). CONCLUSION: For patients with CSP, UAE followed by D&C on the same day (0-12 h) appears to have more advantages in hospitalization and recovery time, while the long time interval (12-72 h) may have a lower risk of inflammation and a more rapid decrease in serum ß-hCG level within 24 h after D&C surgery. The treatment of CSP should be individualized based on the conditions of patients.

Overexpression of ARHGAP30 suppresses growth of cervical cancer cells by downregulating ribosome biogenesis.

We aimed to identify whether Rho GTPase activating proteins (RhoGAPs) were downregulated in cervical cancers and might be targeted to reduce the growth of cervical cancer using the GEO database and immunohistochemical analysis to identified changes in transcription and protein levels. We analyzed their proliferation, clone formation ability, and their growth as subcutaneous tumors in mice. To detect ARHGAP30 localization in cells, immunofluorescence assays were conducted. Mass spectrometry combined with immunoprecipitation experiments were used to identify binding proteins. Protein interactions were validated with co-immunoprecipitation assays. Western-blot and q-PCR were applied to analyze candidate binding proteins that were associated with ribosome biogenesis. Puromycin incorporation assay was used to detect the global protein synthesis rate. We identified that ARHGAP30 was the only downregulated RhoGAP and was related to the survival of cervical cancer patients. Overexpression of ARHGAP30 in cervical cancer cells inhibited cell proliferation and migration. ARHGAP30 immunoprecipitated proteins were enriched in the ribosome biogenesis process. ARHGAP30 was located in the nucleous and interacted with nucleolin (NCL). Overexpression of ARHGAP30 inhibited rRNA synthesis and global protein synthesis. ARHGAP30 overexpression induced the ubiquitination of NCL and decreased its protein level in Hela cells. The function of ARHGAP30 on cervical cancer cell ribosome biogenesis and proliferation was independent of its RhoGAP activity as assessed with a RhoGAP-deficient plasmid of ARHGAP30R55A . Overall, the findings revealed that ARHGAP30 was frequently downregulated and associated with shorter survival of cervical cancer patients. ARHGAP30 may suppress growth of cervical cancer by reducing ribosome biogenesis and protein synthesis through promoting ubiquitination of NCL.

ADGRG1 enriches for functional human hematopoietic stem cells following ex vivo expansion-induced mitochondrial oxidative stress.

The heterogeneity of human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) under stress conditions such as ex vivo expansion is poorly understood. Here, we report that the frequencies of SCID-repopulating cells were greatly decreased in cord blood (CB) CD34+ HSCs and HPCs upon ex vivo culturing. Transcriptomic analysis and metabolic profiling demonstrated that mitochondrial oxidative stress of human CB HSCs and HPCs notably increased, along with loss of stemness. Limiting dilution analysis revealed that functional human HSCs were enriched in cell populations with low levels of mitochondrial ROS (mitoROS) during ex vivo culturing. Using single-cell RNA-Seq analysis of the mitoROS low cell population, we demonstrated that functional HSCs were substantially enriched in the adhesion GPCR G1-positive (ADGRG1+) population of CD34+CD133+ CB cells upon ex vivo expansion stress. Gene set enrichment analysis revealed that HSC signature genes including MSI2 and MLLT3 were enriched in CD34+CD133+ADGRG1+ CB HSCs. Our study reveals that ADGRG1 enriches for functional human HSCs under oxidative stress during ex vivo culturing, which can be a reliable target for drug screening of agonists of HSC expansion.

TNPO1-mediated nuclear import of ARID1B promotes tumor growth in ARID1A-deficient gynecologic cancer.

Karyopherin-ß proteins are critically involved in cancer progression and have been reported as potential biomarkers and therapeutic targets for tumor treatment. However, TNPO1, as an important karyopherin-ß family member, underlying functional roles in cancers remain largely unclear. In this study, under integrated gene-expression profiling screen of karyopherin-ß in gynecologic cancer, we identify TNPO1 as a pivotal contributor to the gynecologic cancer progression. Remarkably, ARID1A-deficient gynecologic cancer cells are specifically vulnerable to the genetic perturbations of TNPO1 in vitro and in vivo. Mechanistically, TNPO1 is selectively responsible for nuclear import of ARID1B, which is a synthetic lethal target in ARID1A-inactivating mutation cancers. Furthermore, TNPO1 or ARID1B knockdown changes chromatin accessibility that results in loss of H3K4me1 and H3K27ac marker, diminishing activated transcription factor of the AP-1 family, and inactivating the PI3K/AKT signaling pathway by reducing growth pathway genes expression including PIK3CA and FGFR2. Together, this work indicates that the oncogenic function of TNPO1 and maybe represent a novel therapeutic strategy to treat ARID1A-deficient gynecologic cancer.

Nuclear-translocation of ACLY induced by obesity-related factors enhances pyrimidine metabolism through regulating histone acetylation in endometrial cancer.

Endometrial cancer (EC) is becoming one of the most common gynecologic malignancies. Lipid metabolism is a hallmark feature of cancers. The molecular mechanisms underlying lipid metabolism in EC remain unclear. In this study, we revealed that many lipid metabolism-related genes were aberrantly expressed in endometrial cancer tissues, especially ACLY. Upregulated ACLY promoted EC cell proliferation and colony formation, and attenuated apoptosis. Mechanistically, cotreatment with obesity-related factors (estradiol, insulin and leptin) promoted nuclear translocation of ACLY through Akt-mediated phosphorylation of ACLY at Ser455. Nuclear-localized ACLY increased histone acetylation levels, thus resulting in upregulation of pyrimidine metabolism genes, such as DHODH. Moreover, STAT3 altered the ACLY expression at the transcriptional level via directly binding to its promoter region. In conclusion, our findings clarify the roles and mechanisms of ACLY in endometrial cancer and ACLY could link obesity risk factors to the regulation of histone acetylation. We believe that novel therapeutic strategies for EC can be designed by targeting the ACLY axis.