Fstl1 Promotes Glioma Growth Through the BMP4/Smad1/5/8 Signaling Pathway

Abstract

Background: Gliomas result in the highest morbidity and mortality rates of intracranial primary central nervous system tumors because of their aggressive growth characteristics and high postoperative recurrence. They are characterized by genetic instability, intratumoral histopathological variability and unpredictable clinical behavior in patients. Proliferation is a key aspect of the clinical progression of malignant gliomas, complicating complete surgical resection and enabling tumor regrowth and further proliferation of the surviving tumor cells. Methods: The expression of Fstl1 was detected by western blotting and qRT-PCR. We used cell proliferation and colony formation assays to measure proliferation. Then, flow cytometry was used to analyze cell cycle progression. The expression of Fstl1, p-Smad1/5/8 and p21 in GBM tissue sections was evaluated using immunohistochemical staining. Furthermore, we used coimmunoprecipitation (Co-IP) and immunoprecipitation to validate the relationship between Fstl1, BMP4 and BMPR2. Finally, we used orthotopic xenograft studies to measure the growth of tumors in vivo. Results: We found that follistatin-like 1 (Fstl1) was upregulated in high-grade glioma specimens and that its levels correlated with poor prognosis. Fstl1 upregulation increased cell proliferation, colony formation and cell cycle progression, while its knockdown inhibited these processes. Moreover, Fstl1 interacted with bone morphogenetic protein (BMP) 4, but not BMP receptor (BMPR) 2, and competitively inhibited their association. Furthermore, Fstl1 overexpression suppressed the activation of the BMP4/Smad1/5/8 signaling pathway, while BMP4 overexpression reversed this effect. Conclusion: Our study demonstrated that Fstl1 promoted glioma growth through the BMP4/Smad1/5/8 signaling pathway, and these findings suggest potential new glioblastoma treatment strategies.

Entry and exit of chemotherapeutically-promoted cellular dormancy in glioblastoma cells is differentially affected by the chemokines CXCL12, CXCL16, and CX3CL1

“…Apart from this, upregulation of FSTL1, a homolog of FSTL3, increased the TMZ resistance of GBM cells [67] and was correlated with proliferation and colony formation [68]. FSTL3 is a secreted glycoprotein involved in the regulation of various biological effects through its binding to members of the TGFβ superfamily.…”

Integrated TCGA and GEO analysis showed that SMAD7 is an independent prognostic factor for lung adenocarcinoma.

“…For SMAD5, it has been reported that miR-145 can promote the migration and migration of esophageal cancer cells by inhibiting the expression of SMAD5 [40]. Fstl1 can promote glioma growth through SMAD1 / SMAD5 / SMAD8 [41]. At the same time, SMAD5 expression increases in prostate cancer, which is closely related to postoperative survival [40].…”

Integrated TCGA and GEO analysis showed that SMAD7 is an independent prognostic factor for lung adenocarcinoma

“…[ 39 ] Fstl1 can promote glioma growth through SMAD1/SMAD5/SMAD8. [ 40 ] At the same time, SMAD5 expression increases in prostate cancer, which is closely related to postoperative survival. [ 39 ] For the SMAD6 gene, high expression of it can promote the development of glioma.…”