Yi Shi

Nutrient stress diverts RRN3 from rRNA transcription to alternative polyadenylation of autophagy mRNAs in ovarian cancer

Abstract Stress-induced alternative processing of mRNA is emerging as an essential mechanism to drive almost every hallmark of cancer. Through a genome-wide screening based on an abnormal transcriptional readthrough event favoring the malignant progression of ovarian carcinoma (OC), we identified novel mRNA processing regulators including RRN3, an essential factor for the transcriptional initiation of rRNA. The long-read RNA sequencing and PAR-CLIP analyses revealed that RRN3 was involved in the usage of alternative polyadenylation (APA) sites, resulting in the altered stability of autophagy-related mRNAs. More interestingly, we discovered that nutrient-deprivation-induced phosphorylation of RRN3 at serine 199 was sufficient to divert RRN3 out of the nucleolus to the nuclear plasma, where RRN3 regulated the APA of autophagy mRNAs, such as OPTN, to enhance their stability and eventually promoted autophagy. Further in vivo experiments showed that nutrient-stress-triggered switch of RRN3 from rRNA transcription to APA regulation was essential for the growth and dissemination of OC in mice.

The association between human papillomavirus infection, vaginal microecology, and cervical intraepithelial neoplasia in women from Xinjiang, China

AbstractPurposeThis study analyzes the relationship between human papillomavirus (HPV) infection, vaginal microecology, and cervical lesions to provide a basis for the prevention and treatment of cervical cancer (CC) in the Xinjiang region.MethodsReal‐time quantitative PCR was used for HPV genotyping and viral load. The Gram staining and dry biochemical enzyme kit were utilized to diagnose vaginal secretions. The χ2 test and Logistic regression analysis were used for statistical analysis.ResultsThe HPV infection rate among women in the Xinjiang region was 30.29%, of which the single HPV infection accounts for 77%. HPV16 and HPV52 were the main infection types. There was significant differences in the HPV infection rate and infection types among the Han, Uighur, Hui, and Kazakh ethnic groups. The viral load of HPV16 and HPV52 increases with the upgrade of cervical lesions. There were significant differences in vaginal microecology evaluation indicators H2O2, SNA, LE, GUS, trichomonas, clue cells, and lactobacilli among different ethnic groups. HPV negative patients with varying grades of cervical lesions exhibit a notable variance in H2O2 and LE, which is statistically significant. Single HPV infection and high viral load HPV significantly increase the risk of CC.ConclusionsThis study indicates that HPV infection and vaginal microecology differ among ethnic groups, which have a strong correlation with the progression of CC, offering guidance on CC screening and interventions in the Xinjiang area.

A systematic CRISPR screen reveals an IL-20/IL20RA-mediated immune crosstalk to prevent the ovarian cancer metastasis

Transcoelomic spread of cancer cells across the peritoneal cavity occurs in most initially diagnosed ovarian cancer (OC) patients and accounts for most cancer-related death. However, how OC cells interact with peritoneal stromal cells to evade the immune surveillance remains largely unexplored. Here, through an in vivo genome-wide CRISPR/Cas9 screen, we identified IL20RA, which decreased dramatically in OC patients during peritoneal metastasis, as a key factor preventing the transcoelomic metastasis of OC. Reconstitution of IL20RA in highly metastatic OC cells greatly suppresses the transcoelomic metastasis. OC cells, when disseminate into the peritoneal cavity, greatly induce peritoneum mesothelial cells to express IL-20 and IL-24, which in turn activate the IL20RA downstream signaling in OC cells to produce mature IL-18, eventually resulting in the polarization of macrophages into the M1-like subtype to clear the cancer cells. Thus, we show an IL-20/IL20RA-mediated crosstalk between OC and mesothelial cells that supports a metastasis-repressing immune microenvironment.

Metabolic Gatekeeper ACAD9 Coordinates Linoleic Acid Metabolism and Redox Homeostasis via Mitochondrial Complex I to Drive Ovarian Cancer Progression.

Balancing high metabolic activity with redox homeostasis is crucial for cancer progression, particularly in high-grade serous ovarian cancer (HGSOC), which thrives in a lipid-rich environment abundance in free fatty acids, yet the key molecular regulators of this balance remain undefined. Through an in vivo genome-wide CRISPR/Cas9 knockout screen in an orthotopic ovarian cancer (OC) mouse model, we identify ACAD9 as a pivotal driver of OC progression, with its elevated expression correlating with poor patient prognosis. Multi-omics integration analysis and mechanism studies reveal ACAD9's dual role in maintaining OC metabolic homeostasis. ACAD9 preserves electron transport chain integrity and regulates linoleic acid (LA) metabolism to sustain energy production while mitigating oxidative stress. ACAD9 deficiency triggers mitochondrial respiratory collapse, inducing metabolic crisis marked by oxidative phosphorylation failure and reactive oxygen species (ROS) accumulation. Strikingly, under LA-enriched condition, ACAD9 loss redirects LA flux from β-oxidation toward membrane lipid biosynthesis, increasing polyunsaturated fatty acids incorporation. This membrane remodeling synergizes with ROS overload to create a "perfect storm" triggering ferroptosis. Our findings elucidate the dual metabolic guardianship of ACAD9 in OC, demonstrating its critical role in orchestrating mitochondrial respiration and lipid homeostasis to evade ferroptosis, which offer a potential target for the treatment of OC.