Search

Background and Purpose: Because of cervical cancer (CC) metastasis, the prognosis of diagnosed patients is poor. However, the molecular mechanisms and therapeutic approach for metastatic CC remain elusive. Experimental Approach: In this study, we first evaluated the effect of resveratrol (RSV) on CC cell migration and metastasis. Via an activity‐based protein profiling (ABPP) approach, a photoaffinity probe of RSV (RSV‐P) was synthesized, and the protein targets of RSV in HeLa cells were identified. Based on target information and subsequent in vivo and in vitro validation experiments, we finally elucidated the mechanism of RSV corresponding to its antimetastatic activity. Key Results: The results showed that RSV concentration‐dependently suppressed CC cell migration and metastasis. A list of proteins was identified as the targets of RSV, through the ABPP approach with RSV‐P, among which fatty acid binding protein 5 (FABP5) attracted our attention based on The Cancer Genome Atlas (TCGA) database analysis. Subsequent knockout and overexpression experiments confirmed that RSV directly interacted with FABP5 to inhibit fatty acid transport into the nucleus, thereby suppressing downstream matrix metalloproteinase‐2 (MMP2) and matrix metalloproteinase‐9 (MMP9) expression, thus inhibiting CC metastasis. Conclusions and Implications: Our study confirmed the key role of FABP5 in CC metastasis and provided important target information for the design of therapeutic lead compounds for metastatic CC. [ABSTRACT FROM AUTHOR]

Abstract Background An estimated 119,300 new cases of cervical cancer occur annually in China, accounting for 372,00 deaths. Cutaneous metastasis from cervical cancer is a rare event, with an incidence of 0.1–1.3% and typically a preterminal occurrence. Scalp metastasis from cervical cancer is exceptionally anecdotal, with only a dozen examples well documented. Case presentation The patient is a 33-year-old Chinese woman who was diagnosed with International Federation of Gynecology and Obstetrics stage IVB cervical cancer in November 2021. From December 2021 to April 2022, the patient was enrolled in the clinical trial of sintilimab combined with chemotherapy and radiotherapy for treatment of stage IV cervical cancer and underwent six cycles of immunotherapy and chemotherapy (sintilimab plus paclitaxel liposome and cisplatin). Treatment was well tolerated and led to a partial response. The masses adjacent to the spine and iliac bone was largely reduced. Thus, radiotherapy of the metastatic residues was carried out and followed by radiotherapy to the primary tumor at the cervix uteri. However, by the time of the radiotherapy completion in October 2022, the patient noticed painless nodules at the left scapular region and the right hypochondrium. The following month, more nodules occurred on the scalp and trunk, including the left axilla, anterior abdomen, and left back, along with a lesion invading the sternum that caused acute bone pain. The cutaneous masses were white, discrete with a rubbery consistency, and fixed to the skin. Several nodules increased in size and eventually ulcerated. Fine‑needle aspiration cytology of the left back swellings revealed metastatic squamous cell carcinoma, P16 positive. No visceral or brain metastasis was observed at this point. Conclusions Cervical cancer metastases to the scalp are extremely uncommon. When a scalp metastasis is present, it might be the only symptomatic sign of disease progression or widespread metastatic lesions. So far, there is no clear guideline regarding skin metastases treatment. Such skin lesions warrant a thorough radiologic and pathologic workup to form a comprehensive management plan.

Background: An estimated 119,300 new cases of cervical cancer occur annually in China, accounting for 372,00 deaths. Cutaneous metastasis from cervical cancer is a rare event, with an incidence of 0.1–1.3% and typically a preterminal occurrence. Scalp metastasis from cervical cancer is exceptionally anecdotal, with only a dozen examples well documented. Case presentation: The patient is a 33-year-old Chinese woman who was diagnosed with International Federation of Gynecology and Obstetrics stage IVB cervical cancer in November 2021. From December 2021 to April 2022, the patient was enrolled in the clinical trial of sintilimab combined with chemotherapy and radiotherapy for treatment of stage IV cervical cancer and underwent six cycles of immunotherapy and chemotherapy (sintilimab plus paclitaxel liposome and cisplatin). Treatment was well tolerated and led to a partial response. The masses adjacent to the spine and iliac bone was largely reduced. Thus, radiotherapy of the metastatic residues was carried out and followed by radiotherapy to the primary tumor at the cervix uteri. However, by the time of the radiotherapy completion in October 2022, the patient noticed painless nodules at the left scapular region and the right hypochondrium. The following month, more nodules occurred on the scalp and trunk, including the left axilla, anterior abdomen, and left back, along with a lesion invading the sternum that caused acute bone pain. The cutaneous masses were white, discrete with a rubbery consistency, and fixed to the skin. Several nodules increased in size and eventually ulcerated. Fine‑needle aspiration cytology of the left back swellings revealed metastatic squamous cell carcinoma, P16 positive. No visceral or brain metastasis was observed at this point. Conclusions: Cervical cancer metastases to the scalp are extremely uncommon. When a scalp metastasis is present, it might be the only symptomatic sign of disease progression or widespread metastatic lesions. So far, there is no clear guideline regarding skin metastases treatment. Such skin lesions warrant a thorough radiologic and pathologic workup to form a comprehensive management plan. [ABSTRACT FROM AUTHOR]

