OBJECTIVE:To characterize clinicopathologic features of microsatellite instability-high (MSI-high) gynecologic malignancies in Japan and evaluate outcomes of pembrolizumab in MSI-high endometrial cancer, including an exploratory assessment of MLH1 promoter methylation and obesity. METHODS:Gynecologic malignancies undergoing routine MSI testing at 11 institutions were registered (KCOG-G1902S). Clinicopathologic data of MSI-high cases were collected from medical records. Patients with MSI-high endometrial cancer treated with pembrolizumab were prospectively followed (KCOG-G1903S). MLH1 promoter methylation was assessed in tumors with MLH1 loss, and exploratory analyses evaluated outcomes according to MLH1 methylation status and body mass index (BMI). RESULTS:Among 529 tumors tested, 56 (10.6%) were MSI-high, most arising in the endometrium (52/251; 20.7%). MSI-high tumors from other organs were predominantly endometrioid. All MSI-high tumors showed mismatch repair protein loss on immunohistochemistry; 41/56 (73.2%) demonstrated PMS2 and/or MLH1 loss. Pembrolizumab was administered to 25 patients with MSI-high endometrial cancer. The objective response rate was 48% (12/25), with median progression-free survival (PFS) of 21.2 months and overall survival of 58.1 months. MLH1 promoter methylation was detected in 17/18 tumors with MLH1 loss. In exploratory analyses, patients with at least one favorable factor (absence of MLH1 methylation and/or BMI ≥30 kg/m²) had higher response rates (77.8% vs. 31.3%, p=0.041) and longer PFS (p=0.039). CONCLUSION:MSI-high gynecologic malignancies arise predominantly in the endometrium. Pembrolizumab demonstrated durable activity in MSI-high endometrial cancer. MLH1 promoter methylation status, and possibly obesity, may provide clinically relevant insights into the heterogeneity of pembrolizumab response. These findings are exploratory and require validation in larger cohorts.
OBJECTIVE:Cervical cancer remains a major public health challenge among women in China. This study aimed to comprehensively assess long-term trends and future projections of cervical cancer burden in China. METHODS:Data on cervical cancer in China from 1990 to 2023 were extracted from Global Burden of Disease Study2023. Prevalence, incidence, deaths, years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life years (DALYs), and age-standardized rates (ASRs) were analyzed. Temporal trends were evaluated using estimated annual percentage change (EAPC) and Joinpoint regression. Das Gupta decomposition quantified the contributions of population growth, aging, and epidemiological change. Nordpred was used to project deaths and DALYs from 2024 to 2045. RESULTS:From 1990 to 2023, prevalent cervical cancer cases increased from 445,795 (95% uncertainty interval [UI]=301,749-642,609) to 752,306 (95% UI=481,273 to 1,011,544). YLDs increased by 62%, whereas YLLs decreased by 4%. Overall DALYs decreased slightly from 1,457,115 (95% UI=1,070,025 to 2,064,940) to 1,430,054 (95% UI=896,628 to 1,874,757), while deaths increased by 16%. Age-standardized DALYs rate (ASDR) declined from 294.14 to 132.72 per 100,000 population, with an EAPC of -2.43 (95% confidence interval=-2.54 to -2.33). Decomposition showed that population aging and growth offset favorable epidemiological changes, and projections suggested continued declines in ASDR with relatively stable deaths through 2045. CONCLUSION:Despite sustained declines in ASRs, the absolute burden of cervical cancer in China remains considerable due to demographic shifts. These findings underscore the urgent need to strengthen human papillomavirus vaccination coverage and expand equitable cervical cancer screening programs.
