Cervical cancer, which is a significant public health concern in women, currently lacks effective therapeutic drugs. Matrine, a constituent of the traditional Chinese herb Sophora flavescentis Radix, is known for its anti-cervical cancer properties and ability to induce programmed cell death. The induction of cancer cell ferroptosis, which is a novel cell death pattern, can become an effective clinical therapy for tumor in the future. However, the effect of matrine on ferroptosis in cervical cancer remains to be elucidated. In this study, we investigated whether matrine induces ferroptosis in cervical cancer and elucidated the underlying mechanisms. We established an SiHa-derived tumor-bearing mouse model using CB17 severe combined immunodeficient (SCID) mice and administered a group of matrine (25, 50, and 75 mg/kg) and cisplatin (2 mg/kg). We meticulously tracked alterations in body weight and tumor size and evaluated liver and kidney health using haematoxylin and eosin (H&E) staining. Using Gene Expression Omnibus (GEO) Dataset (GSE201309), we evaluated the relationship between the effects of matrine on malignant tumor cells and ferroptosis. In vitro, tetrazolium-based colorimetric (MTT), lactate dehydrogenase (LDH) and colony formation assays were used to study the effects of matrine on SiHa cell activity and cytotoxicity. We assessed ferroptosis-related protein abundance using western blotting and ferroptosis-related indices in cells using confocal immunofluorescence microscopy. The interaction of matrine with a protein linked to ferroptosis was studied using cellular thermal shift assay (CETSA). The effects of matrine on Piezo1 expression were investigated using calcium imaging. We also used Piezo1-specific siRNA to explore the role of Piezo1 in ferroptosis. Matrine administration effectively inhibited tumor growth in a SiHa-derived tumor-bearing mouse model without inducing noticeable harm. The analysis results of GEO data set show matrine-induced effects in tumor cells were indeed involved in the process of ferroptosis. Treatment with matrine resulted in a significant reduction in GPX4 protein levels and a concurrent increase in lipid peroxide and Fe²⁺ content, suggesting matrine-induced modulation of ferroptosis. Matrine promoted SiHa cell death in vitro, as evidenced by the results of MTT and LDH assays. Cell death coincides with increases in intracellular Fe²⁺, reactive oxygen species (ROS), and lipid peroxides. Our study also revealed significant upregulation of Piezo1 expression through the action of matrine, whereas transferrin receptor (Tfr) and System Xc- (xCT) expression and interaction remained unaffected. We provided further evidence that matrine induces calcium influx through the Piezo1 channel, thereby potentially influencing ferroptosis. Transfection with Piezo1 siRNA reversed the effects of matrine in SiHa cell. Our findings indicate that matrine exerts a protective effect against cervical cancer by inducing ferroptosis through the activation of Piezo1, but not xCT or Tfr.

PIWI-interacting RNAs (piRNAs) are a type of non-coding RNAs that interact with PIWI proteins, which are members of the argonaute family. Originally described in the germline, piRNAs are also expressed in human somatic cells in a tissue-specific manner. piRNAs are involved in spermatogenesis, germ stem-cell maintenance, silencing of transposon, epigenetic and genomic regulation and rearrangement. A large number of studies have demonstrated that expression of piRNAs is involved in many kinds of disease, including cancer. Abnormal expression of piRNAs is emerging as a critical player in cancer cell proliferation, apoptosis, invasion, and migration in vitro and in vivo. Functionally, piRNAs maintain genomic integrity by repressing the mobilization of transposable elements, and regulate the expression of downstream target genes via transcriptional or post-transcriptional mechanisms. Furthermore, altered expression of piRNAs in cancer is linked to clinical outcome, highlighting the important role that they may play as novel diagnostic and prognostic biomarkers, and as therapeutic targets for cancer therapy. In this review, we focus on the biogenesis and the functional roles of piRNAs in cancers, discuss emerging insights into the roles of piRNAs in the occurrence, progression, and treatment of cancers, reveal various mechanisms underlying piRNAs-mediated gene regulation, and highlight their potential clinical utilities as biomarkers as well as potential targets for cancer treatment.

Background: Shikonin, the main ingredient of Lithospermum erythrorhizon, has been reported to have antitumor effects via multiple targets and signaling pathways. However, the detailed mechanism underlying the effects in cervical cancer still remained unknown. Methods: MTT, wound-healing, transwell assays and flow cytometry experiments were used to measure cell growth, migration, invasion, and cell cycle analysis. Western blot was used to examine protein levels of Snail, Vimentin and E-cadherin. The expression level of miR-183-5p was measured via qRT-PCR. The E-cadherin promoter activity was detected via Secrete-PairTM Dual Luminescence Assay Kit. The transient transfection experiments were used for silencing of E-cadherin and overexpression of Snail genes. Tumor xenograft and bioluminescent imaging experiments were carried out to confirm the in vitro findings. Results: We showed that shikonin inhibited cell viability, migration and invasion, and induced cell cycle arrest in a dose-dependent manner in cervical cancer Hela and C33a cells. Mechanistically, we found that shikonin increased miR-183-5p expression and inhibited expression of transcription factor Snail protein. The mimics of miR-183-5p reduced, while the inhibitors of miR-183-5p reversed shikonin-inhibited Snail protein expression. In addition, shikonin decreased Vimentin, increased E-cadherin protein expressions and E-cadherin promoter activity, the latter was reversed in cells transfected with exogenous Snail overexpression vectors. Moreover, silencing of E-cadherin significantly abolished shikonin-inhibited cervical cancer cell growth. Similar findings were also observed in vivo using one xenograft mouse model. Conclusion: Our results show that shikonin inhibits EMT through inhibition of Snail and stimulation of miR-183-5p expressions, which resulted in induction of E-cadherin expression. Thus, blockade of EMT could be a novel mechanism underlying the anti-cervical cancer effects of shikonin.

Non-coding RNAs (ncRNAs) have received significant attention over the last few years. Malat1, as one of the most extensively studied ncRNAs, is believed to be not only a potential biomarker for disease diagnosis and prognosis, but also a candidate drug target for gynecological cancers. This potential is supported by a growing body of experimental evidence demonstrating that Malat1 participates in the occurrence, progression, and metastasis of tumors. Research has also shown that Malat1 can influence patient survival by regulating a range of target genes and signaling pathways. However, previous review articles have generally failed to consider the role of Malat1 in gynecological cancer in detail. In the present review, we summarize recent progress in research relating to the clinical relevance of Malat1 and the molecular mechanisms underlying the action of this ncRNA. Besides, we put forward some action points for further research after taking into consideration the sub-location and other essential properties of Malat1, which might enable us to have a better understanding of the potential of this molecule regarding clinical diagnosis and treatment.