DNA Damage-driven Inflammatory Cytokines: Reprogramming of Tumor Immune Microenvironment and Application of Oncotherapy.

DNA damage occurs across tumorigenesis and tumor development. Tumor intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment (TIME) and dominate tumor progression. Accumulating evidence documents that multiple signaling pathways, including cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein (ATM/ATR), are activated downstream of DNA damage and they are associated with the secretion of diverse cytokines. These cytokines possess multifaced functions in the anti-tumor immune response. Thus, it is necessary to deeply interpret the complex TIME reshaped by damaged DNA and tumor-derived cytokines, critical for the development of effective tumor therapies. This manuscript comprehensively reviews the relationship between the DNA damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these cytokines. We also summarize clinical trials targeting signaling pathways and cytokines associated with DNA damage and provide future perspectives on emerging technologies.

Macrophages facilitate tumor cell PD-L1 expression via an IL-1ß-centered loop to attenuate immune checkpoint blockade.

Tumor-associated macrophages (TAMs) play critical roles in reprogramming other immune cells and orchestrating antitumor immunity. However, the interplay between TAMs and tumor cells responsible for enhancing immune evasion remains insufficiently understood. Here, we revealed that interleukin (IL)-1ß was among the most abundant cytokines within the in vitro tumor-macrophage coculture system, and enhanced IL-1ß expression was associated with impaired cytotoxicity of CD8+ T cells in human ovarian cancer, indicating the possibility that IL-1ß mediated immunosuppression during tumor-TAMs crosstalk. Mechanistically, we demonstrated that IL-1ß significantly boosted programmed death-ligand 1 (PD-L1) expression in tumor cells via the activation of the nuclear factor-κb signaling cascade. Specifically, IL-1ß released from TAMs was triggered by lactate, the anaerobic metabolite of tumor cells, in an inflammasome activation-dependent manner. IL-1ß sustained and intensified immunosuppression by promoting C-C motif chemokine ligand 2 secretion in tumor cells to fuel TAMs recruitment. Importantly, IL-1ß neutralizing antibody significantly curbed tumor growth and displayed synergistic antitumor efficacies with anti-PD-L1 antibody in tumor-bearing mouse models. Together, this study presents an IL-1ß-centered immunosuppressive loop between TAMs and tumor cells, highlighting IL-1ß as a candidate therapeutic target to reverse immunosuppression and potentiate immune checkpoint blockade.

Platelet RNA enables accurate detection of ovarian cancer: an intercontinental, biomarker identification study.

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.

Oncological big data platforms for promoting digital competencies and professionalism in Chinese medical students: a cross-sectional study.

OBJECTIVES: Advancements in big data technology are reshaping the healthcare system in China. This study aims to explore the role of medical big data in promoting digital competencies and professionalism among Chinese medical students. DESIGN, SETTING AND PARTICIPANTS: This study was conducted among 274 medical students who attended a workshop on medical big data conducted on 8 July 2021 in Tongji Hospital. The workshop was based on the first nationwide multifunction gynecologic oncology medical big data platform in China, at the National Union of Real-World Gynecologic Oncology Research & Patient Management Platform (NUWA platform). OUTCOME MEASURES: Data on knowledge, attitudes towards big data technology and professionalism were collected before and after the workshop. We have measured the four skill categories: doctor‒patient relationship skills, reflective skills, time management and interprofessional relationship skills using the Professionalism Mini-Evaluation Exercise (P-MEX) as a reflection for professionalism. RESULTS: A total of 274 students participated in this workshop and completed all the surveys. Before the workshop, only 27% of them knew the detailed content of medical big data platforms, and 64% knew the potential application of medical big data. The majority of the students believed that big data technology is practical in their clinical practice (77%), medical education (85%) and scientific research (82%). Over 80% of the participants showed positive attitudes toward big data platforms. They also exhibited sufficient professionalism before the workshop. Meanwhile, the workshop significantly promoted students' knowledge of medical big data (p<0.05), and led to more positive attitudes towards big data platforms and higher levels of professionalism. CONCLUSIONS: Chinese medical students have primitive acquaintance and positive attitudes toward big data technology. The NUWA platform-based workshop may potentially promote their understanding of big data and enhance professionalism, according to the self-measured P-MEX scale.

Elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation.

Finely tuned mitogen-activated protein kinase (MAPK) signaling is important for cancer cell survival. Perturbations that push cells out of the MAPK fitness zone result in cell death. Previously, in a screen of the North China Pharmaceutical Group Corporation's pure compound library of microbial origin, we identified elaiophylin as an autophagy inhibitor. Here, we demonstrated a new role for elaiophylin in inducing excessive endoplasmic reticulum (ER) stress, ER-derived cytoplasmic vacuolization, and consequent paraptosis by hyperactivating the MAPK pathway in multiple cancer cells. Genome-wide CRISPR/Cas9 knockout library screening identified SHP2, an upstream intermediary of the MAPK pathway, as a critical target in elaiophylin-induced paraptosis. The cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) assay further confirmed the direct binding between the SHP2 and elaiophylin. Inhibition of the SHP2/SOS1/MAPK pathway through SHP2 knockdown or pharmacological inhibitors distinctly attenuated elaiophylin-induced paraptosis and autophagy inhibition. Interestingly, elaiophylin markedly increased the already-elevated MAPK levels and preferentially killed drug-resistant cells with enhanced basal MAPK levels. Elaiophylin overcame drug resistance by triggering paraptosis in multiple tumor-bearing mouse models resistant to platinum, taxane, or PARPi, suggesting that elaiophylin might offer a reasonable therapeutic strategy for refractory ovarian cancer.

Artificial intelligence performance in image-based ovarian cancer identification: A systematic review and meta-analysis.

Background: Accurate identification of ovarian cancer (OC) is of paramount importance in clinical treatment success. Artificial intelligence (AI) is a potentially reliable assistant for the medical imaging recognition. We systematically review articles on the diagnostic performance of AI in OC from medical imaging for the first time. Methods: The Medline, Embase, IEEE, PubMed, Web of Science, and the Cochrane library databases were searched for related studies published until August 1, 2022. Inclusion criteria were studies that developed or used AI algorithms in the diagnosis of OC from medical images. The binary diagnostic accuracy data were extracted to derive the outcomes of interest: sensitivity (SE), specificity (SP), and Area Under the Curve (AUC). The study was registered with the PROSPERO, CRD42022324611. Findings: Thirty-four eligible studies were identified, of which twenty-eight studies were included in the meta-analysis with a pooled SE of 88% (95%CI: 85-90%), SP of 85% (82-88%), and AUC of 0.93 (0.91-0.95). Analysis for different algorithms revealed a pooled SE of 89% (85-92%) and SP of 88% (82-92%) for machine learning; and a pooled SE of 88% (84-91%) and SP of 84% (80-87%) for deep learning. Acceptable diagnostic performance was demonstrated in subgroup analyses stratified by imaging modalities (Ultrasound, Magnetic Resonance Imaging, or Computed Tomography), sample size (≤300 or >300), AI algorithms versus clinicians, year of publication (before or after 2020), geographical distribution (Asia or non Asia), and the different risk of bias levels (≥3 domain low risk or < 3 domain low risk). Interpretation: AI algorithms exhibited favorable performance for the diagnosis of OC through medical imaging. More rigorous reporting standards that address specific challenges of AI research could improve future studies. Funding: This work was supported by the Natural Science Foundation of China (No. 82073647 to Q-JW and No. 82103914 to T-TG), LiaoNing Revitalization Talents Program (No. XLYC1907102 to Q-JW), and 345 Talent Project of Shengjing Hospital of China Medical University (No. M0268 to Q-JW and No. M0952 to T-TG).