OBJECTIVE:Fertility preservation (FP) is crucial for young women diagnosed with ovarian cancer (OvCa) due to the potential gonadal toxicity of chemotherapy. The Asian Society of Gynecologic Oncology (ASGO) Special Task Force on FP conducted a survey to evaluate FP practices across Asia, aiming to enhance cancer survivorship and fertility outcomes for adolescent and young adult (AYA) patients. METHODS:The survey included responses from 10 Asian regions, focusing on FP indications, surgical and chemotherapy practices, and ovarian function monitoring. Data were collected from representative institutions, and the study was approved by the Ethics Committee of Nagoya University. RESULTS:The findings showed significant variability in FP practices. Definitions of AYA patients varied across regions, affecting eligibility for FP interventions. Age limits for fertility-sparing surgery (FSS) ranged from 35 to 45 years across regions, with differing criteria for histological types and cancer stages. While all regions performed FSS, practices regarding surgery extent, chemotherapy management, and follow-up care were inconsistent. Seven regions had OvCa patient registries, but none maintained FP-specific registries. Regular ovarian function monitoring and the use of assisted reproductive technology were also unevenly implemented. CONCLUSION:The study highlights the need for standardized guidelines across Asia to harmonize oncologic safety with FP. Addressing these differences through collaborative efforts within ASGO is essential to improve patient outcomes and provide consistent care for AYA patients seeking FP during cancer treatment.
OBJECTIVE:Cervical cancer remains a critical global health threat. Despite its member states accounting for more than 85% of global gross domestic product (GDP), no comprehensive assessment of cervical cancer burden exists across the diverse Group of Twenty (G20) economies. This study aimed to characterize long-term cervical cancer burden trends and project future epidemiological trajectories among G20 reproductive-age females. METHODS:Using Global Burden of Disease 2021 data, we analyzed cervical cancer disability-adjusted life years (DALYs) among females aged 15-49 years in G20 countries (1990-2021) via Joinpoint regression, health inequality indices, Das Gupta decomposition, and Bayesian age-period-cohort projection to 2035. RESULTS:In 2021, cervical cancer generated 2.27 million DALYs among G20 reproductive-age females, with age-standardized rates ranging from 24.89 (Saudi Arabia) to 667.65 (South Africa) per 100,000. Overall rates declined (annual average percent change [AAPC]=-1.40%) (1990-2021), with China achieving a notable reduction (AAPC=-1.51%), but increased in Russia (AAPC=1.70%), Japan (AAPC=0.65%), Italy (AAPC=0.33%), and South Africa (AAPC=0.14%). Sociodemographic Index (SDI)-related inequality narrowed (1990: Slope Index of Inequality [SII]=-349.58, Concentration Index=-0.21; 2021: SII=-261.82, Concentration Index=-0.18), but persisted. Population growth (+23.99%) and age structure changes (+20.92%) drove DALY increases in the G20, offset by epidemiological improvements (-43.92%). Most G20 countries will see declining burden by 2035, while South Africa faces the largest increase. CONCLUSION:Differentiated, evidence-based strategies tailored to national burden characteristics, addressing demographic shifts, key health system gaps, and human papillomavirus genotype disparities, are critically needed to successfully achieve the World Health Organization 2030 global cervical cancer elimination targets.
OBJECTIVE:To investigate whether mismatch repair deficiency (dMMR) affects treatment outcomes in early-stage high-intermediate risk (HIR) endometrial cancer (EC) patients receiving adjuvant therapy. METHODS:This retrospective study included patients with 2009 International Federation of Gynecology and Obstetrics stage I-II EC who underwent complete staging surgery from August 2006 to December 2022 at Kaohsiung Chang Gung Memorial Hospital. HIR stage I EC was defined using PORTEC and GOG-99 criteria. Stage II disease was considered low risk if meeting all criteria: endometrioid histology, grade 1-2, absence of lymphovascular invasion, and no lymph node involvement. Patients received adjuvant external beam radiation therapy (EBRT) or vaginal brachytherapy. Clinicopathological characteristics and 5-year disease-free survival (DFS) were analyzed. RESULTS:Among the 137 included patients with a median follow-up of 55 months, MMR status was available for all cases, and 32.1% were classified as dMMR. In 115 patients receiving adjuvant radiation, dMMR was associated with higher parity (97.6% vs. 71.2%, p=0.001) and showed a trend toward higher ER expression (170.5 vs. 136.7, p=0.126). Five-year DFS was comparable between MMR-proficient (pMMR) and dMMR groups overall (90.3% vs. 88.6%, p=0.881), in radiation-only patients (91.9% vs. 90.2%, p=0.846), and EBRT-only patients (85.4% vs. 85.2%, p=0.908). Cox regression revealed no significant predictors of DFS including MMR status. CONCLUSION:MMR status did not impact survival outcomes in early-stage HIR EC patients receiving adjuvant therapy, suggesting limited prognostic value and questioning routine MMR testing cost-effectiveness in this subgroup.
