Biology subjects

Mohapatra, I.

Publications and source records attributed to Mohapatra, I..

3 recordsLinked to original sources

bioRxiv2026

A SRC-Annexin A2 axis that couples membrane repair to microRNA export during radiation stress in glioblastoma

Repair of ionizing-radiation (IR)-induced membrane damage is essential for cell survival, and Annexin A2 (ANXA2) mediates this repair by promoting shedding of microvesicles containing both damaged lipid and ANXA2. Here, we show that coupling this process to microRNA export contributes to radiation resistance of glioblastoma, the most common adult brain cancer. Structural modeling and mutational analysis identify that ANXA2 tyrosine 23 (Y23) phosphorylation, required for its IR-induced localization to damaged membranes, is also essential for binding miR-603, a critical regulator of glioblastoma cell state. This binding is required for IR-induced miR-603 export, indicating that the repair program recruiting ANXA2 also positions it to load miR-603 into microvesicles. Mutations that abolish ROS-induced sulfenylation and activation of SRC (SRC-C185A/C245A) suppressed ANXA2-Y23 phosphorylation, microvesicle shedding, and miR-603 export. The epistatic interaction between ANXA2-Y23A, SRC-C185A/C245A, and miR-603 delineates a therapeutically targetable radiation-response network that couples membrane repair with miRNA export.

cancer biology↗

bioRxiv2025

Modulating populational variance of methyl-guanine methyl transferase expression through miR-181d degradation: a novel mechanism of temozolomide resistance

Intratumoral heterogeneity plays a pivotal role in cancer evolution, providing the substrate for adaptation to selective pressures, including treatment with chemotherapy. Here, we show that micro-RNA regulation of variance in the expression of the DNA repair protein methyl-guanine methyl transferase (MGMT) contributes to this heterogeneity and acquired therapeutic resistance. In cell lines derived from glioblastomas, the most common form of primary brain tumor, treatment with standard-of-care temozolomide chemotherapy triggers a feed-forward loop between polyribonucleotide nucleotidyltransferase 1 (PNPT1) and miR-181d, an MGMT regulating miRNA, expediting miR-181d degradation. This degradation requires the activation of Ataxia Telangiectasia and Rad3-related (ATR) kinase. The degradation of miR-181d in glioblastoma cells increased both the mean and the variance of MGMT expression in the cell population. Subclone reconstituted cell populations with similar populational mean MGMT levels but with differences in the variance of MGMT expression exhibited differential temozolomide sensitivity, with the higher MGMT variance population showing increased resistance. This resistance is suppressed by exogenously transfected miR-181d. These findings suggest a key role for miRNA in regulating intra-tumoral heterogeneity through modulation of key DNA repair enzymes and provide a compelling rationale for miRNA delivery as a platform for glioblastoma therapy. Significance StatementThis study demonstrates a mechanistic link between a feed-forward loop mediating microRNA degradation and cell-to-cell variance in gene expression, and the contribution of this mechanism to intratumoral heterogeneity and therapeutic resistance. We show that when glioblastoma, the most common form of adult primary brain tumor, is treated with standard-of-care chemotherapy, temozolomide, a feed-forward loop between miR-181d and PNPT1 is initiated, causing rapid degradation of miR-181d. This degradation increases the cell-to-cell variability in methyl-guanine methyl transferase (MGMT) expression, expanding intra-tumoral heterogeneity and contributing to acquired temozolomide resistance. This process can be suppressed by therapeutic delivery of microRNA, providing compelling considerations for clinical translation.

cancer biology↗

bioRxiv2025

Spatial differentiation of proteome in cervical cancer tissues using Imaging Mass Spectrometry

Cervical cancer, which is the fourth most common gynaecological cancer across the globe, has a poorly understood molecular pathogenesis and etiology. Current methods of diagnosis are based on cytology, histology and presence of Human Papillomavirus (HPV). Shortcomings of these methods lie with poor quality of smears which is very common in Papanicolaou (pap) smears, limited sensitivity in terms of early detection, dependence on presence of HPV, etc. Due to its high sensitivity and non-targeted approach, Matrix Assisted Laser Desorption Ionization based Imaging Mass Spectrometry (MALDI-IMS) might be advantageous to understand the pathogenesis, molecular mechanism, precise identification of surgical margins and identification of novel biomarkers. Since it can also identify proteins in the extracellular matrix, it is especially beneficial for the tissue types with sparse cells and excessive extracellular matrix. Although tissue proteome profiling for cervical cancer were reported, the heterogeneous distribution of proteins across cervical cancer tissues havent been explored. In this study, we employed a non-targeted MALDI-IMS based approach to profile the spatial distribution of proteins within cervical cancer tissues. We observed overexpression of Keratin 5 and Prelamin A/C in the region of cervical cancer tissues which were categorically labelled with cancerous morphology using histopathological examination. Both these proteins have been earlier associated with progression and aggressiveness of other cancers like breast and prostate cancers. However, no such reports are available for cervical cancer. Further studies are required on a large dataset to validate and quantitate these proteins as biomarkers for early diagnosis and prognosis of cervical cancer.

cancer biology↗