Sintilimab combined with bevacizumab in relapsed/persistent ovarian clear cell carcinoma (INOVA): an investigator-initiated, multicentre clinical trial-a study protocol of clinical trial.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) has an abysmal prognosis with a median overall survival (OS) of 25.3 months because of a low response to chemotherapy. The 5-year disease-specific survival rate after recurrence is 13.2%, with more than two-thirds of the patients dying within a year. Therefore, it is urgent to explore new therapeutic options for OCCC. Based on the characteristic immune-suppressive tumour microenvironment derived from the gene expression profile of OCCC, the combination of immunoantiangiogenesis therapy might have certain efficacy in recurrent/persistent OCCC. This trial aims to evaluate the efficacy and safety of sintilimab and bevacizumab in patients who have failed platinum-containing chemotherapy with recurrent or persistent OCCC. METHOD AND ANALYSIS: In this multicentre, single-arm, open-label, investigator-initiated clinical trial, 38 patients will be assigned to receive sintilimab 200 mg plus bevacizumab 15 mg/kg every 3 weeks. The eligibility criteria include histologically diagnosed patients with recurrent or persistent OCCC who have been previously treated with at least one-line platinum-containing chemotherapy; patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-2 with an expected survival greater than 12 weeks. The exclusion criteria include patients previously treated with immune checkpoint inhibitor and patients with contraindications of bevacizumab and sintilimab. The primary endpoint is the objective response rate. The secondary endpoints are progression-free survival, time to response, duration of response, disease control rate, OS, safety and quality of life. Statistical significance was defined as p<0.05. ETHICS AND DISSEMINATION: This trial was approved by the Research Ethics Commission of Tongji Medical College of Huazhong University of Science and Technology (2020-S337). The protocol of this study is registered at www. CLINICALTRIALS: gov. The trial results will be published in peer-reviewed journals and at conferences. TRIAL REGISTRATION NUMBER: NCT04735861; Clinicaltrials. gov.

Machine learning based early warning system enables accurate mortality risk prediction for COVID-19.

Soaring cases of coronavirus disease (COVID-19) are pummeling the global health system. Overwhelmed health facilities have endeavored to mitigate the pandemic, but mortality of COVID-19 continues to increase. Here, we present a mortality risk prediction model for COVID-19 (MRPMC) that uses patients' clinical data on admission to stratify patients by mortality risk, which enables prediction of physiological deterioration and death up to 20 days in advance. This ensemble model is built using four machine learning methods including Logistic Regression, Support Vector Machine, Gradient Boosted Decision Tree, and Neural Network. We validate MRPMC in an internal validation cohort and two external validation cohorts, where it achieves an AUC of 0.9621 (95% CI: 0.9464-0.9778), 0.9760 (0.9613-0.9906), and 0.9246 (0.8763-0.9729), respectively. This model enables expeditious and accurate mortality risk stratification of patients with COVID-19, and potentially facilitates more responsive health systems that are conducive to high risk COVID-19 patients.

Truncated Bid Regulates Cisplatin Response via Activation of Mitochondrial Apoptosis Pathway in Ovarian Cancer.

Refractoriness to conventional chemotherapy is a major challenge in the treatment of advanced ovarian cancer (OC). There is increasing evidence that mitochondrial priming correlates with cisplatin response in various cancers. Notably, Bim and Bid, two of the proapoptotic BH3-only proteins, are recognized as the most effective inducers of mitochondrial priming in OC. In this study, we constructed two tumor-specific oncolytic adenoviruses (Ads) coding for Bim (Ad-Bim) or truncated Bid (Ad-tBid), respectively, and performed gain-of-function assays in nine OC cell lines. Ad-tBid exhibited significant antitumor efficacy than the controls. On addition of Ad-tBid pretreatment, mito-primed cells displayed more sensitivity to cisplatin both in vitro and ex vivo. We also found that Ad-tBid induced mitochondrial apoptosis in a Bak-dependent manner. Furthermore, a combined cisplatin plus Ad-tBid therapy markedly inhibited tumor growth in a subcutaneous xenotransplanted tumor model. In mice bearing peritoneal disseminated OC, intraperitoneal administration of Ad-tBid potentiated the antitumor effect of cisplatin. Our findings suggest that Ad-tBid enhances cisplatin response in OC cells, establishing the potential treatment of advanced OC via a combination of cisplatin and Ad-tBid.

C/EBPß enhances platinum resistance of ovarian cancer cells by reprogramming H3K79 methylation.