OBJECTIVE:Uterine cancer mortality is rising in the U.S. while other cancer deaths decline, posing a major public health challenge. High BMI is the strongest modifiable risk factor, but its full burden and associated inequalities remain poorly characterized. METHODS:Using data from Global Burden of Disease 2023 and National Health and Nutrition Examination Survey (NHANES, 1999-2023), we assessed national and state-level trends in uterine cancer mortality (age-standardized mortality rate [ASMR]) and disability-adjusted life years (age-standardized disability-adjusted life year rate [ASDR]) from 1990-2023. We employed Joinpoint regression, frontier analysis, and AutoRegressive Integrated Moving Average forecasting. Individual-level BMI associations were evaluated using weighted multivariable logistic regression. RESULTS:The ASMR and ASDR for high BMI-related uterine cancer in the U.S. significantly exceeded global averages, with the gap widening. The fastest increase occurred during 2009-2017. Significant geographic disparities were identified; West Virginia and Mississippi were consistent hotspots with high burden and rapid growth. A state's socio-demographic index was negatively correlated with the growth rate (estimated annual percentage change) of ASMR (ρ=-0.709) and ASDR (ρ=-0.726), indicating faster deterioration in socioeconomically disadvantaged regions. NHANES analysis confirmed a significant, dose-response relationship between BMI and uterine cancer risk (adjusted odds ratio per 1-unit BMI increase=1.03, 95% confidence interval=1.01-1.06), which strengthened over time. Subgroup analyses revealed stronger associations in obese individuals, non-Hispanic whites, and women aged ≥50 years. CONCLUSION:High BMI drives the rising and unequal uterine cancer burden in the U.S., underscoring the urgent need for interventions targeting both obesity and health inequities.
OBJECTIVE:To compare perioperative outcomes after robotic-assisted vs. conventional laparoscopic total hysterectomy in frail women with endometrial cancer. METHODS:This retrospective study included female patients aged ≥50 years with endometrial cancer and frailty who received either robotic-assisted or conventional laparoscopic total hysterectomy, extracting data from the Nationwide Readmissions Database from 2016 to 2020. Frailty was defined using the Hospital Frailty Risk Score. Patients with lymph node invasion, metastatic disease, missing key variables, or sample weight were excluded. Outcomes included perioperative complications, length of stay (LOS), and 30- and 90-day readmission. Logistic and linear regression analyses were performed to compare outcomes between surgical approaches. RESULTS:In total, 1,212 patients with endometrial cancer and frailty were included. Robotic-assisted surgery was associated with significantly shorter LOS (adjusted beta=-0.34; 95% confidence interval [CI]=-0.46, -0.21; p<0.001), lower odds of sepsis (adjusted odds ratio [aOR]=0.57; 95% CI=0.34, 0.94; p=0.027) and surgical site infection (p=0.025), but higher odds of pneumonia (aOR=2.01; 95% CI=1.06, 3.84; p=0.033). CONCLUSION:Robotic-assisted hysterectomy in frail patients was associated with shorter LOS and fewer infection-related complications but a higher risk of pneumonia. Further studies are needed to optimize surgical decision-making in this population.
