Prostate cancer (PC) is a major cause of cancer death in men. The disease has a great disparity in prognosis. Although low grade PCs with Gleason scores ≤ 6 are indolent, high-risk PCs are likely to relapse and metastasize. The standard of care for metastatic PC (mPC) remains androgen deprivation therapy (ADT). Resistance commonly occurs in the form of castration resistant PC (CRPC). Despite decades of research efforts, CRPC remains lethal. Understanding of mechanisms underpinning metastatic progression represents the overarching challenge in PC research. This progression is regulated by complex mechanisms, including those regulating PC cell proliferation, epithelial–mesenchymal transition (EMT), and androgen receptor (AR) signaling. Among this PC metastatic network lies an intriguing suppressor of PC metastasis: the Raf kinase inhibitory protein (RKIP). Clinically, the RKIP protein is downregulated in PC, and showed further reduction in mPC. In xenograft mouse models for PC, RKIP inhibits metastasis. In vitro, RKIP reduces PC cell invasion and sensitizes PC cells to therapeutic treatments. Mechanistically, RKIP suppresses Raf-MEK-ERK activation and EMT, and modulates extracellular matrix. In return, Snail, NFκB, and the polycomb protein EZH2 contribute to inhibition of RKIP expression. In this review, we will thoroughly analyze RKIP’s tumor suppression actions in PC.

Taxifolin inhibits breast cancer (BC) via novel mechanisms. In a syngeneic mouse BC model, taxifolin suppressed 4T-1 cell-derived allografts. RNA-seq of 4T-1 tumors identified 36 differentially expressed genes (DEGs) upregulated by taxifolin. Among their human homologues, 19, 7, and 2 genes were downregulated in BCs, high-proliferative BCs, and BCs with high-fatality risks, respectively. Three genes were established as tumor suppressors and eight were novel to BC, including HNRN, KPRP, CRCT1, and FLG2. These four genes exhibit tumor suppressive actions and reside in 1q21.3, a locus amplified in 70% recurrent BCs, revealing a unique vulnerability of primary and recurrent BCs with 1q21.3 amplification with respect to taxifolin. Furthermore, the 36 DEGs formed a multiple gene panel (DEG36) that effectively stratified the fatality risk in luminal, HER2+, and triple-negative (TN) equivalent BCs in two large cohorts: the METABRIC and TCGA datasets. 4T-1 cells model human TNBC cells. The DEG36 most robustly predicted the poor prognosis of TNBCs and associated it with the infiltration of CD8+ T, NK, macrophages, and Th2 cells. Of note, taxifolin increased the CD8+ T cell content in 4T-1 tumors. The DEG36 is a novel and effective prognostic biomarker of BCs, particularly TNBCs, and can be used to assess the BC-associated immunosuppressive microenvironment.

Using an LL2 cell-based syngeneic mouse LC model, taxifolin suppressed allografts along with the appearance of 578 differentially expressed genes (DEGs). These DEGs were associated with enhancement of processes related to the extracellular matrix and lymphocyte chemotaxis as well as the reduction in pathways relevant to cell proliferation. From these DEGs, we formulated 12-gene (TxflSig) and 7-gene (TxflSig1) panels; both predicted response to ICB (immune checkpoint blockade) therapy more effectively in non-small-cell lung cancer (NSCLC) than numerous well-established ICB biomarkers, including PD-L1. In both panels, the mouse counterparts of ITGAL, ITGAX, and TMEM119 genes were downregulated by taxifolin. They were strongly associated with immune suppression in LC, evidenced by their robust correlations with the major immunosuppressive cell types (MDSC, Treg, and macrophage) and multiple immune checkpoints in NSCLC and across multiple human cancer types. ITGAL, ITGAX, and IIT (ITGAL-ITGAX-TMEM119) effectively predicted NSCLC’s response to ICB therapy; IIT stratified the mortality risk of NSCLC. The stromal expressions of ITGAL and ITGAX, together with tumor expression of TMEM119 in NSCLC, were demonstrated. Collectively, we report multiple novel ICB biomarkers—TxflSig, TxflSig1, IIT, ITGAL, and ITGAX—and taxifolin-derived attenuation of immunosuppressive activities in NSCLC, suggesting the inclusion of taxifolin in ICB therapies for NSCLC.

Papillary renal cell carcinoma (pRCC) is an aggressive but minor type of RCC. The current understanding and management of pRCC remain poor. We report here OIP5 being a novel oncogenic factor and possessing robust prognostic values and therapeutic potential. OIP5 upregulation is observed in pRCC. The upregulation is associated with pRCC adverse features (T1P < T2P < CIMP, Stage1 + 2 < Stage 3 < Stage 4, and N0 < N1) and effectively stratifies the fatality risk. OIP5 promotes ACHN pRCC cell proliferation and xenograft formation; the latter is correlated with network alterations related to immune regulation, metabolism, and hypoxia. A set of differentially expressed genes (DEFs) was derived from ACHN OIP5 xenografts and primary pRCCs (n = 282) contingent to OIP5 upregulation; both DEG sets share 66 overlap genes. Overlap66 effectively predicts overall survival (p < 2 $\times$ 10⁻¹⁶) and relapse (p < 2 $\times$ 10⁻¹⁶) possibilities. High-risk tumors stratified by Overlap66 risk score possess an immune suppressive environment, evident by elevations in Treg cells and PD1 in CD8 T cells. Upregulation of PLK1 occurs in both xenografts and primary pRCC tumors with OIP5 elevations. PLK1 displays a synthetic lethality relationship with OIP5. PLK1 inhibitor BI2356 inhibits the growth of xenografts formed by ACHN OIP5 cells. Collectively, the OIP5 network can be explored for personalized therapies in management of pRCC patients.

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.

Background/Objectives: Autoimmunity towards podocyte antigens causes membranous nephropathy (MN). Numerous MN target antigens (MNTAgs) have been reported, including PLA2R1, THSD7A, NTNG1, TGFBR3, HTRA1, NDNF, SEMA3B, FAT1, EXT1, CNTN1, NELL1, PCDH7, EXT2, PCSK6, and NCAM1, but their podocyte expression has not been thoroughly studied. Methods: We screened CZ CELLxGene single-cell RNA (scRNA) sequence datasets for those of adult, fetal, and mouse kidneys and analyzed the above MNTAgs’ expression. Results: In adult kidneys, most MNTAgs are present in podocytes, except PCSK6 and NCAM1. PLA2R1 is expressed significantly more than other MNTAgs in podocytes and is a major podocyte marker, consistent with PLA2R1 as the dominant MNTAg. Additionally, PLA2R1 is a top-upregulated gene in the podocytes of chronic kidney disease, acute kidney injury, and diabetic nephropathy, indicating its general role in causing podocyte injury. PLA2R1, NTNG1, HTRA1, and NDNF display podocyte-enriched expression along with elevated chromatin accessibility in podocytes, suggesting transcription initiation contributing to their preference expression in podocytes. In the fetal kidney, most MNTAgs are expressed in podocytes. While PLA2R1 is weakly present in podocytes, SEMA3B is abundantly expressed in immature and mature podocytes, supporting SEMA3B as a childhood MNTAg. In mouse kidneys, Thsd7a is the only MNTAg with a prominent level and podocyte-specific expression. Conclusions: Most MNTAgs are present in podocytes in adults and during renal development. In adults, PLA2R1 expression is highly enriched in podocytes and significantly upregulated in multiple kidney diseases accompanied by proteinuria. In mouse kidneys, Thsd7a is specifically expressed in podocytes at an elevated level.