Jie Wang

Germline Mutational Landscape and Novel Targetable RAD51D Variant in Chinese Patients With Ovarian Cancer

PURPOSE Genetic variants of ovarian cancer (OV) show ethnic differences, but data from the Chinese population are still insufficient. Here, we elucidate the inheritance landscape in Chinese patients with OV and examine the functional implications of a Chinese-enriched RAD51D variant. METHODS Between 2015 and 2018, 373 consecutive patients with OV were prospectively enrolled. Variants of BRCA1/2, other homologous recombination repair (HRR) genes, and DNA mismatch repair (MMR) genes were analyzed using next-generation sequencing. An enriched RAD51D variant was identified, and its functional effects were examined using Cell Counting Kit-8, colony formation, transwell migration, and drug sensitivity assays. RESULTS Overall, 31.1% (116/373) of patients had at least one pathogenic or likely pathogenic germline variant. BRCA1 and BRCA2 accounted for 16.09% and 5.36%, respectively, with one patient having both variants. In addition, 32 (8.58%) patients carried other HRR gene variants, whereas three (0.8%) patients had MMR gene variants. The RAD51D variant ranked third (8/373, 2.1%), and its rate was much higher than that in other populations. Remarkably, all eight patients harbored the RAD51D K91fs variant (c.270_271dup, p.Lys91Ilefs*13) and demonstrated satisfactory platinum response and favorable prognosis. This variant confers enhanced sensitivity to poly (ADP-ribose) polymerase inhibitors in OV cells. However, the effects on platinum sensitivity were inconsistent across different cell lines. Against the background of the TP53 variant, RAD51D K91fs variant showed increased sensitivity to cisplatin. CONCLUSION Our study revealed the inheritance landscape of OV and identified an enriched RAD51D variant in Chinese patients with OV. This can serve as an important reference for OV management and a potential therapeutic target.

Identifying miRNA biomarkers for breast cancer and ovarian cancer: a text mining perspective

microRNA (miRNAs) are small, non-coding RNAs that mediate post-transcriptional gene silencing. Numerous studies have demonstrated the critical role of miRNAs in the development of breast cancer and ovarian cancer. To reduce potential bias from individual studies, a more comprehensive approach of exploring miRNAs in cancer research is essential. This study aims to explore the role of miRNAs in the development of breast cancer and ovarian cancer. Abstracts of the publications were tokenized and the biomedical terms (miRNA, gene, disease, species) were identified and extracted for vectorization. Predictive analyses were conducted with four machine learning models: K-Nearest Neighbors (KNN), Support Vector Machines (SVM), Random Forest (RF), and Naïve Bayes. Both holdout validation and cross-validation were utilized. Feature importance will be identified for miRNA-cancer networks construction. We found that miR-182 is highly specific to female cancers. miR-182 targets different genes in regulating breast cancer and ovarian cancer. Naïve Bayes provided a promising prediction model for breast cancer and ovarian cancer with miRNAs and genes combination, with an accuracy score greater than 60%. Feature importance identified miR-155 and miR-199 are critical for breast cancer and ovarian cancer prediction, with miR-155 being highly related to breast cancer, whereas miR-199 being more associated with ovarian cancer. Our approach effectively identified potential miRNA biomarkers associated with breast cancer and ovarian cancer, providing a solid foundation for generating novel research hypotheses and guiding future experimental studies.

MAP4K4 and WT1 mediate SOX6‐induced cellular senescence by synergistically activating the ATF2–TGFβ2–Smad2/3 signaling pathway in cervical cancer

SRY‐box transcription factor 6 (SOX6) is a member of the SOX gene family and inhibits the proliferation of cervical cancer cells by inducing cell cycle arrest. However, the final cell fate and significance of these cell‐cycle‐arrested cervical cancer cells induced by SOX6 remains unclear. Here, we report that SOX6 inhibits the proliferation of cervical cancer cells by inducing cellular senescence, which is mainly mediated by promoting transforming growth factor beta 2 (TGFB2) gene expression and subsequently activating the TGFβ2–Smad2/3–p53–p21WAF1/CIP1–Rb pathway. SOX6 promotes TGFB2 gene expression through the MAP4K4–MAPK (JNK/ERK/p38)–ATF2 and WT1–ATF2 pathways, which is dependent on its high‐mobility group (HMG) domain. In addition, the SOX6‐induced senescent cervical cancer cells are resistant to cisplatin treatment. ABT‐263 (navitoclax) and ABT‐199 (venetoclax), two classic senolytics, can specifically eliminate the SOX6‐induced senescent cervical cancer cells, and thus significantly improve the chemosensitivity of cisplatin‐resistant cervical cancer cells. This study uncovers that the MAP4K4/WT1–ATF2–TGFβ2 axis mediates SOX6‐induced cellular senescence, which is a promising therapeutic target in improving the chemosensitivity of cervical cancer.