OBJECTIVE:To describe cell-free DNA (cfDNA)-inferred putative clonal hematopoiesis (CH) candidates during first-line platinum-based chemotherapy followed by poly(ADP-ribose) polymerase inhibitor (PARPi) maintenance in ovarian cancer. METHODS:In SCRUM-Japan MONSTAR-SCREEN-1, we analyzed clinically reported paired tumor tissue and plasma cfDNA profiling (324-gene assays). Baseline (B1) data were assessed in 35 treatment-naïve patients; longitudinal cfDNA was available at B1, after platinum without progression (B2), and during/after PARPi without progression (B3) in 8 patients. Putative CH candidates were defined as pathogenic variants (variant allele frequency <40%) in prespecified CH-related genes detected in plasma but not detected in matched tumor tissue at clinical reporting thresholds. RESULTS:At B1, putative CH candidates were reported in 19/35 patients (54.3%), most commonly DNMT3A; positivity was associated with age ≥60 years. In the longitudinal cohort, tumor-derived TP53 variants were below the assay reporting threshold at B3 in all patients, whereas putative CH TP53 variants were reported in 0/8 patients at B1 and 6/8 patients at B3. DNA damage response gene candidates (TP53/ATM/CHEK2) more frequently became detectable above the reporting threshold during B2-B3 than during B1-B2, while epigenetic-gene candidates showed relatively stable detectability. No therapy-related myeloid neoplasm events were observed during follow-up. CONCLUSION:This paired tissue-plasma longitudinal analysis highlights an interpretive challenge in cfDNA testing during first-line platinum-to-PARPi maintenance therapy: putative CH candidates may become detectable as tumor-derived cfDNA declines. Given cfDNA-only inference without matched WBC sequencing and the small serial cohort, these observations are supportive of prior reports of CH dynamics but require validation in larger WBC-integrated cohorts. TRIAL REGISTRATION:UMIN-CTR Clinical Trial Identifier: UMIN000036749.
OBJECTIVE:The standard surgery for stage IB uterine cervical cancer is radical hysterectomy (RH). However, RH is highly invasive, and there is a need to establish less invasive techniques. METHODS:We conducted a prospective, single-arm trial to evaluate the efficacy and safety of modified radical hysterectomy (MRH)in patients with International Federation of Gynecology and Obstetrics 2008 stage IB1 cervical cancer involving a tumor diameter of ≤2 cm measured on magnetic resonance imaging. The protocol treatment consisted of MRH and adjuvant (chemo)radiotherapy if indicated. The primary endpoint was 5-year overall survival (OS). The expected OS was set at 95.8%; i.e., the OS of RH in our previous observational study. RESULTS:Of 225 eligible patients, 193 (85.8%) had pT1b1 (Union for International Cancer Control 7th) disease, and 184 (81.8%) had a pathological maximum tumor diameter of ≤2 cm. Parametrial involvement, lymph node metastasis, stromal invasion involving ≥2/3 of the stroma, and surgical margins of <1 cm (including carcinoma in situ) were observed in 3 (1.3%), 16 (7.1%), 30 (13.3%), and 11 (4.9%) patients, respectively. The 5-year OS and relapse-free survival rates were 98.2% (90% confidence interval [CI]=96.0%-99.2%) and 94.7% (95% CI=90.8%-96.9%), respectively. The median time to the disappearance of residual urine after urethral catheter removal was 1 day. There were no treatment-related deaths. Grade 3/4 adverse events were observed in 17 patients (7.6%). CONCLUSION:MRH may be as effective as and less invasive than RH for stage IB1 uterine cervical cancer involving a tumor diameter of ≤2 cm. TRIAL REGISTRATION:Japan Registry of Clinical Trials Identifier: jRCTs031180167.