Chemoresistance is a major unmet clinical obstacle in ovarian cancer treatment. Epigenetics plays a pivotal role in regulating the malignant phenotype, and has the potential in developing therapeutically valuable targets that improve the dismal outcome of this disease. Here we show that a series of transcription factors, including C/EBPß, GCM1, and GATA1, could act as potential modulators of histone methylation in tumor cells. Of note, C/EBPß, an independent prognostic factor for patients with ovarian cancer, mediates an important mechanism through which epigenetic enzyme modifies groups of functionally related genes in a context-dependent manner. By recruiting the methyltransferase DOT1L, C/EBPß can maintain an open chromatin state by H3K79 methylation of multiple drug-resistance genes, thereby augmenting the chemoresistance of tumor cells. Therefore, we propose a new path against cancer epigenetics in which identifying and targeting the key regulators of epigenetics such as C/EBPß may provide more precise therapeutic options in ovarian cancer.

MMP26: A potential biomarker for prostate cancer.

The application of prostate-specific antigen (PSA) in the screening and diagnosis of prostate cancer (PCa) has improved the clinical management of PCa patients. However, the PSA assay has been faced with criticism due to its potential association with over-diagnosis and subsequent overtreatment of indolent patients. Matrix metalloproteinase-26 (MMP26) is a member of matrix metalloproteinases (MMPs) and has been reported to be highly expressed in many cancers. This investigation evaluated the potential of serum MMP26 as a biomarker for PCa. The level of serum MMP26 was measured by enzyme-linked immunosorbent assay (ELISA) in 160 subjects including PCa group (n=80), benign prostatic hyperplasia (BPH) group (n=40) and control group (n=40). Furthermore, we evaluated the expression of MMP26 in tissues by immunohistochemistry. The results showed the serum MMP26 levels were significantly higher in PCa group than in BPH group and control group. Similarly, the MMP26 protein was positive in PCa tissues and negative in BPH tissues and control tissues. In conclusion, these results suggested MMP26 could be used as a potential serum biomarker in the diagnosis of PCa.

Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C.

PURPOSE: Lymphatic vessels are mainly regarded as passive conduits for the dissemination of cancer cells. In this study, we investigate whether and how the tumor-associated lymphatic vessels may play an active role in tumor metastasis. EXPERIMENTAL DESIGN: In situ laser capture microdissection of lymphatic vessels followed by cDNA microarray analysis was used to determine the expression profiling of lymphatic endothelial cells (LEC). Gene expression levels and activity of signaling pathways were measured by real-time RT-PCR, ELISA, or immunoblotting. Lymphangiogenesis was assessed by IHC. Lymph node metastasis was measured using fluorescence imaging. The effects of SEMA4C on lymphangiogenesis in vitro were evaluated using migration assay and tube-formation assay of LECs. RESULTS: Tumor-associated LECs are molecularly and functionally different from their normal counterparts. In addition to expressing high levels of membrane-bound SEMA4C, tumor-associated LECs also produced soluble SEMA4C (sSEMA4C). Increased serum sSEMA4C was detected in patients with breast cancer and cervical cancer. Patients with metastasis had much higher levels of serum sSEMA4C. sSEMA4C promoted lymphangiogenesis by activating PlexinB2-ERBB2 signaling in LECs, and promoted the proliferation and migration of tumor cells by activating PlexinB2-MET signaling, thus promoting lymphatic metastasis. Although the SEMA4C signaling pathways differ between LECs and tumor cells, RHOA activation was necessary for the effects of SEMA4C in both types of cells. CONCLUSIONS: Tumor-associated LECs produce sSEMA4C to promote lymphatic metastasis of tumors. Our results suggest that SEMA4C and RHOA might be potential therapeutic targets, and that higher serum sSEMA4C could be a marker for breast cancer and cervical cancer. Clin Cancer Res; 23(1); 214-24. ©2016 AACR.

SIX1 coordinates with TGFß signals to induce epithelial-mesenchymal transition in cervical cancer.

Epithelial-mesenchymal transition (EMT) plays a critical role in promoting tumor invasion and metastasis. However, the key cofactors that modulate the signal transduction to induce EMT have note been fully explored to date. The present study reports that sine oculis homeobox homolog 1 (SIX1) is able to promote EMT of cervical cancer by coordinating with transforming growth factor (TGF)ß-SMAD signals. The expression of SIX1 was negatively correlated with the expression of the epithelial marker E-cadherin in two independent groups of cervical cancer specimens. SIX1 could promote the transition of mesenchymal phenotype in the presence of active TGFß signals in vitro and in vivo. TGFß-SMAD signals were required for the SIX1-mediated promotion of EMT and metastatic capacity of cervical cancer cells. Together, SIX1 and TGFß cooperated to induce more remarkable changes in the transition of phenotype than each of them alone, and coordinated to promote cell motility and tumor metastasis in cervical cancer. These results suggest that the coordination of SIX1 and TGFß signals may be crucial in the EMT program, and that SIX1/TGFß may be considered a valuable marker for evaluating the metastatic potential of cervical cancer cells, or a therapeutic target in the treatment of cervical cancer.

