B7-H3 inhibits the IFN-γ-dependent cytotoxicity of Vγ9Vδ2 T cells against colon cancer cells

The immunoregulatory protein B7-H3, a member of the B7 family, has been confirmed to be highly expressed in colon cancer. However, the exact influence of B7-H3 on the features and antitumor ability of γδT cells in colon cancer remains unknown. In the present study, we investigated that the proportions of B7-H3+ γδT cells were distinctly increased in the peripheral blood and tumor tissues of colon cancer patients. B7-H3 blockade or knockdown promoted proliferation, inhibited cell apoptosis and induced the expression of activation markers (CD25 and CD69) on Vδ2 T cells. In contrast, treatment with the B7-H3 agonist 4H7 had the opposite effect. Furthermore, B7-H3 suppressed IFN-γ expression by inhibiting T-bet in Vδ2 T cells. Moreover, B7-H3 mediated the inhibition of Vδ2 T cell cytotoxicity via the downregulation of IFN-γ and perforin/granzyme B expression. More importantly, blocking the B7-H3 function significantly enhanced the cytotoxicity of Vδ2 T cells against colon cancer cells in vivo. Therefore, the inhibition or blockade of B7-H3 is a potential immunotherapeutic approach for colon cancer

sj-docx-3-tct-10.1177_15330338231164359 - Supplemental material for LINC00460 Facilitates Cell Proliferation and Inhibits Ferroptosis in Breast Cancer Through the miR-320a/MAL2 Axis

Supplemental material, sj-docx-3-tct-10.1177_15330338231164359 for LINC00460 Facilitates Cell Proliferation and Inhibits Ferroptosis in Breast Cancer Through the miR-320a/MAL2 Axis by Chuanqiang Zhang, Liang Xu, Xiaowei Li, Yueqiu Chen, Tongguo Shi and Qiang Wang in Technology in Cancer Research & Treatment</p

sj-docx-1-tct-10.1177_15330338231164359 - Supplemental material for LINC00460 Facilitates Cell Proliferation and Inhibits Ferroptosis in Breast Cancer Through the miR-320a/MAL2 Axis

Supplemental material, sj-docx-1-tct-10.1177_15330338231164359 for LINC00460 Facilitates Cell Proliferation and Inhibits Ferroptosis in Breast Cancer Through the miR-320a/MAL2 Axis by Chuanqiang Zhang, Liang Xu, Xiaowei Li, Yueqiu Chen, Tongguo Shi and Qiang Wang in Technology in Cancer Research & Treatment</p

Circular RNA circLDLR facilitates cancer progression by altering the miR-30a-3p/SOAT1 axis in colorectal cancer

Abstract Colorectal cancer (CRC) is the third most common malignancy worldwide. Circular RNAs (circRNAs) have been reported to play critical regulatory roles in tumorigenesis, serving as tumor biomarkers and therapeutic targets. However, the contributions of circRNAs to CRC tumorigenesis are unclear. In our study, high expression of circLDLR was found in CRC tissues and cells and was closely associated with the malignant progression and poor prognosis of CRC patients. We demonstrated that circLDLR boosts growth and metastasis of CRC cells in vitro and in vivo, and modulates cholesterol levels in vitro. Mechanistically, we showed that circLDLR competitively binds to miR-30a-3p and prevents it from reducing the SOAT1 level, facilitating the malignant progression of CRC. In sum, our findings illustrate that circLDLR participates in CRC tumorigenesis and metastasis via the miR-30a-3p/SOAT1 axis, serving as a potential biomarker and therapeutic target in CRC

ER Stress Mediates TiAl6V4 Particle-Induced Peri-Implant Osteolysis by Promoting RANKL Expression in Fibroblasts.

Wear particle-induced osteolysis is a major cause of aseptic loosening, which is one of the most common reasons for total hip arthroplasty (THA) failure. Previous studies have shown that the synovial fibroblasts present in the periprosthetic membrane are important targets of wear debris during osteolysis. However, the interaction mechanisms between the wear debris and fibroblasts remain largely unknown. In the present study, we investigated the effect of ER (endoplasmic reticulum) stress induced by TiAl6V4 particles (TiPs) in human synovial fibroblasts and calvarial resorption animal models. The expression of ER stress markers, including IRE1-α, GRP78/Bip and CHOP, were determined by western blot in fibroblasts that had been treated with TiPs for various times and concentration. To address whether ER stress was involved in the expression of RANKL, the effects of ER stress blockers (including 4-PBA and TUDCA) on the expression of RANKL in TiPs-treated fibroblasts were examined by real-time PCR, western blot and ELISA. Osteoclastogenesis was assessed by tartrate resistant acid phosphatase (TRAP) staining. Our study demonstrated that ER stress markers were markedly upregulated in TiPs-treated fibroblasts. Blocking ER stress significantly reduced the TiPs-induced expression of RANKL both in vitro and in vivo. Moreover, the inhibition of ER stress ameliorated wear particle-induced osteolysis in animal models. Taken together, these results suggested that the expression of RANKL induced by TiPs was mediated by ER stress in fibroblasts. Therefore, down regulating the ER stress of fibroblasts represents a potential therapeutic approach for wear particle-induced periprosthetic osteolysis

