Cervical cancer is one of the most common cancers in women worldwide. The outcome of patients with metastatic cervical cancer is poor. We reviewed the relevant literature concerning the treatment and diagnosis of metastatic cervical cancer. There are two types of metastasis related to different treatments and survival rates: hematogenous metastasis and lymphatic metastasis. Patients with hematogenous metastasis have a higher risk of death than those with lymphatic metastasis. In terms of diagnosis, fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and PET-computed tomography are effective tools for the evaluation of distant metastasis. Concurrent chemoradiotherapy and subsequent chemotherapy are well-tolerated and efficient for lymphatic metastasis. As for lung metastasis, chemotherapy and/or surgery are valuable treatments for resistant, recurrent metastatic cervical cancer and chemoradiotherapy may be the optimal choice for stage IVB cervical cancer. Chemotherapy and bone irradiation are promising for bone metastasis. A better survival is achieved with multimodal therapy. Craniotomy or stereotactic radiosurgery is an optimal choice combined with radiotherapy for solitary brain metastases. Chemotherapy and palliative brain radiation may be considered for multiple brain metastases and other organ metastases.

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The aberrant expression of long noncoding RNAs (lncRNAs) has been reported frequently in specific cancers, including high-grade serous ovarian cancer (HGSOC). The purpose of the present study was to explore the clinical significance and underlying mechanisms of a significantly dysregulated lncRNA (NEAT1) in HGSOC. Our results showed that elevated NEAT1 expression in human HGSOC specimens correlated with a poor prognosis. Functional experiments demonstrated that knockdown of NEAT1 significantly prohibited ovarian cancer cell proliferation and invasion in vitro and restrained tumor growth in vivo. LIN28B was identified by bioinformatics analysis along with experimental evidence as a direct actor that enhanced NEAT1 stability. A rescue functional assay confirmed that the LIN28B/NEAT1 axis contributed to oncogenic functions in ovarian cancer cells. Moreover, gene expression profile data and dual luciferase reporter assay results demonstrated that NEAT1 functioned as a competing endogenous RNA (ceRNA) for miR-506 to promote cell proliferation and migration. Taken together, our results showed that NEAT1, stabilized by LIN28B, promoted HGSOC progression by sponging miR-506. Thus, NEAT1 can be regarded as a vital diagnostic biomarker for HGSOC and a therapeutic target.

Although PD-L1 has been shown to play a well-characterized role in inhibiting antitumor immunity via engagement of its receptor PD-1 in T lymphocytes, little is known about the tumor cell-intrinsic function of PD-L1 and its association with prognosis. Here, we investigate this issue and dissect the molecular mechanisms underlying the role of PD-L1 in glucose metabolism, proliferation, migration, and invasion in human cervical cancer cells. As a result, we found that PD-L1 overexpression in cervical cancer cells increases glucose metabolism and metastasis-related behaviors. Mechanistically, PD-L1 bound directly to integrin β4 (ITGB4), activating the AKT/GSK3β signaling pathway and consequently inducing the expression of the transcriptional repressor SNAI1. SNAIL in turn influenced the expression of genes involved in the epithelial-to-mesenchymal transition and regulated glucose metabolism by inhibiting SIRT3 promoter activity. High expression of PD-L1 and ITGB4 in human cervical carcinomas was significantly associated with lymph node metastasis and poor prognosis. Finally, F-fluorodeoxyglucose microPET/CT and bioluminescence imaging analyses of cervical xenograft tumors in mice revealed that PD-L1 overexpression markedly increases tumor glucose uptake and promotes lymph node metastasis. Together, these results demonstrate that PD-L1 can promote the growth and metastasis of cervical cancer by activating the ITGB4/SNAI1/SIRT3 signaling pathway, and also suggest the possibility of targeting PD-L1 and its downstream effectors as a potential approach for interfering with cervical cancer growth and metastasis.

Background:There are limited data comparing the prognosis and fertility outcomes of the patients with early cervical cancer treated by trans-vaginal radical trachelectomy (VRT) or abdominal radical trachelectomy (ART).The objective of this study was to compare the surgical and pathologic characteristics, the prognosis and fertility outcomes of the patients treated by VRT or ART.Methods:Matched-case study based on a prospectively maintained database of patients underwent radical trachelectomy in 10 centres of China was designed to compare the prognosis and fertility outcomes of the patients treated by VRT or ART.Results:Totally 150 cases, 77 in the VRT and 73 in the ART group, were included. VRT and ART provide similar surgical and pathological outcomes except larger specimens obtained by ART. In the ART group, no patient developed recurrent diseases, but, in the VRT group, 7 (9.8%) patients developed recurrent diseases and 2 (1.6%) patients died of the tumours (P=0.035). The rate of pregnancy in the VRT group was significantly higher than those of ART (39.5% vs 8.8% P=0.003). The patients with tumour size >2 cm showed significant higher recurrent rate (11.6% vs 2.4%, P<0.05) and lower pregnant rate (12.5% vs 32.1%, P=0.094) compared with the patients with tumour size <2 cm.Conclusion:Patients treated by ART obtained better oncology results, but their fertility outcomes were unfavourable compared with VRT. Tumour size <2 cm should be emphasised as an indication for radical trachelectomy for improving the outcome of fertility and prognosis.