Abstract Background Metastasis is the main cause of mortality in cervical cancer (CC). Circular RNAs (circRNAs) have been demonstrated to play a crucial role in carcinoma biology. However, the expression and function of circRNAs in cervical cancer metastasis are still unclear. Methods In the present study, we identified a circRNA with an N6-methyladenosine (m6A) modification, circCCDC134, whose expression was increased in CC tissues by circRNA-Seq and qPCR. CircCCDC134 upregulation in CC was fine-tuned by ALKBH5-mediated m6A modification, which enhanced its stability in a YTHDF2-dependent manner. The functional experiments illustrated that circCCDC134 enhanced tumour proliferation and metastasis in vitro and in vivo. For the comprehensive identification of RNA-binding proteins, circRNA pull-down and mass spectrometry (ChIRP-MS), chromatin immunoprecipitation-seq (Chip-seq), RNA binding protein immunoprecipitation (RIP) and luciferase reporter assays were used to perform mechanistic investigations. Results The results revealed that circCCDC134 recruited p65 in the nucleus and acted as a miR-503-5p sponge to regulate the expression of MYB in the cytoplasm, ultimately stimulating HIF1A transcription and facilitating CC growth and metastasis. Conclusion: These findings indicate that circCCDC134 is an important therapeutic target and provide new regulatory model insights for exploring the carcinogenic mechanism of circCCDC134 in CC.

Background: Metastasis is the main cause of mortality in cervical cancer (CC). Circular RNAs (circRNAs) have been demonstrated to play a crucial role in carcinoma biology. However, the expression and function of circRNAs in cervical cancer metastasis are still unclear. Methods: In the present study, we identified a circRNA with an N6-methyladenosine (m6A) modification, circCCDC134, whose expression was increased in CC tissues by circRNA-Seq and qPCR. CircCCDC134 upregulation in CC was fine-tuned by ALKBH5-mediated m6A modification, which enhanced its stability in a YTHDF2-dependent manner. The functional experiments illustrated that circCCDC134 enhanced tumour proliferation and metastasis in vitro and in vivo. For the comprehensive identification of RNA-binding proteins, circRNA pull-down and mass spectrometry (ChIRP-MS), chromatin immunoprecipitation-seq (Chip-seq), RNA binding protein immunoprecipitation (RIP) and luciferase reporter assays were used to perform mechanistic investigations. Results: The results revealed that circCCDC134 recruited p65 in the nucleus and acted as a miR-503-5p sponge to regulate the expression of MYB in the cytoplasm, ultimately stimulating HIF1A transcription and facilitating CC growth and metastasis. Conclusion: These findings indicate that circCCDC134 is an important therapeutic target and provide new regulatory model insights for exploring the carcinogenic mechanism of circCCDC134 in CC. [ABSTRACT FROM AUTHOR]

Abstract Background Metastasis is a major challenge in cervical cancer treatment. Previous studies have shown that the dual functional protein apurinic/apyrimidinic endonuclease 1 (APE1) promotes tumor metastasis and is overexpressed in cervical cancer. However, the biological role and mechanism of APE1 in cervical cancer metastasis have rarely been studied. Methods We used gene set enrichment analysis (GSEA) to determine the APE1-related signaling pathways in cervical cancer. To investigate the role and mechanism of APE1 in cervical cancer metastasis and invasion, immunohistochemistry, immunofluorescence, western blotting, secondary structure prediction, coimmunoprecipitation, luciferase reporter, and electrophoretic mobility shift assays were performed. The inhibitory effects of the APE1 redox function inhibitor APX3330 on cervical cancer metastasis were evaluated using animal models. Results Clinical data showed that high expression of APE1 was associated with lymph node metastasis in cervical cancer patients. GSEA results showed that APE1 was associated with epithelial to mesenchymal transition (EMT) in cervical cancer. Ectopic expression of APE1 promoted EMT and invasion of cervical cancer cells, whereas inhibition of APE1 suppressed EMT and invasion of cervical cancer cells in a redox function-dependent manner. Notably, APE1 redox function inhibitor APX3330 treatment dramatically suppressed cervical cancer cell lymph node and distant metastasis in vivo. Furthermore, we found that APE1 enhanced the interaction between ZEB1 and the E-cadherin promoter by binding to ZEB1, thereby suppressing the expression of E-cadherin, a negative regulator of EMT. Conclusion Our findings help to elucidate the role played by APE1 in cervical cancer metastasis and targeting APE1 redox function may be a novel strategy for inhibiting cervical cancer metastasis.