B7-H3 confers stemness characteristics to gastric cancer cells by promoting glutathione metabolism through AKT/pAKT/Nrf2 pathway

Abstract. Background:. Cancer stem-like cells (CSCs) are a small subset of cells in tumors that exhibit self-renewal and differentiation properties. CSCs play a vital role in tumor formation, progression, relapse, and therapeutic resistance. B7-H3, an immunoregulatory protein, has many protumor functions. However, little is known about the mechanism underlying the role of B7-H3 in regulating gastric cancer (GC) stemness. Our study aimed to explore the impacts of B7-H3 on GC stemness and its underlying mechanism. Methods:. GC stemness influenced by B7-H3 was detected both in vitro and in vivo. The expression of stemness-related markers was examined by reverse transcription quantitative polymerase chain reaction, Western blotting, and flow cytometry. Sphere formation assay was used to detect the sphere-forming ability. The underlying regulatory mechanism of B7-H3 on the stemness of GC was investigated by mass spectrometry and subsequent validation experiments. The signaling pathway (Protein kinase B [Akt]/Nuclear factor erythroid 2-related factor 2 [Nrf2] pathway) of B7-H3 on the regulation of glutathione (GSH) metabolism was examined by Western blotting assay. Multi-color immunohistochemistry (mIHC) was used to detect the expression of B7-H3, cluster of differentiation 44 (CD44), and Nrf2 on human GC tissues. Student's t-test was used to compare the difference between two groups. Pearson correlation analysis was used to analyze the relationship between two molecules. The Kaplan-Meier method was used for survival analysis. Results:. B7-H3 knockdown suppressed the stemness of GC cells both in vitro and in vivo. Mass spectrometric analysis showed the downregulation of GSH metabolism in short hairpin B7-H3 GC cells, which was further confirmed by the experimental results. Meanwhile, stemness characteristics in B7-H3 overexpressing cells were suppressed after the inhibition of GSH metabolism. Furthermore, Western blotting suggested that B7-H3-induced activation of GSH metabolism occurred through the AKT/Nrf2 pathway, and inhibition of AKT signaling pathway could suppress not only GSH metabolism but also GC stemness. mIHC showed that B7-H3 was highly expressed in GC tissues and was positively correlated with the expression of CD44 and Nrf2. Importantly, GC patients with high expression of B7-H3, CD44, and Nrf2 had worse prognosis (P = 0.02). Conclusions:. B7-H3 has a regulatory effect on GC stemness and the regulatory effect is achieved through the AKT/Nrf2/GSH pathway. Inhibiting B7-H3 expression may be a new therapeutic strategy against GC

ER stress mediated the upregulation of RANKL and the RANKL/OPG ratio in TiPs-stimulated fibroblasts.

<p>(A and B) The gene expression of RANKL and OPG in fibroblasts from each group were examined by real-time PCR. (C, E and G) Western blots analysis of RANKL and OPG from each group. (D, F and H) The density of western blots bands shown in (C, E and G) was quantified using the ImageJ software. (I) The expression of sRANKL in the supernatants of fibroblasts from each group were quantified by ELISA. Data are represented as the means ± S.E.M from three independent experiments. *P < 0.05, **P < 0.01 versus control; #P < 0.05, ##P<0.01 versus TiPs group.</p

Activation of ER stress following exposure to TiPs in fibroblasts.

<p>(A and C) Western blots analysis of IRE1-α, Bip and CHOP in fibroblasts following treatment with TiPs for various time periods and concentrations. (B and D) The density of western blots bands shown in (A and C) were quantified using ImageJ software. Data are represented as the means ± S.E.M from three independent experiments. *P < 0.05, **P < 0.01.</p

ER stress inhibitors ameliorated TiPs-induced mouse calvarial osteolysis and osteoclastogenesis.

<p>(A) Representative micro-CT with three-dimensional reconstructed images from each group. (B and C) Bone volume/total volume (BV/TV) and percentage of total porosity of each sample were measured. (D) Toluidine blue staining of calvaria derived from each group. Scale bar, 1mm. (E) Bone resorption of calvaria (%) in (D). (F) Histochemical staining with TRAP of calvaria derived from each group. Scale bar, 25 μm. Data are presented as the mean± S.E.M. n = 7 mice per group. *P < 0.05, **P < 0.01 versus sham; #P<0.05, ##P<0.01 versus TiPs group.</p