OBJECTIVE:Little is known about patients with advanced ovarian cancer (AOC) who do not undergo cytoreductive surgery but receive maintenance therapy with poly (ADP-ribose) polymerase inhibitors (PARPis). We aimed to investigate the efficacy of PARPi maintenance therapy in nonsurgical patients. METHODS:We retrospectively analyzed the clinical records of patients newly diagnosed with stage III/IV ovarian cancer between April 2014 and March 2024 who did not undergo cytoreductive surgery and responded to first-line chemotherapy. The Kaplan-Meier method was used to estimate the survival outcomes. Adjustment for confounding using propensity score matching (PSM) was performed to compare progression-free survival (PFS) and overall survival (OS) between patients who received PARPi maintenance therapy and those who did not. RESULTS:Eighty-six patients (11.5%) out of 751 newly diagnosed AOC patients were eligible; of these patients, 52 (60.5%) had received PARPi maintenance therapy, and 34 (39.5%) had not. The median PFS and OS for the PARPi maintenance group were 9.8 months (95% confidence interval [CI]=7.2-14.8 months) and 29.2 months (95% CI=21.9 months-not available), respectively. After PSM (27 matched pairs), PFS was prolonged in the PARPi maintenance group compared to the no PARPi maintenance group (log-rank test p<0.001; hazard ratio [HR]=0.34; 95% CI=0.18-0.64). Similarly, OS was prolonged in the PARPi maintenance group compared to the no PARPi maintenance group (p=0.019; HR=0.45; 95% CI=0.23-0.89). CONCLUSION:Patients with AOC who are not undergoing cytoreductive surgery may be a crucial population that benefits from PARPi maintenance therapy.
OBJECTIVE:To evaluate changes in initial debulking surgery extensiveness among advanced ovarian cancer (OC) patients alongside increasing neoadjuvant chemotherapy (NACT) use. METHODS:This retrospective cohort study analyzed patients with distant disease in the Surveillance, Epidemiology, and End Results summary stage who underwent initial debulking surgery between 2013 and 2019 using the Cancer Public Library Database in South Korea. We evaluated temporal trends in extensive surgery by surgical site and compared primary debulking surgery (PDS) versus interval debulking surgery (IDS) subgroups. Extensive surgery was defined as standard surgery plus ≥1 additional complex procedure(s) involving nongenital tract organs or extra-abdominal metastatic sites. RESULTS:Among 5,500 patients, 23.6% received NACT. The IDS proportion increased during the study period (p for trend <0.01). The proportion of extensive surgery remained stable at 45.4%-49.2% (p for trend=0.54). Bowel surgery decreased from 73.5% to 65.2% (p for trend=0.02), whereas thoracic surgery increased from 31.8% to 44.2% (p for trend <0.01). Extensive surgery was more frequent in IDS versus PDS (p<0.01). In IDS compared to PDS, bowel surgery declined over time (p for trend=0.02) and was less frequent (59.6% vs. 74.4%, p<0.01), while thoracic (49.5% vs. 35.8%, p<0.01) and other extra-abdominal surgeries (5.0% vs. 2.9%, p<0.01) were more common. CONCLUSION:Increased NACT use was accompanied by constant overall extensive surgery, with greater bowel preservation and more frequent thoracic and other extra-abdominal surgeries in patients with advanced OC who underwent IDS.
