Cervical cancer (CC) with early metastasis of the primary tumor results in poor prognosis and poor therapeutic outcomes. MicroRNAs (miRNAs) are small, noncoding RNA molecules that play a substantial role in regulating gene expression post-transcriptionally and influence the development and progression of tumors. Numerous studies have discovered that miRNAs play significant roles in the invasion and metastasis of CC by affecting specific pathways, including Notch, Wnt/β-catenin, and phosphoinositide-3 kinase (PI3K)-Akt pathways. miRNAs also effectively modulate the process of epithelial-mesenchymal transition. Many studies provide new insights into the role of miRNAs and the pathogenesis of metastatic CC. In this review, we will offer an overview and update of our present understanding of the potential roles of miRNAs in metastatic CC.

The role of miRNAs in the invasion and metastasis of cervical cancer.

Esophageal squamous cell carcinoma (ESCC) is one of the most common and aggressive malignancies in China. Cancer-associated fibroblasts (CAFs) can actively communicate with and stimulate tumor cells, thereby contributing to the development and progression of tumors. Yet, whether CAFs-derived exosomes have a role in the progression of ESCC is largely unknown. Here, we find that Sonic Hedgehog (SHH) is highly expressed in CAFs lysis solution, conditioned medium of cultured CAFs (CAF-CM) and CAFs-derived exosomes, and esophageal cancer cell lines educated by CAF-CM and CAFs-derived exosomes can improve their growth and migration abilities in vitro and in vivo. Besides, those effects can be partly neutralized by cyclopamine, inhibitor of the Hedgehog signaling pathway. Thus, our research elucidates the crucial role of CAFs-derived exosomes in the growth and progression of ESCC, and may open up new avenues in the treatment of ESCC.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.2873

Exosomal Sonic Hedgehog derived from cancer-associated fibroblasts promotes proliferation and migration of esophageal squamous cell carcinoma.

Chemosensitivity is one of the key factors affecting the therapeutic effect on cancer, but the clinical application of corresponding drugs is rare. Hypoxia, a common feature of many solid tumors, including hepatocellular carcinoma (HCC), has been associated with resistance to chemotherapy in part through the activation of the Sonic Hedgehog (SHh) pathway. Hypoxia has also been associated with the increased SUMOylation of multiple proteins, including GLI family proteins, which are key mediators of SHh signaling, and has become a promising target to develop drug-resistant drugs for cancer treatment. However, there are few target drugs to abrogate chemotherapy resistance. Saikosaponin-d (Ssd), one of the main bioactive components of Radix bupleuri, has been reported to exert multiple biological effects, including anticancer activity. Here, we first found that Ssd inhibits the malignant phenotype of HCC cells while increasing their sensitivity to the herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) drug system under hypoxia in vitro and in vivo. Furthermore, we had explored that GLI family activation and extensive protein SUMOylation were characteristics of HCC cells, and hypoxia could activate the SHh pathway and promote epithelial-mesenchymal transition (EMT), invasion, and chemosensitivity in HCC cells. SUMOylation is required for hypoxia-dependent activation of GLI proteins. Finally, we found that Ssd could reverse the effects promoted by hypoxia, specifically active sentrin/small ubiquitin-like modifier (SUMO)-specific protease 5 (SENP5), a SUMO-specific protease, in a time- and dose-dependent manner while inhibiting the expression of SUMO1 and GLI proteins. Together, these findings confirm the important role of Ssd in the chemoresistance of liver cancer, provide some data support for further understanding the molecular mechanisms of Ssd inhibition of malignant transformation of HCC cells, and provide a new perspective for the application of traditional Chinese medicine in the chemical resistance of liver cancer.

/pdf/saikosaponin-d-inhibits-the-hepatoma-cells-and-enhances-42vccnazxp.pdf

Saikosaponin-d Inhibits the Hepatoma Cells and Enhances Chemosensitivity Through SENP5-Dependent Inhibition of Gli1 SUMOylation Under Hypoxia.

Resistance to therapy and metastasis remains one of the leading causes of mortality due to cervical cancer despite advances in detection and treatment. The mechanism of epithelial to mesenchymal transition (EMT) provides conceptual explanation to the invasiveness and metastatic spread of cancer but it has not been fully understood in cervical cancer. This study aims to investigate the mechanism by which silencing of E-cadherin gene regulates EMT leading to proliferation, invasion, and chemoresistance of cervical cancer cells through the Hedgehog (Hh) signaling pathway. We developed an in vitro EMT model by the knockdown of E-cadherin expression in cervical cancer cell lines. To understand the role of developmental pathway like Hh in the progression of cervical cancer, we investigated the expression of Hh pathway mediators by array in E-cadherin low cervical cancer cells and observed upregulation of Hh pathway. This was further validated on low passage patient-derived cell lines and cervical carcinoma tissue sections from cervical cancer patients. Further, we evaluated the role of two inhibitors (cyclopamine and GANT58) of the Hh pathway on invasiveness and apoptosis in E-cadherin low cervical cancer cells. In conclusion, we observed that inhibition of Hh pathway with GANT58 along with current therapeutic procedures could be more effective in targeting drug-resistant EMT cells and bulk tumor cells in cervical cancer.

