B7-H3 silencing by RNAi inhibits tumor progression and enhances chemosensitivity in U937 cells

Abstract

BackgroundThe role of B7-H3 in acute monocytic leukemia U937 cells has not been thoroughly investigated.Materials and methodsB7-H3 knockdown in the U937 cell line was performed using small hairpin (sh)RNA lentivirus transduction. The effects on cell proliferation, cycle, migration, and invasion were investigated by Cell Counting Kit-8 assay, methyl cellulose colony-forming assay, propidium iodide staining, and Transwell assays in vitro. Changes in cell growth inhibition and apoptosis, when combined with chemotherapy drugs, were determined using the Cell Counting Kit-8 and Annexin V-FITC/PI assays. U937 xenograft models were used to assess the effects of B7-H3 on tumorigenicity and the therapeutic effect of B7-H3 knockdown in combination with chemotherapy drugs in vivo.ResultsDownregulation of B7-H3 significantly decreased U937 cell growth and colony-forming ability. The mean inhibition rate of tumor growth with B7-H3 knockdown was 59.4%, and the expression of both Ki-67 and PCNA in xenografts was significantly reduced. After B7-H3 silencing, the U937 cell cycle was arrested at the G0/G1 phase. The cell migration rate of B7-H3 knockdown cells was reduced more than fivefold, and invasion capacity decreased by 86.7%. B7-H3 RNAi profoundly increased the antitumor effect of chemotherapy in vitro and in vivo. On day 19, inhibition rates of tumor growth in B7-H3 shRNA combined with idarubicin, cytarabine, and idarubicin plus cytarabine were 70.5%, 80.0%, and 90.0%, respectively (P=0.006, P=0.004, and P=0.016, respectively).ConclusionB7-H3 may promote U937 cell progression, and shRNA targeting B7-H3 significantly enhances sensitivity to chemotherapeutic drugs. These results may provide new insight into the function of B7-H3 and a promising therapeutic approach targeting B7-H3 in acute monocytic leukemia.

Astragaloside IV Enhances Cisplatin Chemosensitivity in Non-Small Cell Lung Cancer Cells Through Inhibition of B7-H3

“…A recent study from Chen et al demonstrated that induced expression of B7-H3 on the lung cancer cells and macrophages suppressed T-cell mediating anti-tumor immune response [29]. Furthermore, it is reported that inhibition of B7-H3 by siRNA significantly suppresses cell migration and invasion, enhances sensitivity to chemotherapeutic drugs in acute monocytic leukemia U937 cells [30]. In pancreatic carcinoma, it is suggested that silencing of B7-H3 increases gemcitabine sensitivity through induction of surviving-dependent apoptosis [31].…”

Molecular Pathways: Targeting B7-H3 (CD276) for Human Cancer Immunotherapy

“…Based on a few preclinical animal studies, the combination of B7-H3 blockade and chemotherapy looks promising ( Figure 1F ). Indeed, the silencing of B7-H3 through shRNA in an histiocytic lymphoma derived human cell line, U937, in combination with the anti-neoplastic drug Ara-C led to 80% tumor reduction compared to the 40% inhibition observed in wild-type U937 cells combined with Ara-C in a mouse xenograft model (58). Similarly, shRNA silencing of B7-H3 in a murine model of breast cancer, combined with the chemotherapeutic Paclitaxel, showed approximately 80% reduction in tumor growth compared to the untreated wild-type cells (38).…”

New checkpoints in cancer immunotherapy

“…B7‐H3 knockdown by RNA interference in pancreatic cancer as well as gastric cancer decreased tumor cell migration and transwell invasion up to 50% in vitro, as described in Figure . In the context of oral carcinoma, esophageal carcinoma, breast cancer as well as acute monocytic leukemia, knockdown of B7‐H3 suppressed tumor cell proliferation, while restoration of B7‐H3 expression enhanced tumor growth. In addition, silencing of B7‐H3, through lentivirus‐mediated delivery of stable short hairpin RNA, was observed to increase the sensitivity of the human pancreatic carcinoma cell line Patu8988 to gemcitabine as a result of enhanced drug‐induced apoptosis, indicating that B7‐H3 induces gemcitabine resistance in pancreatic carcinoma cells .…”