Background: Metastasis is a major challenge in cervical cancer treatment. Previous studies have shown that the dual functional protein apurinic/apyrimidinic endonuclease 1 (APE1) promotes tumor metastasis and is overexpressed in cervical cancer. However, the biological role and mechanism of APE1 in cervical cancer metastasis have rarely been studied. Methods: We used gene set enrichment analysis (GSEA) to determine the APE1-related signaling pathways in cervical cancer. To investigate the role and mechanism of APE1 in cervical cancer metastasis and invasion, immunohistochemistry, immunofluorescence, western blotting, secondary structure prediction, coimmunoprecipitation, luciferase reporter, and electrophoretic mobility shift assays were performed. The inhibitory effects of the APE1 redox function inhibitor APX3330 on cervical cancer metastasis were evaluated using animal models. Results: Clinical data showed that high expression of APE1 was associated with lymph node metastasis in cervical cancer patients. GSEA results showed that APE1 was associated with epithelial to mesenchymal transition (EMT) in cervical cancer. Ectopic expression of APE1 promoted EMT and invasion of cervical cancer cells, whereas inhibition of APE1 suppressed EMT and invasion of cervical cancer cells in a redox function-dependent manner. Notably, APE1 redox function inhibitor APX3330 treatment dramatically suppressed cervical cancer cell lymph node and distant metastasis in vivo. Furthermore, we found that APE1 enhanced the interaction between ZEB1 and the E-cadherin promoter by binding to ZEB1, thereby suppressing the expression of E-cadherin, a negative regulator of EMT. Conclusion: Our findings help to elucidate the role played by APE1 in cervical cancer metastasis and targeting APE1 redox function may be a novel strategy for inhibiting cervical cancer metastasis. [ABSTRACT FROM AUTHOR]

Tumor metastasis remains a major obstacle for improving overall cancer survival in cervical cancer ( CC), which may be due to the existence of tumor microenvironment-related cancer stem cells ( CSCs) and epithelial-mesenchymal transition ( EMT). The mechanism underlying these processes needs to be further elucidated. Here, we report that TGF-β1, one of the key microenvironmental stimuli, can enhance CSC characteristics, facilitate the EMT, and induce CK17. Silencing CK17 expression attenuated CSC-like properties without affecting the EMT markers induced by TGF-β1, whereas forced overexpression of CK17 promoted lymphatic metastasis in vivo even without EMT inducement. Inhibitors of ERK1/2 signaling drastically decreased the induction of CK17 mediated by TGF-β1. By combined computational and experimental approaches, we identified and validated that MZF1 was a key transcription factor binding to the promoter of CK17. Taken together, these results demonstrate that CK17 induced by the TGF-β1- ERK1/2- MZF1 signaling pathway facilitates metastasis by promoting the acquisition of CSC properties rather than by inducing the EMT process in CC, suggesting that this CK17-related signaling pathway might be a suitable target for the development of therapy for CC metastasis. [ABSTRACT FROM AUTHOR]

Introduction Bevacizumab has been applied clinically to advanced and recurrent cervical cancer, after showing improved overall survival in the GOG 240 trial. We report two cases of patients with recurrent cervical cancer who showed remarkable decrease in pleural effusion by chemotherapy combined with bevacizumab. Case 1 A 41-year-old patient with stage IIB cervical adenocarcinoma who presented with cervical carcinoma recurrence in the lung and paraaortic/ supraclavicular lymph nodes after primary treatments with concurrent chemoradiotherapy (CCRT), total hysterectomy, and paclitaxel-carboplatin (TC) therapy. As symptomatic pleural effusion emerged after irinotecan-cisplatin therapy and radiotherapy, paclitaxel-cisplatin-bevacizumab (Pac-Cis-Bev) was administered and relieved the pleural effusion promptly and the respiratory distress and back pain symptoms over 13 months. Case 2 The second case involved a 53-year-old patient with stage IIIB cervical squamous cell carcinoma who had a pulmonary recurrence following treatment with CCRT. As pleural effusion emerged at the end of the six-month drug holiday, after a total of 21 cycles of TC or Pac-Cis-Bev therapy to treat the recurrence, topotecan-paclitaxel-bevacizumab (Topo-Pac-Bev) was administered. Respiratory distress was relieved in two weeks, and the pleural effusion disappeared almost completely after two months. The patient received 12 cycles of Topo-Pac-Bev, in total. Conclusion The present two patients have survived over three years, without problematic symptoms, after pulmonary recurrences with pleural effusion, despite that the three-year survival rate for recurrent/metastatic cervical cancer has been reported to be less than 5% without bevacizumab therapy. Chemotherapies that contain bevacizumab present promising regimens for recurrent cases with pleural effusion, despite the uncommon risks of bladder-vaginal or recto-vaginal fistulas. [ABSTRACT FROM AUTHOR]