Yao Zhang

Endoplasmic reticulum stress-driven LncRNA signature predicts cervical cancer prognosis and guides personalized immunotherapy: a multi-omics and functional validation study

Abstract Endoplasmic reticulum (ER) stress is a key driver of tumor progression and therapeutic resistance. However, the prognostic role of ER stress-related long non-coding RNAs (lncRNAs) in cervical cancer has not been systematically elucidated. In this study, an ER stress-related lncRNA signature was constructed to evaluate patient prognosis and therapeutic responsiveness. Transcriptomic datasets derived from The Cancer Genome Atlas and the Genotype-Tissue Expression project were integrated, leading to the identification of 197 ER stress-associated differentially expressed genes and 1077 co-expressed lncRNAs. A prognostic 8-lncRNA model was developed using univariate/multivariate Cox regression and least absolute shrinkage and selection operator analysis. The model was validated by survival analysis (Kaplan–Meier and receiver operating characteristic curves), immune infiltration profiling (CIBERSORT and single-sample gene set enrichment analysis), and drug sensitivity analysis. Patients classified into the high-risk category showed significantly shorter overall survival (OS) (log-rank P < .001) and higher chemosensitivity to PI3K/mTOR inhibitors, whereas the low-risk group showed high immune activity (CD8+ T-cell infiltration and checkpoint expression) along with improved responsiveness to Wnt pathway inhibitors. The predictive capacity of the model (area under the curve, AUC: 0.806–0.856) exceeded that of conventional clinical parameters. Functional validation further revealed that LIPE-AS1, a representative high-risk lncRNA, promotes cervical cancer cell proliferation, migration, and invasion. These results introduce a novel ER stress-associated lncRNA signature with prognostic and therapeutic value, thus providing a potential basis for personalized immunotherapeutic and chemotherapeutic strategies in cervical cancer.

Long Noncoding RNA KCNMB2-AS1 Stabilized by N6-Methyladenosine Modification Promotes Cervical Cancer Growth Through Acting as a Competing Endogenous RNA

Long noncoding RNA (lncRNA) is emerging as an essential regulator in the development and progression of cancer, including cervical cancer (CC). In this study, we found a CC-related lncRNA, KCNMB2-AS1, which was significantly overexpressed in CC and linked to poor outcomes. Depletion of KCNMB2-AS1 remarkably inhibited CC cell proliferation and induced apoptosis. In vivo xenograft models revealed that knockdown of KCNMB2-AS1 evidently delayed tumor growth. Mechanistically, KCNMB2-AS1 was predominantly located in the cytoplasm and served as a competing endogenous RNA to abundantly sponge miR-130b-5p and miR-4294, resulting in the upregulation of IGF2BP3, a well-documented oncogene in CC. Moreover, IGF2BP3 was able to bind KCNMB2-AS1 by three N6-methyladenosine (m6A) modification sites on KCNMB2-AS1, in which IGF2BP3 acted as an m6A “reader” and stabilized KCNMB2-AS1. Thus, KCNMB2-AS1 and IGF2BP3 formed a positive regulatory circuit that enlarged the tumorigenic effect of KCNMB2-AS1 in CC. Together, our data clearly suggest that KCNMB2-AS1 is a novel oncogenic m6A-modified lncRNA in CC, targeting KCNMB2-AS1 and its related molecules implicate the therapeutic possibility for CC patients.

Retracted: Long non‐coding RNA ARAP1‐AS1 promotes tumorigenesis and metastasis through facilitating proto‐oncogene c‐Myc translation via dissociating PSF/PTB dimer in cervical cancer

AbstractLong non‐coding RNA (lncRNA) is emerging as a pivotal regulator in tumorigenesis and aggressive progression. Here, we focused on an oncogenic lncRNA, ARAP1 antisense RNA 1 (ARAP1‐AS1), which was notably upregulated in cervical cancer (CC) tissues, cell lines and serum. High ARAP1‐AS1 expression was closely associated with larger tumor size, advanced FIGO stage as well as lymph node metastasis. Importantly, it was identified as an effective diagnostic and prognostic biomarker for CC. In vitro and in vivo assays showed that knockdown of ARAP1‐AS1 inhibited, while overexpression of ARAP1‐AS1 promoted CC cell growth and dissemination. Stepwise mechanistic dissection unveiled that ARAP1‐AS1 could directly interact with PSF to release PTB, resulting in accelerating the internal ribosome entry site (IRES)‐driven translation of proto‐oncogene c‐Myc, thereby facilitating CC development and progression. Moreover, c‐Myc was able to transcriptionally activate ARAP1‐AS1 by directly binding to the E‐box motif located on ARAP1‐AS1 promoter. Taken together, our findings clearly reveal the crucial role of ARAP1‐AS1 in CC tumorigenesis and metastasis via regulation of c‐Myc translation, targeting ARAP1‐AS1 and its related regulatory loop implicates the therapeutic possibility for CC patients.