Temozolomide (TMZ) resistance is a major cause of recurrence and poor prognosis in glioblastoma (GBM). Recently, increasing evidences suggested that long noncoding RNAs (LncRNAs) modulate GBM biological processes, especially in resistance to chemotherapy, but their role in TMZ chemoresistance has not been fully illuminated. Here, we found that LncRNA SOX2OT was increased in TMZ-resistant cells and recurrent GBM patient samples, and abnormal expression was correlated with high risk of relapse and poor prognosis. Knockdown of SOX2OT suppressed cell proliferation, facilitated cell apoptosis, and enhanced TMZ sensitivity. In addition, we identified that SOX2OT regulated TMZ sensitivity by increasing SOX2 expression and further activating the Wnt5a/β-catenin signaling pathway in vitro and in vivo. Mechanistically, further investigation revealed that SOX2OT recruited ALKBH5, which binds with SOX2, demethylating the SOX2 transcript, leading to enhanced SOX2 expression. Together, these results demonstrated that LncRNA SOX2OT inhibited cell apoptosis, promoted cell proliferation, and TMZ resistance by upregulating SOX2 expression, which activated the Wnt5a/β-catenin signaling pathway. Our findings indicate that LncRNA SOX2OT may serve as a novel biomarker for GBM prognosis and act as a therapeutic target for TMZ treatment.

Astrocytes are critical for ischemic stroke, and understanding their role in mesenchymal stem cell (MSC)-mediated protection against ischemic injury is important. The paracrine capacity of MSCs has been proposed as the principal mechanism contributing to the protection and repair of brain tissue. In the present study, an in vitro oxygen-glucose deprivation (OGD) model was used to mimic ischemic injury. OGD-induced astrocytes were reperfused with MSC-conditioned medium (MSC-CM) or co-cultured with MSCs for 24 h to create an environment abundant in paracrine factors. The results indicated that both situations could protect astrocytes from apoptosis, increase cell metabolic activity, and reduce glial fibrillary acidic protein (GFAP) overexpression; however, the effects of co-culturing with MSCs were more positive. Paracrine factors suppressed the activation of p38 MAPK, JNK, and their downstream targets p53 and STAT1. Inhibition of p38 MAPK, JNK, p53, and STAT1 attenuated astrocyte injury and/or GFAP upregulation. Activation of p38 MAPK and JNK suppressed the beneficial effects of paracrine factors, resulting in decreased survival and GFAP overexpression. These results suggest that paracrine factors inhibit p38 MAPK and JNK, and most likely by regulating their downstream targets, p53 and STAT1, to promote astrocyte survival associated with GFAP downregulation after ischemic stroke in vitro.

Temozolomide (TMZ) and radiation therapy combination for glioblastoma (GB) patients has been considered as the most effective therapy after surgical procedure. However, the overall clinical prognosis remains unsatisfactory due to intrinsic or developing resistance to TMZ. Recently, increasing evidence suggested that long noncoding RNAs (lncRNAs) play a critical role in various biological processes of tumors, and have been implicated in resistance to various drugs. However, the role of lncRNAs in TMZ resistance is poorly understood. Here, we found that the expression of lncRNA AC003092.1 was markedly decreased in TMZ resistance (TR) of GB cells (U87TR and U251TR) compared with their parental cells (U87 and U251). In patients with glioma, low levels of lncRNA AC003092.1 were correlated with increased TMZ resistance, higher risk of relapse, and poor prognosis. Overexpression of lncRNA AC003092.1 enhances TMZ sensitivity, facilitates cell apoptosis, and inhibits cell proliferation in TMZ-resistant GB cells. In addition, we identified that lncRNA AC003092.1 regulates TMZ chemosensitivity through TFPI-2-mediated cell apoptosis in vitro and in vivo. Mechanistically, further investigation revealed that lncRNA AC003092.1 regulates TFPI-2 expression through miR-195 in GB. Taken together, these data suggest that lncRNA AC003092.1 could inhibit the function of miR-195 by acting as an endogenous CeRNA, leading to increased expression of TFPI-2; this promotes TMZ-induced apoptosis, thereby making GB cells more sensitive to TMZ. Our findings indicate that overexpression of lncRNA AC003092.1 may be a potential therapy to overcome TMZ resistance in GB patients.

Resistance to temolozomide (TMZ), the standard chemotherapy agent for treating glioblastomas (GBM), is a major clinical problem for patients with GBM. Recently, long noncoding RNAs (lncRNAs) have been implicated in chemotherapy resistance in various cancers. In this study, we found that the level of the lncRNA RP11-838N2.4 was lower in TMZ-resistant GBM cells (U87TR, U251TR) compared to the parental, non-resistant GBM cells (U87, U251). In GBM patients, the decreased level of lncRNA RP11-838N2.4 correlated with higher risk of GBM relapse, as well as shorter postoperative survival times. We further found that lncRNA RP11-838N2.4 could enhances the cytotoxic effects of temozolomide to GBM cells both in vivo and in vitro. Moreover, lncRNA RP11-838N2.4 acts as an endogenous sponge, suppressing the function of miR-10a through conserved sequences and increasing the expression of EphA8 that enhanced the rate of cell apoptosis, thereby intensified sensitivity of GBM cells to TMZ. Additionally, lncRNA RP11-838N2.4 inhibited the activity of transforming growth factor-β (TGF-β) independent of miR-10a. Finally, Characterization of lncRNA RP11-838N2.4 could contribute to strategies for enhancing the efficacy of TMZ.

Limited benefits and clinical utility of temozolomide (TMZ) for glioblastoma (GB) are frequently compromised by the development of acquired drug resistance. Overcoming TMZ resistance and uncovering the underlying mechanisms are challenges faced during GB chemotherapy. In this study, we reported that connective tissue growth factor (CTGF) was associated with GB chemoresistance and significantly upregulated in TMZ-treated GB cells. CTGF knockdown promoted TMZ-induced cell apoptosis and enhanced chemosensitivity, whereas its overexpression markedly conferred TMZ resistance in vitro and in vivo. Moreover, CTGF promoted TMZ resistance through stem-like properties acquisition and CD44 interference reversed the CTGF-induced TMZ resistance. Mechanistically, further investigation revealed that the TMZ-induced CTGF upregulation was tissue growth factor (TGF-β) dependent, and regulated by TGF-β1 activation through Smad and ERK1/2 signaling. Together, our results suggest a pivotal role of CTGF-mediated TMZ resistance through TGF-β1-dependent activation of Smad/ERK signaling pathways. These data provide us insights for identifying potential targets that are beneficial for overcoming TMZ resistance in GB.