Sonic hedgehog pathway activation regulates cervical cancer stem cell characteristics during epithelial to mesenchymal transition.

Backgrounds The purpose of this study was to investigate clinical role and functional effects of miR-431 expression in papillary thyroid carcinoma (PTC). Methods Expression of miR-431 in PTC patient tissue samples and plasma samples was examined by using qRT-PCR methods. Cell migration and invasion capacity were evaluated using transwell assays. Western blot analysis was performed to detect protein expression after miR-431 overexpression in PTC cells. Results We demonstrated that miR-431 expression was lower in PTC tissues and plasma samples compared to their corresponding controls. MiR-431 expression was particularly lower in PTC patients with lymph node (LN) metastasis. In vitro, miR-431 overexpression significantly inhibited cell migration, invasion and EMT process by upregulating E-cadherin and downregulating Vimentin expression. Additionally, wedemonstrated that miR-431 overexpression suppressed Hedgehog (Hh) signaling pathway by downregulating Gli1 expression. Conclusion Our results indicated that miR-431 could serve as a predictor for PTC patients with positive lymph node metastasis and a potential target of PTC treatment.

Downregulation of MiR-431 expression associated with lymph node metastasis and promotes cell invasion in papillary thyroid carcinoma.

Ovarian cancer (OC) is the leading cause of cancer-related death among all gynecological tumors. N6-methyladenosine (m6A)-related regulators play essential roles in various tumors, including OC. However, the expression of m6A RNA methylation regulators and the related regulatory network in OC and their correlations with prognosis remain largely unknown. In the current study, we obtained the genome datasets of OC from GDC and GTEx database and analyzed the mRNA levels of 21 key m6A regulators in OC and normal human ovarian tissues. The expression levels of 7 m6A regulators were lower in both the OC tissues and the high-stage group. Notably, the 5-year survival rate of patients with OC presenting low VIRMA expression or high HNRNPA2B1 expression was higher than that of the controls. Next, a risk score model based on the three selected m6A regulators (VIRMA, IGF2BP1, and HNRNPA2B1) was built by performing a LASSO regression analysis, and the moderate accuracy of the risk score model to predict the prognosis of patients with OC was examined by performing ROC curve, nomogram, and univariate and multivariate Cox regression analyses. In addition, a regulatory network of miRNAs-m6A regulators-m6A target genes, including 2 miRNAs, 3 m6A regulators, and 47 mRNAs, was constructed, and one of the pathways, namely, miR-196b-5p-IGF2BP1-PTEN, was initially validated based on bioinformatic analysis and assay verification. These results demonstrated that the risk score model composed of three m6A RNA methylation regulators and the related network of miRNAs-m6A regulators-m6A target genes is valuable for predicting the prognosis of patients with OC, and these molecules may serve as potential biomarkers or therapeutic targets in the future.

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A Risk Score Model Incorporating Three m6A RNA Methylation Regulators and a Related Network of miRNAs-m6A Regulators-m6A Target Genes to Predict the Prognosis of Patients With Ovarian Cancer.

The study aimed to investigate the mechanism by which the sonic Hedgehog (SHH) gene silencing acts upon epithelial-mesenchymal transition (EMT), proliferation, invasion, and migration of cervical cancer (CC) cells via the Hedgehog signaling pathway. RT-qPCR and Western blotting were all employed to detect the SHH mRNA and protein expressions. HeLa and CasKi cells were cultured and subsequently divided into the blank, negative control (NC), and SHH-RNAi groups. A cell counting kit-8 (CCK-8) assay was utilized for cell proliferation. Cell migration and invasion ability were evaluated through scratching test and Transwell assay. The mRNA and protein expressions of the Hedgehog signaling pathway-related factors were detected using RT-qPCR and Western blotting, respectively. After tumor xenograft in nude mice, tumor growth was subsequently observed. SHH mRNA and protein expressions were greater in the SHH-RNAi group than in the blank and NC groups. Compared with the blank group and NC groups, the SHH-RNAi group displayed inhibited levels of proliferation, migration, invasion abilities, as well as a decreased in the Hh signaling pathway-related factors, as well as a reduction in the mRNA and protein expressions of N-cadherin and Vimentin, however, on the contrary increased expressions of E-cadherin were observed. Following tumor xenograft in nude mice, tumor growth was exhibited vast levels of inhibition, particularly in the SHH-RNAi group in comparison to the blank and the NC groups. During the study it was well established that SHH gene silencing suppresses EMT, proliferation, invasion, and migration of CC cells through the repression of the Hedgehog signaling pathway.

SHH gene silencing suppresses epithelial-mesenchymal transition, proliferation, invasion, and migration of cervical cancer cells by repressing the hedgehog signaling pathway.

Chen-Chen Ren

Papers

A Risk Score Model Incorporating Three m6A RNA Methylation Regulators and a Related Network of miRNAs-m6A Regulators-m6A Target Genes to Predict the Prognosis of Patients With Ovarian Cancer.

SHH gene silencing suppresses epithelial-mesenchymal transition, proliferation, invasion, and migration of cervical cancer cells by repressing the hedgehog signaling pathway.