Determination of Potential Therapeutic Targets and Prognostic Markers of Ovarian Cancer by Bioinformatics Analysis

This study is to study the expression of CXCRs in ovarian cancer tissues and their value in prognosis. The expressions of CXCR1‐CXCR7 mRNA between ovarian tumor tissues and normal tissues and in different pathological types of ovarian tumor tissues were compared by ONCOMINE online tool. The relationship between the expression of CXCRs and clinical pathological staging was studied by GEPIA. Kaplan‐Meier plotter online tool was used to analyze prognosis. Finally, GO and KEGG analyses and protein interaction network analysis were performed for CXCRs by the DAVID software to predict their function, and cBioPortal was used to identify the key functional genes. The expression of CXCR3/4/7 mRNA in ovarian cancer tissues was higher than that in normal ovarian tissues, and the expression of CXCR4 was the highest (fold change = 306.413, P < 0.05). The expression of CXCR1/2/3/4/7 mRNA in different pathological types of ovarian tumors was significantly different (P < 0.05). Only CXCR5 expression level was associated with tumor staging. Survival analysis showed that high CXCR7 mRNA expression and low CXCR5/6 expression were associated with the shortening of overall survival. High CXCR4/7 expression and low CXCR5/6 expression were associated with the shortening of progression‐free survival. High CXCR2/4 expression and low CXCR5/6 expression were closely related to the shortening of postprogressing survival. Protein interaction network analysis showed that GNB1, PTK2, MAPK1, PIK3CA, GNB4, GNA11, KNG1, and ARNT proteins were closely related to the CXC receptor family. CXCR3/4/7 are potential therapeutic targets, and CXCR2/4/5/6/7 are new markers for the prognosis of ovarian cancer.

MAP4K4 mediates the SOX6-induced autophagy and reduces the chemosensitivity of cervical cancer

AbstractThere are nearly 40% of cervical cancer patients showing poor response to neoadjuvant chemotherapy that can be induced by autophagy, however, the underlying mechanism has not yet been fully clarified. We previously found thatSex-determining region of Y-related high-mobility-group box 6(SOX6), a tumor suppressor gene or oncogene in several cancers, could induce autophagy in cervical cancer. Accordingly, this study aims to investigate the mechanism of SOX6-induced autophagy and its potential significance in the platinum-based chemotherapy of cervical cancer. Firstly, we found that SOX6 could promote autophagy in cervical cancer cells depending on its HMG domain.Mitogen-activated protein kinase kinase kinase kinase-4(MAP4K4) gene was identified as the direct target gene of SOX6, which was transcriptionally upregulated by binding the HMG domain of SOX6 protein to its double-binding sites withinMAP4K4gene promoter. MAP4K4 mediated the SOX6-induced autophagy through inhibiting PI3K-Akt-mTOR pathway and activating MAPK/ERK pathway. Further, the sensitivity of cervical cancer cells to cisplatin chemotherapy could be reduced by the SOX6-induced autophagy in vitro and in vivo, while such a phenomenon could be turned over by autophagy-specific inhibitor and MAP4K4 inhibitor, respectively. Moreover, cisplatin itself could promote the expression of endogenous SOX6 and subsequently the MAP4K4-mediated autophagy in cervical cancer cells, which might in turn reduce the sensitivity of these cells to cisplatin treatment. These findings uncovered the underlying mechanism and potential significance of SOX6-induced autophagy, and shed new light on the usage of MAP4K4 inhibitor or autophagy-specific inhibitor for sensitizing cervical cancer cells to the platinum-based chemotherapy.