Abstract. Colorectal cancer is one of the most common malignancies in the world. Overactivity of phosphatidylinositol 3-kinase (PI3K) is frequently detected in colorectal carcinoma. PI3K signaling plays a pivotal role in intracellular signal transduction pathways involved in cell growth, cellular transformation, and tumorigenesis. To specifically inhibit PI3K activity in colorectal cancer cells, we constructed a siRNA against the PI3K regulatory subunit p85· and transfected it into LoVo and SW480 cells. In the present study, treatment of colorectal cancer cells with PI3K p85·-specific siRNA inhibited cell proliferation, induced G1 phase cell cycle arrest and sensitized colorectal cancer cells to 5-FU-induced apoptosis. Furthermore, depletion of PI3K p85· resulted in significant activation of three Forkhead box class O (FoxO) transcription factors, which inhibited the expression of cyclin D1, cdk4 and induced expression of p27/Kip1. Activation of FoxO transcription factors also increased the expression of FasL. Thus, our results indicate that siRNA-mediated gene silencing of PI3K p85· may be a useful therapeutic strategy for colorectal carcinoma.
Purpose
For patients with lung malignancies with RET rearrangement, the efficacy of immune checkpoint inhibitors is limited. The characteristics of the tumour immune microenvironment (TIME) and molecular pathological features of these patients have not been well elucidated.
Methods
The pathology and TIME characteristics of 29 patients with lung malignancies with RET rearrangement were retrospectively analysed, and their relationships with clinical efficacy and prognosis were investigated. Gene detection relied on high-throughput sequencing, and TIME detection was based on multiplex immunohistochemistry technology.
Results
Of the 29 patients, 86% (25/29) had adenocarcinoma, and the acinar type accounted for the greatest percentage of patients, followed by the solid type, regardless of whether the disease was early or locally advanced and metastatic. In addition, we report a novel KIF5B-RET(k24:R8) rearrangement in pulmonary sarcoma. The density of CD8 + T cells in the tumour stroma in the early-stage patients was significantly higher than that in the locally advanced and metastatic patients (P = 0.014). The proportion of M2 macrophages in the tumour stroma was significantly higher than that in the tumour parenchyma (P = 0.046). Although the difference was not statistically significant (P = 0.098), patients positive for M2 macrophage infiltration into the tumour parenchyma (≥ 5%) may have had a better prognosis.
Conclusions
A novel KIF5B-RET rearrangement variant in pulmonary sarcoma shows similar TIME characteristics to lung cancer. Among patients with lung malignancies with RET rearrangement, patients with M2 macrophage infiltration into the tumour parenchyma may have a better prognosis, but further studies with larger cohorts are needed.
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