Genetic Profiles Associated with Chemoresistance in Patient-Derived Xenograft Models of Ovarian Cancer

Abstract

Purpose Recurrence and chemoresistance (CR) are the leading causes of death in patients with high-grade serous carcinoma (HGSC) of the ovary. The aim of this study was to identify genetic changes associated with CR mechanisms using a patient-derived xenograft (PDX) mouse model and genetic sequencing. Materials and Methods To generate a CR HGSC PDX tumor, mice bearing subcutaneously implanted HGSC PDX tumors were treated with paclitaxel and carboplatin. We compared gene expression and mutations between chemosensitive (CS) and CR PDX tumors with whole exome and RNA sequencing and selected candidate genes. Correlations between candidate gene expression and clinicopathological variables were explored using the Cancer Genome Atlas (TCGA) database and the Human Protein Atlas (THPA). Results Three CR and four CS HGSC PDX tumor models were successfully established. RNA sequencing analysis of the PDX tumors revealed that 146 genes were significantly up-regulated and 54 genes down-regulated in the CR group compared with the CS group. Whole exome sequencing analysis showed 39 mutation sites were identified which only occurred in CR group. Differential expression of SAP25 , HLA-DPA1 , AKT3 , and PIK3R5 genes and mutation of TMEM205 and POLR2A may have important functions in the progression of ovarian cancer chemoresistance. According to TCGA data analysis, patients with high HLA-DPA1 expression were more resistant to initial chemotherapy (p=0.030; odds ratio, 1.845). Conclusion We successfully established CR ovarian cancer PDX mouse models. PDX-based genetic profiling study could be used to select some candidate genes that could be targeted to overcome chemoresistance of ovarian cancer.

Function, Regulation and Biological Roles of PI3Kγ Variants

“…Of some pathophysiological relevance appear observations that overexpression of the non-catalytic p101 subunit of PI3Kγ led to oncogenic cellular transformation and malignancy, whereas the loss of p101 was reported to be sufficient to reduce in vivo tumor growth and metastasis to a similar extent to that of p110γ [51,204]. Of note upregulated p101 expression was associated with the progression of ovarian cancer chemoresistance in patient-derived xenograft murine models of ovarian cancer [205]. Interestingly, in contrast to the proposed tumor-promoting potential of p101 and p110γ, the Thr-607-phosphorylated p87 adapter may harbor tumor suppressor activity and attenuation of cell migration by forming a negative regulatory complex with p110γ to control PI3Kγ signaling [51,206].…”

HCP5, as the sponge of miR-1291, facilitates AML cell proliferation and restrains apoptosis via increasing PIK3R5 expression

“…PIK3R5, as a member of PI3Ks, plays essential roles in cell growth, motility, and intracellular trafficking [ 13 , 14 ]. Abnormal expression of PIK3R5 exerts crucial roles in ovarian cancer [ 15 ]. Meanwhile, miRNAs, as a class of short non-coding RNAs, play diverse effects in cancers via modulating genes expression at post-transcriptional levels.…”

CD83, a Novel MAPK Signaling Pathway Interactor, Determines Ovarian Cancer Cell Fate

“…Besides CD83 , a large number of the CD83 highly-associated genes (Person correlation >0.5, p < 0.01) within ovarian cancer transcriptome showed higher expression in ovarian cancer cells, especially in the EpCAM + /CD45 + subtypes ( Figure S1 ). CD83 highly-associated genes, such as ITGAM , IL1B , CYBB , PIK3R5 , BTK, and OSM , ectopically express in ovarian cancer cells or tissues, involving in ovarian cancer progression, hypoxia networks, and the development of chemoresistance [ 44 , 45 , 46 , 47 , 48 , 49 ]. Finally, we found that ovarian cancer patients’ survival inversely correlated with the level of CD83 expression in 907 ovarian cancer patients (low CD83 expression: 652, the high expression: 255), as patients with high CD83 expression lived significantly shorter compared with their counterparts with low CD83 expression ( Figure 1 d).…”