Effect of BRCA2 mutation on familial breast cancer survival: A systematic review and meta-analysis.

Reports of BRCA2 genetic mutations on the prognosis of familial breast cancer (BC) patients have been contradictory. True difference in survival, if it exists, would have important implications for genetic counseling and in treatment of hereditary BC. The purpose of this study was to compare overall survival rate (OSR) among BRCA2 mutation carriers, non-carriers and sporadic BC patients. We searched the PUBMED and EMBASE databases and retrieved 4529 articles using keywords that included breast cancer, BRCA, prognosis and survival. Nine articles were selected for systematic review and among them 6 were included in our meta-analysis. We used the fixed and random effect models to calculate the summary odds ratio (OR) and corresponding 95% confidence interval (CI). BRCA2 mutation carriers had significantly higher long-term OSR than non-carriers (OR=0.69 [95% CI=0.5-0.95]), while both short-term and long-term OSR of BRCA2 mutation carriers did not differ from those of patients with sporadic disease (OR=1.11 [95% CI=0.74-1.65]; 0.85 [95% CI=0.38-1.94], respectively). For BC-specific survival rate (BCSSR), BRCA2 mutation carriers had a similar BCSSR to the non-carriers (OR=0.61 [95% CI=0.28-1.34]). There was no significant difference in disease-free survival (DFS) between BRCA2 mutation carriers and patients with sporadic disease. Our results suggest that BRCA2 mutation increases long-term OSR in hereditary BC, which reminds us a new prospect of management of the disease.

Increased survival and prolonged longevity mainly contribute to the temperature-adaptive evolutionary strategy in invasive Bemisia tabaci (Hemiptera: Aleyrodidae) Middle East Asia Minor 1.

With increasing global climate change, analyses of stress-inducing conditions have important significance in ecological adaptation and the biological distribution of species. To reveal the difference in temperature-adaptive strategy between Turpan and Beijing populations of Bemisia tabaci (Gennadius) Middle East Asia Minor 1 (MEAM1) under high-temperature stress conditions, we compared thermal tolerance and life history traits between Beijing and Turpan populations of MEAM1 after exposure to different heat shock treatments for different times. The experimental design reflected the nature of heat stress conditions suffered by MEAM1. The results showed that eggs, red-eyed pupae, and adults of the Turpan population were more heat tolerant than those of the Beijing population under the same stress conditions. Additionally, it was found that longevity and F1 adult survival rate were significantly higher in the Turpan population than in the Beijing population after heat shock stress, but egg number and F1 female ratio were not significantly different between Turpan population and Beijing population. Overall, it was suggested that heat tolerance and longevity traits were the most relevant for climate characteristics and not reproductive traits, and improved heat tolerance and prolonged longevity were important adaptive strategies that helped MEAM1 to survive in harsh high-temperature conditions such as Turpan arid desert climate. The present results provided further insight into the modes of heat tolerance and the ways in which survival and longevity traits respond to environmental selection pressures.

SIX1 promotes tumor lymphangiogenesis by coordinating TGFß signals that increase expression of VEGF-C.

