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PIK3R3, part of the regulatory domain of PI3K, is upregulated in sarcoma stem-like cells and promotes invasion, migration, and chemotherapy resistance.

ABSTRACT: To identify drivers of sarcoma cancer stem-like cells (CSCs), we compared gene expression using RNA sequencing between HT1080 fibrosarcoma and SK-LMS-1 leiomyosarcoma spheroids (which are enriched for CSCs) compared with the parent populations. The most overexpressed survival signaling-related gene in spheroids was phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3), a regulatory subunit of PI3K, which functions in tumorigenesis and metastasis. In a human sarcoma microarray, PIK3R3 was also overexpressed by 4.1-fold compared with normal tissues. PIK3R3 inhibition using shRNA in the HT1080, SK-LMS-1, and DDLS8817 dedifferentiated liposarcoma in spheroids and in CD133+ cells (a CSC marker) reduced expression of CD133 and the stem cell factor Nanog and blocked spheroid formation by 61-71%. Mechanistic studies showed that in spheroid cells, PIK3R3 activated AKT and ERK signaling. Inhibition of PIK3R3, AKT, or ERK using shRNA or inhibitors decreased expression of Nanog, spheroid formation by 68-73%, and anchorage-independent growth by 76-91%. PIK3R3 or ERK1/2 inhibition similarly blocked sarcoma spheroid cell migration, invasion, secretion of MMP-2, xenograft invasion into adjacent normal tissue, and chemotherapy resistance. Together, these results show that signaling through the PIK3R3/ERK/Nanog axis promotes sarcoma CSC phenotypes such as migration, invasion, and chemotherapy resistance, and identify PIK3R3 as a potential therapeutic target in sarcoma.

SUBMITTER: Yoon C

PROVIDER: S-EPMC8319167 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundOvarian cancer is the most lethal gynecologic disease and is one of the most commonly diagnosed cancers among women worldwide. The phosphatidylinositol 3-kinase (PI3K) family plays an important regulatory role in various cancer signaling pathways, including those involved in ovarian cancer development; however, its exact function remains to be fully understood. We conducted this study to understand the role of P13K in the molecular mechanisms underlying ovarian cancer development.MethodsTo determine the differential gene expression of phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3), a regulatory subunit of PI3K, in normal, tumor, and metastatic ovary tissues, TNM plotter analysis was performed. The microarray dataset GSE53759 was downloaded from Gene Expression Omnibus. ROC plotter analysis was conducted to understand the potential of PIK3R3 as a predictive marker for effectiveness of therapy in ovarian cancer. muTarget was used to identify mutations that alter PIK3R3 expression in ovarian cancer. To determine the interacting partners for PIK3R3 in ovarian tissues, the interactome-atlas tool was used. The Kyoto encyclopedia of genes and genomes (KEGG) analysis was conducted to identify the pathways in which these interacting partners were primarily enriched.ResultsPIK3R3 was overexpressed in ovarian and metastatic tumors. Elevated PIK3R3 levels were observed in ovarian cancer stem cells, wherein inhibiting PIK3R3 expression significantly reduced the size of ovarian cancer spheroids. Treatment of ovarian cancer stem cells with PF-04691502 (10 μM), an inhibitor of both PI3K and mTOR kinases, also reduced the size of spheroids and the level of OCT4. PIK3R3 was highly expressed in ovarian cancer with several somatic mutations and was predicted better outcomes in patients undergoing Avastin® chemotherapy using bioinformatic tool. Protein interaction analysis showed that PIK3R3 interacts with 157 genes, including GRB2, EGFR, ERBB3, PTK2, HCK, IGF1R, YES1, and PIK3CA, in the ovary. KEGG enrichment analysis revealed that the interacting partners of PIK3R3 are involved in the ErbB signaling pathway, proteoglycans in cancer, FoxO, prolactin, chemokine, and insulin signaling pathways.ConclusionsPIK3R3 plays a pivotal role in ovarian cancer development and is therefore a potential candidate for developing novel therapeutic approaches.

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PIK3R3, part of the regulatory domain of PI3K, is upregulated in sarcoma stem-like cells and promotes invasion, migration, and chemotherapy resistance.

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