PNMA5 Promotes Radiotherapy Resistance in Colorectal Cancer by Regulating Angiogenic Factor Secretion and Apoptosis

Abstract Colorectal cancer (CRC) is a frequent cancer in the digestive tract, and its occurrence and death rates are high all over the world, so it is a big health issue; PNMA5 can promote radiotherapy resistance in CRC, and it does so by regulating the release of angiogenic factors and cell death; this experiment used both cell and animal CRC models to verify the role of PNMA5. In this study, we generated PNMA5 models where we either overexpress or knock down genes in HT-29 cells. Six groups were included: HT- 29 control, HT- 29+RT, HT- 29- NC, HT- 29- si- PNMA5, HT- 29- OE- PNMA5, and HT- 29- OE- PNMA5+RT. TUNEL assay measures the level of apoptosis and apoptosis by flow cytometry. For paracrine proangiogenic capacity, we performed HUVEC tube formation assays and ELISA. In vivo. Tumor cells were put into nude mice, and these mice were treated with radiation; the purpose was to check how sensitive the tumors were to radiotherapy and to measure the density of micro vessels (MVD). To figure out which pathways PNMA5 controls downstream, we ran transcriptomic sequencing (RNA‑seq) followed by GSEA. The results show that in cell experiments, after receiving 18 Gy radiation, HT29 cells with PNMA5 overexpression grew more quickly and showed a lower death rate; Western blot analyses revealed that BCL‑2 expression was raised and BAX activation was inhibited by PNMA5; and ELISA together with tube formation assays confirmed that PNMA5 enhanced the secretion of VEGF, FGF‑1, and TGF‑β1, which then improved the tube‑formation ability of blood vessel endothelial cells. Inside a living organism, the growth rate and micro vessel density (MVD) of tumors in the OE‑PNMA5 group got significantly bigger than controls when exposed to radiotherapy. Transcriptomic sequencing further revealed that, PNMA5 does not directly activate the transcription of the VEGF gene. Instead, it activates STAT1 and IRF7, maintaining the interferon response and chemokine-related signals. This, in turn, alters the secretions of tumor cells, and through paracrine pathways, indirectly promotes angiogenesis, thereby causing radiotherapy resistance. Therefore, we can conclude that PNMA5 mediates radiotherapy resistance in colorectal cancer in two aspects. One is its synergistic effect with the intrinsic apoptosis inhibition of cells, and the other is its alteration of tumor secreted substances, which promotes angiogenesis through paracrine pathways; PNMA5 activates STAT1 and IRF7, thereby influencing the interconnection of the microenvironment and providing a new perspective for radiotherapy resistance.