Lymphatic vessels are one of the major routes for the dissemination of cancer cells. Malignant tumors release growth factors such as VEGF-C to induce lymphangiogenesis, thereby promoting lymph node metastasis. Here, we report that sine oculis homeobox homolog 1 (SIX1), expressed in tumor cells, can promote tumor lymphangiogenesis and lymph node metastasis by coordinating with TGFß to increase the expression of VEGF-C. Lymphangiogenesis and lymph node metastasis in cervical cancer were closely correlated with higher expression of SIX1 in tumor cells. By enhancing VEGF-C expression in tumor cells, SIX1 could augment the promoting effect of tumor cells on the migration and tube formation of lymphatic endothelial cells (LEC) in vitro and lymphangiogenesis in vivo. SIX1 enhanced TGFß-induced activation of SMAD2/3 and coordinated with the SMAD pathway to modulate VEGF-C expression. Together, SIX1 and TGFß induced much higher expression of VEGF-C in tumor cells than each of them alone. Despite its effect in promoting VEGF-C expression, TGFß could inhibit lymphangiogenesis by directly inhibiting tube formation by LECs. However, the increased production of VEGF-C not only directly promoted migration and tube formation of LECs but also thwarted the inhibitory effect of TGFß on LECs. That is, tumor cells that expressed high levels of SIX1 could promote lymphangiogenesis and counteract the negative effects of TGFß on lymphangiogenesis by increasing the expression of VEGF-C. These findings provide new insights into tumor lymphangiogenesis and the various roles of TGFß signaling in tumor regulation. Our results also suggest that SIX1/TGFß might be a potential therapeutic target for preventing lymph node metastasis of tumor.

Sine oculis homeobox homolog 1 promotes DNA replication and cell proliferation in cervical cancer.

Malignant proliferation is the fundamental trait of tumor cells. The initiation of DNA replication represents a key process for cell proliferation, and has a marked impact on tumorigenesis and progression. Here we report that Sine oculis homeobox homolog 1 (SIX1) functions as a master regulator in DNA replication of cervical cancer cells. The expression of SIX1 was induced by the E7 oncoprotein of human papillomaviruses in cervical intraepithelial neoplasia and cervical cancer. The increase of SIX1 expression resulted in the upregulation of multiple genes related to the initiation of DNA replication, including the genes coding for the proteins in minichromosome maintenance complex (MCM2, MCM3, MCM6), DNA polymerase α-primase complex (POLA1, PRIM1, PRIM2), clamp loader (RFC3, RFC4, RFC5), DNA polymerase δ complex (POLD3) and DNA polymerase ε complex (POLE2). In line with this, the increase of SIX1 expression enhanced DNA synthesis, accelerated G1 to S phase progression, and promoted the proliferation of cervical cancer cells and the growth of cervical cancer. Consistently, knockdown of SIX1 could hamper DNA synthesis, slow down G1 to S phase progression, and suppress tumor cell proliferation and tumor growth. Importantly, SIX1 could more efficiently promote anchorage-independent cell growth. These results suggest that the increase of SIX1 expression could promote tumorigenesis, progression and invasive growth of cervical cancer by promoting DNA replication, and that targeting SIX1 may have significant therapeutic value in cervical cancer treatment.

Sine oculis homeobox homolog 1 promotes α5ß1-mediated invasive migration and metastasis of cervical cancer cells.

Sine oculis homeobox homolog 1 (SIX1) has been supposed to be correlated with the metastasis and poor prognosis of several malignancies. However, the effect of SIX1 on the metastatic phenotype of tumor cells and the underlying mechanisms were still unclear to date. Here we report that SIX1 can promote α5ß1-mediated metastatic capability of cervical cancer cells. SIX1 promoted the expression of α5ß1 integrin to enhance the adhesion capacity of tumor cells in vitro and tumor cell arrest in circulation in vivo. Moreover, higher expression of SIX1 in tumor cells resulted in the increased production of active MMP-2 and MMP-9, up-regulation of anti-apoptotic genes (BCL-XL and BCL2) and down-regulation of pro-apoptotic genes (BIM and BAX), thus promoting the invasive migration and anoikis-resistance of tumor cells. Importantly, blocking α5ß1 abrogated the regulatory effect of SIX1 on the expression of these genes, and also abolished the promotional effect of SIX1 on invasive capability of tumor cells. Furthermore, knock-down of α5 could abolish the promoting effect of SIX1 on the development of metastatic lesions in both experimental and spontaneous metastasis model. Therefore, by up-regulating α5ß1 expression, SIX1 not only promoted the adhesion capacity, but also augmented ECM-α5ß1-mediated regulation of gene expression to enhance the metastatic potential of cervical cancer cells. These results suggest that SIX1/α5ß1 might be considered as valuable marker for metastatic potential of cervical cancer cells, or a therapeutic target in cervical cancer treatment.