OBJECTIVE:While the advantages of laparoscopic surgery (LPS) over open surgery (OPS) for endometrial cancer (EC) have been reported, most evidence comes from high-income countries with limited follow-up periods. To emulate a clinical trial using real-world cohort data to compare the clinical effectiveness, specifically recurrence and mortality rate, between LPS and OPS in patients with apparently early-stage EC. METHODS:A retrospective cohort study was conducted at a tertiary care hospital in Thailand. Treatment effect models with inverse-probability-weighted regression adjustment were employed to balance patient characteristics between the LPS and OPS groups, and subsequently estimated the treatment effect of LPS relative to OPS. RESULTS:From January 2011 to December 2022, 939 patients underwent surgery for EC. With a median follow-up time of 6.0 years (interquartile range=3.7-8.7), LPS significantly reduced the risk of recurrence and death compared to OPS, with a hazard ratio of 0.21 (95% confidence interval [CI]=0.09, 0.50) for recurrence and 0.42 (95% CI=0.24, 0.75) for death. LPS was significantly associated with longer operative time than OPS (mean difference [MD]=79.37 minutes; 95% CI=63.77-94.98) but showed clear advantages in other surgical outcomes, including reduced blood loss (MDs=-210.59 mL; 95% CI=-235.28, -185.89) and shorter hospital stays (MD=-17.25 hours; 95% CI=-25.67, -8.84). CONCLUSION:Real-world data from an upper-middle-income country indicated that LPS may provide superior oncologic outcomes, such as reduced recurrence and mortality rates, as well as improve surgical outcomes, including less blood loss and shorter hospital stays, despite a longer operative time.
BACKGROUND:Concurrent chemoradiotherapy is the standard adjuvant treatment for cervical cancer patients with pathologically confirmed lymph node metastases (International Federation of Gynecology and Obstetrics 2018 stage IIIC1p or IIIC2p) after radical surgery. Yet distant metastasis remains the predominant pattern of failure. In recent years, Immune checkpoint inhibitors combined with platinum-containing chemotherapy has been increasingly valued in the treatment of cervical cancer. Yet the role of postoperative chemo-immunotherapy in this setting remains unclear. There is no high-quality evidence-based evidence. METHODS:This multicenter, prospective, single-arm phase II clinical trial is to evaluate the safety and preliminary efficacy of postoperative chemo-immunotherapy in cervical cancer patients with pathologically confirmed lymph node metastasis after radical hysterectomy, and to explore potential biomarkers associated with treatment response. Fifty-nine carefully selected cervical cancer patients with pathologically confirmed lymph node metastases and programmed death ligand-1 positivity (combined positive score ≥1) after radical surgery will be enrolled. Postoperative treatment is initiated 2-3 weeks after surgery. Each treatment cycle is administered every 21-28 days and consists of chemotherapy (paclitaxel 175 mg/m², cisplatin 75-80 mg/m²) combined with camrelizumab (200 mg). Patients with 3 or more positive lymph nodes or para-aortic lymph node metastases receive 6 cycles of combined chemo-immunotherapy, whereas other patients receive 3 cycles. The primary outcome is 3-year disease-free survival rate. The secondary outcomes are overall survival rate, adverse events and health-related cancer-specific quality of life. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT07167160.
OBJECTIVE:To investigate the association between delayed confirmatory testing and cervical cancer detection among women with abnormal Pap smear results in the Korean national cervical cancer screening program. METHODS:This retrospective cohort study used customized data from the National Health Insurance Service of Korea. Women aged ≥30 years who underwent cervical cancer screening in 2019/2020 were included. After excluding those with prior gynecologic conditions or inadequate screening history, participants were classified according to confirmatory testing within 2 years after abnormal screening results. Outcomes included claims-based detection of cervical cancer (C53) and carcinoma in situ (D06). Adjusted hazard ratios (HRs) were estimated using multivariable Cox proportional hazards models. RESULTS:Among 10,331,369 participants, 64,762 were eligible (20,073 in Group 1 and 44,689 in Group 2). The 2-year detection rate of cervical cancer was 4.6% in Group 2 and 0.6% in Group 1. When including carcinoma in situ, rates were 19.5% and 5.6%, respectively. Delayed confirmatory testing was associated with higher detection rates, which may reflect delayed identification of pre-existing cases rather than a true increase in incidence (adjusted HR for C53+D06=1.45). Disparities by age, income, and region were observed. CONCLUSION:Delayed confirmatory testing was associated with higher cervical cancer detection; however, this likely reflects delayed identification of pre-existing cases rather than a causal increase in cancer occurrence. Improving follow-up systems may help reduce disparities in cancer detection.
