TSPAN8 promotes cancer cell stemness via activation of sonic Hedgehog signaling

Cancer stem cells (CSCs) represent a major source of treatment resistance and tumor progression. However, regulation of CSCs stemness is not entirely understood. Here, we report that TSPAN8 expression is upregulated in breast CSCs, promotes the expression of the stemness gene NANOG, OCT4, and ALDHA1, and correlates with therapeutic resistance. Mechanistically, TSPAN8 interacts with PTCH1 and inhibits the degradation of the SHH/PTCH1 complex through recruitment of deubiquitinating enzyme ATXN3. This results in the translocation of SMO to cilia, downstream gene expression, resistance of CSCs to chemotherapeutic agents, and enhances tumor formation in mice. Accordingly, expression levels of TSPAN8, PTCH1, SHH, and ATXN3 are positively correlated in human breast cancer specimens, and high TSPAN8 and ATXN3 expression levels correlate with poor prognosis. These findings reveal a molecular basis of TSPAN8-enhanced Sonic Hedgehog signaling and highlight a role for TSPAN8 in promoting cancer stemness

Identification of DYNLT1 associated with proliferation, relapse, and metastasis in breast cancer

BackgroundBreast cancer (BC) is the most common malignant disease worldwide. Although the survival rate is improved in recent years, the prognosis is still bleak once recurrence and metastasis occur. It is vital to investigate more efficient biomarkers for predicting the metastasis and relapse of BC. DYNLT1 has been reported that participating in the progression of multiple cancers. However, there is still a lack of study about the correlation between DYNLT1 and BC.MethodsIn this study, we evaluated and validated the expression pattern and prognostic implication of DYNLT1 in BC with multiple public cohorts and BC tumor microarrays (TMAs) of paraffin-embedded tissues collected from the Affiliated Hospital of Jining Medical University. The response biomarkers for immune therapy, such as tumor mutational burden (TMB), between different DYNLT1 expression level BC samples were investigated using data from the TCGA-BRCA cohort utilizing public online tools. In addition, colony formation and transwell assay were conducted to verify the effects of DYNLT1 in BC cell line proliferation and invasion.ResultsThe results demonstrated that DYNLT1 overexpressed in BC and predicted poor relapse-free survival in our own BC TMA cohort. In addition, DYNLT1 induced BC development by promoting MDA-MB-231 cell proliferation migration, and metastasis.ConclusionAltogether, our findings proposed that DYNLT1 could be a diagnostic and prognostic indicator in BC

AEBP1 promotes papillary thyroid cancer progression by activating BMP4 signaling

Papillary thyroid cancer (PTC) is the most prevalent endocrine cancer worldwide. Approximately 30 % of PTC patients will progress into the advanced or metastatic stage and have a relatively poor prognosis. It is well known that epithelial-mesenchymal transition (EMT) plays a pivotal role in thyroid cancer metastasis, resistance to therapy, and recurrence. Clarifying the molecular mechanisms of EMT in PTC progression will help develop the targeted therapy of PTC. The aberrant expression of some transcription factors (TFs) participated in many pathological processes of cancers including EMT. In this study, by performing bioinformatics analysis, adipocyte enhancer-binding protein 1 (AEBP1) was screened as a pivotal TF that promoted EMT and tumor progression in PTC. In vitro experiments indicated that knockout of AEBP1 can inhibit the growth and invasion of PTC cells and reduce the expression of EMT markers including N-cadherin, TWIST1, and ZEB2. In the xenograft model, knockout of AEBP1 inhibited the growth and lung metastasis of PTC cells. By performing RNA-sequencing, dual-luciferase reporter assay, and chromatin immunoprecipitation assay, Bone morphogenetic protein 4 (BMP4) was identified as a downstream target of AEBP1. Over-expression of BMP4 can rescue the inhibitory effects of AEBP1 knockout on the growth, invasion, and EMT phenotype of PTC cells. In conclusion, these findings demonstrated that AEBP1 plays a critical role in PTC progression by regulating BMP4 expression and the AEBP1-BMP4 axis may present novel therapeutic targets for PTC treatment

In vitro CRISPR screening uncovers CRTC3 as a regulator of IFN-γ-induced ferroptosis of hepatocellular carcinoma

Abstract Interferon-gamma (IFN-γ) exerts anti-tumor effects by inducing ferroptosis. Based on CRISPR/Cas9 knockout screening targeting genome-wide protein encoding genes in HepG2 and SK-Hep-1 cell lines, we found that cAMP response element-binding protein (CREB) regulated transcription coactivator 3 (CRTC3) protects tumor cells from drug-induced ferroptosis and significantly inhibits the efficacy of IFN-γ treatment in hepatocellular carcinoma (HCC). Mechanistically, CRTC3 knockout altered tumor cell lipid patterns and increased the abundance of polyunsaturated fatty acids (PUFAs), which enables lipid peroxidation and enhances the susceptibility of HCC cells to ferroptosis inducers. To scavenge for accumulated lipid peroxides (LPO) and maintain redox equilibrium, HCC cells up-regulate SLC7A11 and glutathione peroxidase 4 (GPx4) expressions to enhance the activities of glutamate-cystine antiporter (system xc−) and LPO clearance. As IFN-γ inhibiting system xc−, simultaneous treatment with IFN-γ disrupts the compensatory mechanism, and generates a synergistic effect with CRTC3 knockout to facilitate ferroptosis. Sensitizing effects of CRTC3 depletion were confirmed using typical ferroptosis inducers, including RSL3 and erastin. Sorafeinib, a commonly used target drug in HCC, was repeatedly reported as a ferroptosis inducer. We then conducted both in vitro and vivo experiments and demonstrated that CRTC3 depletion sensitized HCC cells to sorafenib treatment. In conclusion, CRTC3 is involved in the regulation of PUFAs metabolism and ferroptosis. Targeting CRTC3 signaling in combination with ferroptosis inducers present a viable approach for HCC treatment and overcoming drug resistance