Effective Prediction of Prostate Cancer Recurrence through the IQGAP1 Network

Gu, Yan; Lin, Xiaozeng; Kapoor, Anil; Li, Taosha; Major, Pierre; Tang, Damu

doi:10.3390/cancers13030430

Cited by 7 publications

(8 citation statements)

References 101 publications

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“…We analyzed Overlap36’s potential in stratification of poor OS of SKCM. We first matched 34 of the 36 murine genes to the human SKCM PanCancer Atlas dataset (for simplicity, these 34 genes are referred to as Overlap36) and merged them into a megagene (Overlap36 risk score) using coefficients generated by multivariate Cox analysis following our system [ 85 , 86 ] as described in Fig. 1 .…”

Section: Resultsmentioning

confidence: 99%

PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity

Lin

Dong

et al. 2023

J Exp Clin Cancer Res

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Background PCSK9 regulates cholesterol homeostasis and promotes tumorigenesis. However, the relevance of these two actions and the mechanisms underlying PCSK9’s oncogenic roles in melanoma and other cancers remain unclear. Methods PCSK9’s association with melanoma was analysed using the TCGA dataset. Empty vector (EV), PCSK9, gain-of-function (D374Y), and loss-of-function (Q152H) PCSK9 mutant were stably-expressed in murine melanoma B16 cells and studied for impact on B16 cell-derived oncogenesis in vitro and in vivo using syngeneic C57BL/6 and Pcsk9−/− mice. Intratumoral accumulation of cholesterol was determined. RNA-seq was performed on individual tumor types. Differentially-expressed genes (DEGs) were derived from the comparisons of B16 PCSK9, B16 D374Y, or B16 Q152H tumors to B16 EV allografts and analysed for pathway alterations. Results PCSK9 expression and its network negatively correlated with the survival probability of patients with melanoma. PCSK9 promoted B16 cell proliferation, migration, and growth in soft agar in vitro, formation of tumors in C57BL/6 mice in vivo, and accumulation of intratumoral cholesterol in a manner reflecting its regulation of the low-density lipoprotein receptor (LDLR): Q152H, EV, PCSK9, and D374Y. Tumor-associated T cells, CD8 + T cells, and NK cells were significantly increased in D374Y tumors along with upregulations of multiple immune checkpoints, IFNγ, and 143 genes associated with T cell dysfunction. Overlap of 36 genes between the D374Y DEGs and the PCSK9 DEGs predicted poor prognosis of melanoma and resistance to immune checkpoint blockade (ICB) therapy. CYTH4, DENND1C, AOAH, TBC1D10C, EPSTI1, GIMAP7, and FASL (FAS ligand) were novel predictors of ICB therapy and displayed high level of correlations with multiple immune checkpoints in melanoma and across 30 human cancers. We observed FAS ligand being among the most robust biomarkers of ICB treatment and constructed two novel and effective multigene panels predicting response to ICB therapy. The profiles of allografts produced by B16 EV, PCSK9, D374Y, and Q152H remained comparable in C57BL/6 and Pcsk9−/− mice. Conclusions Tumor-derived PCSK9 plays a critical role in melanoma pathogenesis. PCSK9’s oncogenic actions are associated with intratumoral cholesterol accumulation. PCSK9 systemically affects the immune system, contributing to melanoma immune evasion. Novel biomarkers derived from the PCSK9-network effectively predicted ICB therapy responses.

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Section: Resultsmentioning

confidence: 99%

PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity

Lin

Dong

et al. 2023

J Exp Clin Cancer Res

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“…In view of the adrenal gland’s anatomical proximity to the kidney and the blood circulation connections between the two organs, it is intriguing to see a strong prognostic value of SigIQGAP1NW for ACC. The observed prognostic potential of SigIQGAP1NW towards PC would suggest a prognostic value of Sig27gene (Sig27), a prognostic multigene panel of PC constructed using the PC-associated IQGAP1 network [ 24 ] for ACC.…”

Section: Resultsmentioning

confidence: 99%

“…As SigIQGAP1NW and Sig27 were formulated for predicting the fatality risk of ccRCC and recurrence possibility of PC, respectively [ 23 , 24 ], we have determined whether the model or signature size can be optimized. Using both sequential and golden selection (gselection) methods within the BeSS R package, we selected eight variables among the nine component genes of SigIQGAP1NW to formulate SigIQvar8 ( Figure S1A ).…”