OBJECTIVE:Neuroendocrine carcinoma of the cervix (NECC) is a rare yet aggressive malignancy with a poor prognosis. Although antibody-drug conjugates (ADCs) have shown promise in multiple cancers, the expression profiles of relevant ADC targets in NECC remain unclear. This study aimed to systematically evaluate candidate ADC target expression in NECC and explore associations with clinicopathological features and prognosis. METHODS:This study assessed the immunohistochemical expression of 9 ADC targets (including B7-H3, ROR1, DLL3, EGFR, Bcl-2, Nectin-4, TF, c-MET, and SEZ6) in a cohort. Expression levels were semi-quantitatively evaluated and correlated with clinicopathological variables and survival. RESULTS:This study enrolled 173 NECC patients (median age 47 years). Recurrence and mortality rates were 44.5% and 25.4%, respectively. Immunohistochemical profiling was performed in 91 cases with available paraffin-embedded tissues. Near-universal expression of B7-H3 (97.8%) was observed, along with frequent expression of ROR1 (73.6%) and DLL3 (72.5%). Regarding clinicopathological correlations, high B7-H3 expression was associated with parametrial invasion (p=0.039), and EGFR positivity was linked to uterosacral ligament invasion (p=0.034). Among all markers analyzed, only EGFR positivity was significantly associated with increased recurrence risk (p=0.048). Multivariable analysis identified vaginal invasion (hazard ratio [HR]=2.15) and advanced International Federation of Gynecology and Obstetrics stage (HR=3.02) as independent predictors of recurrence (p<0.001). CONCLUSION:This study identifies B7-H3 as the premier ADC target in NECC, with ROR1 and DLL3 as additional promising targets. EGFR demonstrates dual utility for prognostic stratification and therapeutic intervention. These findings provide molecular evidence to guide the development of precision therapy for this aggressive malignancy.
OBJECTIVE:Liver kinase B1 (LKB1) is a tumor suppressor that negatively regulates glucose transporter 1 (GLUT1) in Peutz-Jeghers Syndrome, but its mechanism in cervical cancer is unclear. METHODS:LKB1 expression was detected in cervical cancer specimens by real-time polymerase chain reaction. The double directional genetic manipulation, Nuclear and Cytoplasmic Protein separation technique and immunofluorescence were performed to detect the regulatory relationships among LKB1, pyruvate kinase isozyme type M2 (PKM2), hypoxia-inducible factor 1α (HIF-1α), and GLUT1 in cervical cancer cells, and Plasma Membrane and Cytoplasmic Protein separation technique and glucose uptake assay were used to verify the transport activity of GLUT1. LKB1-overexpression and -knockdown cervical cancer cell lines were generated in vitro. RESULTS:LKB1 messenger RNA level was lower in cervical cancer tissues than in matched paracancerous tissues. LKB1 was highly expressed in the cytoplasm of C33A, but was absent in its nucleus. And LKB1 was absent in SiHa. LKB1 regulated the alternative splicing of PKM1/PKM2. LKB1 overexpression significantly downregulated the PKM2pS37 expression in the nucleus and cytoplasm, the HIF-1α expression in the nucleus, and the GLUT1 expression in the plasma membrane. PKM2 knockdown reduced the nuclear accumulation of HIF-1α. Moreover, PKM2/HIF-1α knockdown reduced the glucose uptake of GLUT1. LKB1 negatively regulated the interaction between PKM2 and HIF-1α via AMPK signaling so as to inhibit the malignant phenotype of cervical cancer cells. CONCLUSION:LKB1 attenuates GLUT1 transport activity by inhibiting the PKM2/HIF-1α pathway, supporting the important roles of PKM2 and HIF-1α in the pathogenesis of cervical cancer.