The purpose of this study was to define the roles of miR-181a in determining sensitivity of cervical cancer to radiation therapy, to explore the underlying mechanism and to evaluate the potential of miR-181a as a biomarker for predicting radio-sensitivity. Tumor specimens from 18 patients with a histological diagnosis of squamous cervical carcinoma (stage IIIB) were used in the micro-RNA profiling and comparison. These patients never received any chemotherapy before radiation therapy. Human cervical cancer cell lines, SiHa and Me180, were used in vitro (cell culture) and in vivo (animal) studies. Transfection of tumor cells with the mimic or inhibitor of miR-181a, and reporter gene assay, were performed to investigate the role of miR-181a in determining radio-sensitivity and the target gene. Higher expression of miR-181a was observed in human cervical cancer specimens and cell lines that were insensitive to radiation therapy, as compared with sensitive cancer specimens and the cell lines. We also found that miR-181a negatively regulated the expression of PRKCD, a pro-apoptotic protein kinase, via targeting its 3'-untranslated region (UTR), thereby inhibiting irradiation-induced apoptosis and decreasing G2/M block. The role of miR-181a in conferring cellular resistance to radiation treatment was validated both in cell culture models and in mouse tumor xenograft models. The effect of miR-181a on radio-resistance was mediated through targeting the 3'-UTR of PRKCD gene. Thus, the expression level of miR-181a in cervical cancer may serve as a biomarker for sensitivity to radiation therapy, and targeting miR-181a may represent a new approach to sensitizing cervical cancer to radiation treatment.

Purpose NF-κB is a transcription factor known to promote tumorigenesis. However, NF-κB is also known to be proapoptotic and may potentially function as a tumor suppressor, although such a functional role has not been extensively investigated in human cancer. Experimental Design A dominant-negative mutant of IκBα with mutations at S32A and S36A was used to inhibit the function of NF-κB in ovarian cancer cell lines. The transcription ability, tumorigenesis, apoptosis, and drug sensitivity were examined in derivative cell lines in comparison with parental cells. We also analyzed the association of nuclear expression of NF-κB p65 with patient survival in an ovarian cancer tissue array. Results We show that NF-κB functions as a tumor suppressor in four ovarian cancer cell lines, but it functions as an oncogene in their aggressive chemoresistant isogenic variants. NF-κB can exert its proapoptotic or antiapoptotic effect by activating or repressing mitogen-activated protein kinase (MAPK) phosphorylation in parental or aggressive chemoresistant variant cell lines. We also show that the nuclear accumulation of p65 in epithelial cancer tissue is associated with a good response to chemotherapy and can predict longer overall survival for patients with ovarian cancer. Conclusions Our data provide strong evidence that NF-κB can function as a biphasic regulator, either suppressing or enhancing ovarian cancer growth through the regulation of MAPK and cellular apoptosis.

Background The tumor suppressor FBW7 is the substrate recognition component of the SCF E3-ubiquitin ligase complex that mediates proteolytic degradation of various oncogenic proteins. However, the role of FBW7 in ovarian cancer progression remains inadequately understood. Methods IP-MASS, co-IP, immunohistochemistry, and western blotting were used to identify the potential substrate of FBW7 in ovarian cancer. The biological effects of FBW7 were investigated using in vitro and in vivo models. LC/MS was used to detect the m6A levels in ovarian cancer tissues. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of YTHDF2. Results We unveil that FBW7 is markedly down-regulated in ovarian cancer tissues and its high expression is associated with favorable prognosis and elevated m6A modification levels. Consistently, ectopic FBW7 inhibits ovarian cancer cell survival and proliferation in vitro and in vivo, while ablation of FBW7 empowers propagation of ovarian cancer cells. In addition, the m6A reader protein, YTHDF2, is identified as a novel substrate for FBW7. FBW7 counteracts the tumor-promoting effect of YTHDF2 by inducing proteasomal degradation of the latter in ovarian cancer. Furthermore, YTHDF2 globally regulates the turnover of m6A-modified mRNAs, including the pro-apoptotic gene BMF. Conclusions Our study has demonstrated that FBW7 suppresses tumor growth and progression via antagonizing YTHDF2-mediated BMF mRNA decay in ovarian cancer.