Lili Zhang, Fang Zhao, Lin Zhang, Ke Jia, Xiaoli Liu, Ping Zhang
The tumor microenvironment, particularly M2-polarized tumor-associated macrophages (TAMs), plays a critical role in cervical cancer (CC) progression. Long non-coding RNAs (lncRNAs) are emerging as potential regulators of macrophage function. This study aimed to investigate the function and mechanism of the lncRNA GNAS-AS1 in M2-like TAMs and its impact on CC progression. M2 macrophages were isolated from clinical CC and adjacent normal tissues. In vitro polarization models were established using THP-1 cells treated with PMA, LPS/IFN-γ (M1), or IL-4 (M2). Functional assays (CCK-8, colony formation, Transwell) were used to assess cancer cell malignant phenotypes after co-culture with macrophages or their supernatants. Mechanistic studies included RNA pulldown, luciferase reporter assays, and western blot. Xenograft and metastatic mouse models were employed to validate the findings in vivo. GNAS-AS1 expression was found to be elevated in M2 TAMs isolated from CC tissues compared to other immune cells and normal tissue-derived M2 macrophages, and its expression correlated with M2 marker levels. In vitro, GNAS-AS1 knockdown attenuated the M2 phenotype, as evidenced by reduced expression of characteristic M2 markers and impaired ability to promote CC cell proliferation and migration. In vivo models showed that GNAS-AS1 knockdown in M2 macrophages suppressed tumor growth and metastasis. Mechanistically, data from binding and rescue experiments are consistent with a model whereby GNAS-AS1 may function by sequestering miR-518c-5p, leading to increased expression of its target, FBXO38, and associated changes in MAPK signaling. These findings suggest that GNAS-AS1 may contribute to the maintenance of M2-like characteristics in TAMs and facilitate CC progression, potentially through a mechanism involving miR-518c-5p sequestering, FBXO38 upregulation, and subsequent modulation of MAPK signaling.