Section: Resultsmentioning

confidence: 99%

“…The current diagnostic ability in these domains needs to be significantly improved. In our recent effort to investigate prognostic multigene panels for clear cell renal cell carcinoma (ccRCC) and prostate cancer (PC), a 9-gene panel (SigIQGAP1NW) for ccRCC and a 27-gene signature (Sig27gene) for PC were formulated [ 23 , 24 ]. Intriguingly, both signatures robustly predict progression-free survival (PFS, relapse) and OS of ACC at levels exceeding their prognostic potential towards ccRCC or PC, highlighting the credibility of both panels as effective prognostic multigene signatures of ACC.…”

Section: Introductionmentioning

confidence: 99%

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Prediction of Adrenocortical Carcinoma Relapse and Prognosis with a Set of Novel Multigene Panels

Lin

et al. 2022

Cancers

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Effective assessment of adrenocortical carcinoma (ACC) prognosis is critical in patient management. We report four novel and robust prognostic multigene panels. Sig27var25, SigIQvar8, SigCmbnvar5, and SigCmbn_B predict ACC relapse at area under the curve (AUC) of 0.89, 0.79, 0.78, and 0.80, respectively, and fatality at AUC of 0.91, 0.88, 0.85, and 0.87, respectively. Among their 33 component genes, 31 are novel. They could be differentially expressed in ACCs from normal tissues, tumors with different severity (stages and lymph node metastasis), ACCs with TP53 mutations, and tumors with differentially expressed immune checkpoints (CTLA4, PD1, TGFBR1, and others). All panels correlate with reductions of ACC-associated CD8+ and/or NK cells. Furthermore, we provide the first evidence for the association of mesenchymal stem cells (MSCs) with ACC relapse (p = 2 × 10−6) and prognosis (p = 2 × 10−8). Sig27var25, SigIQvar8, SigCmbnvar5, and SigCmbn_B correlate with MSC (spearman r ≥ 0.53, p ≤ 1.38 × 10−5). Sig27var25 and SigIQvar8 were derived from a prostate cancer (PC) and clear cell renal cell carcinoma (ccRCC) multigene signature, respectively; SigCmbnvar5 and SigCmbn_B are combinations of both panels, revealing close relationships of ACC with PC and ccRCC. The origin of these four panels from PC and ccRCC favors their prognostic potential towards ACC.

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“…Patients with advanced prostate cancer can receive treatments, such as androgen deprivation therapy (ADT), to achieve a certain period of clinical remission. However, most of the cases progress to castration-resistant prostate cancer (CRPC), and the curative effect for CRPC is not satisfactory ( Beretta et al, 2021 ; Gu et al, 2021 ). Therefore, it is necessary to explore new treatment measures for CRPC.…”

Section: Introductionmentioning

confidence: 99%

Sophocarpine inhibits tumor progression by antagonizing the PI3K/AKT/mTOR signaling pathway in castration-resistant prostate cancer

Wang

Shi

Han

et al. 2022

PeerJ

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Objective The objective of this study was to investigate the inhibitory effect of sophocarpine on the progression of castration-resistant prostate cancer (CRPC) and the underlying molecular mechanism. Methods DU145 and PC3 cells (two CRPC cell lines), incubated with different concentrations of sophocarpine, were used. Cell Counting Kit-8 assay, real-time cellular analysis, and colony formation assay were conducted to evaluate the proliferation of CRPC cells. Cytometry flow analysis was performed to evaluate the apoptosis rate of CRPC cells. Wound healing and Transwell invasion assays were performed and the levels of the epithelial-mesenchymal transition (EMT)-related proteins were determined to analyze cell migration and invasion abilities. A xenografted tumor model of nude mice was used to examine the anti-cancer effect of sophocarpine on CRPC. Western blotting was performed to evaluate the activities of the PI3K/AKT/mTOR signaling pathway both in cells and tumor tissues. Results In vitro tests showed that sophocarpine suppressed the proliferation of CRPC cells, reduced the migration and invasion abilities, and increased the apoptosis rate. In vivo, sophocarpine decreased the weight and volume of tumor tissues. Mechanically, sophocarpine exerted its anti-cancer effects by inactivating PI3K/AKT/mTOR signaling. Conclusion Sophocarpine inhibited the progression of CRPC by downregulating the PI3K/AKT/mTOR signaling pathway and showed a potential to be an anti-cancer agent against CRPC.

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Effective Prediction of Prostate Cancer Recurrence through the IQGAP1 Network

Cited by 7 publications

References 101 publications

PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity

PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity

Prediction of Adrenocortical Carcinoma Relapse and Prognosis with a Set of Novel Multigene Panels

Sophocarpine inhibits tumor progression by antagonizing the PI3K/AKT/mTOR signaling pathway in castration-resistant prostate cancer

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