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Plastin 3 (PLS3) overexpression may serve as a marker for predicting chemotherapeutic outcomes in drug-resistant cancer cells, but the mechanism is unclear. Herein, we show that the down-regulation of PLS3 by PLS3 gene silencing augments the sensitivity of MDA-MB-231 triple-negative breast cancer cells to paclitaxel. Interestingly, a low concentration of paclitaxel was able to induce strong apoptosis in the PLS3-silenced cells. Further study revealed that p38 MAPK signalling was responsible for the increased sensitivity to paclitaxel in these cells, as the p38 MAPK inhibitor SB203580 impaired the changes mediated by PLS3 down-regulation in response to paclitaxel. Therefore, our study identifies PLS3 as a potential target for enhancing the p38 MAPK-mediated apoptosis induced by paclitaxel. Unlike paclitaxel, Abraxane was unable to induce strong apoptosis in the PLS3-silenced cells. As PLS3 was found to be involved in the process of endocytosis in breast cancer cells, the reliance of cellular Abraxane uptake on this process may render it not as efficient as paclitaxel in PLS3-depleted tumour cells. The finding that PLS3 could be a critical regulator of paclitaxel sensitivity may have important implications for breast cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-binding protein 7 (IGFBP7) is a secreted protein and its expression was restrained in varied solid tumours, but there was no report about biological role of IGFBP7 in cholangiocarcinoma (CCA). Here, we found that high expression of IGFBP7 correlated to a better overall survival in CCA patients. To investigate the hypothetic antineoplastic activity of IGFBP7 in CCA, we induced overexpression of IGFBP7 in QBC939 and RBE cells, as well as knockdown in HCCC9810 cells. And the biological functions triggered by level changes of IGFBP7 were assessed, including proliferation, cell cycle distribution, apoptosis and invasion evaluation. Cell growth assessment showed that enhanced IGFBP7 expression significantly retarded proliferation rates of QBC939 and RBE cells while an enhancement was observed in IGFBP7-inhibited HCCC9810 cells. The inhibition of cell viability was induced via G2/M phase arrest and apoptosis. Both QBC939 and RBE cells possess highly invasive ability, and IGFBP7 overexpression attenuated their serious invasiveness by reversing their mesenchymal phenotype to endothelial signature. We next investigated the potential mechanism involving in IGFBP7-induced tumour suppression and found that increased expression of IGFBP7 resulted in decrease of IGF-IR, IRS-1 and phosphor-AKT protein levels, accompanied with elevation of phorsphor-p38MAPK. These results suggest that IGFBP7 might be related to CCA carcinogenesis and metastasis, which further implicates that IGFBP7 might become a prospective benchmark for CCA diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Background: Tumor PD-L1 levels have predictive value in PD-1/PD-L1 checkpoint blockade therapies, yet biopsies can only provide baseline information. Whether PD-L1 expression on circulating tumor cells (CTCs) could serve as an alternative biomarker is of great interest. Design: We established an immunofluorescence assay for semi-quantitative assessment of the PD-L1 expression levels on CTCs with four categories (PD-L1negative, PD-L1low, PD-L1medium and PD-L1high). 35 patients with different advanced gastrointestinal tumors were enrolled in a phase 1 trial of a PD-1 inhibitor, IBI308. The CTC numeration and the PD-L1 expression levels were analyzed. Results: Prior the treatment of IBI308, 97% (34/35) patients had CTCs, ranging from1 to 70 (median 7). 74% (26/35) had PD-L1positive CTCs, and 60% (21/35) had at least one PD-L1high CTCs. The disease control (DC) rate in PD-L1high patients (48%) is much higher than the others (14%). The group with at least 20% abundance of PD-L1high CTCs had even higher DC rate of 64% (9/14), with only 14% DC rate for the rest (3/21). We also observed that the count changes of total CTC, PD-L1postive CTC and PD-L1high CTC correlate quite well with disease outcome (P<0.001, P = 0.002 and 0.007, respectively). In addition, the abundance of PD-L1high CTCs at baseline had predicative significance for progression free survival (PFS). Conclusions: We revealed that the abundance of PD-L1high CTCs at baseline might serve as a predictor to screen patients for PD-1/PD-L1 blockade therapies and measuring the dynamic changes of CTC could indicate the therapeutic response at early time. [ABSTRACT FROM AUTHOR]