Emerging evidence suggest the critical role of circular RNAs (circRNAs) in disease development especially in various cancers. However, the oncogenic role of circRNAs in hepatocellular carcinoma (HCC) is still largely unknown.RNA sequencing was performed to identify significantly upregulated circRNAs in paired HCC tissues and non-tumor tissues. CCK-8 assay, colony formation, transwell, and xenograft mouse models were used to investigate the role of circRNAs in HCC proliferation and metastasis. Small interfering RNA (siRNA) was used to silence gene expression. RNA immunoprecipitation, biotin pull-down, RNA pull-down, luciferase reporter assay and western blot were used to explore the underlying molecular mechanisms.Hsa_circ_0095868, derived from exon 5 of the MDK gene (named circMDK), was identified as a new oncogenic circRNA that was significantly upregulated in HCC. The upregulation of circMDK was associated with the modification of N6-methyladenosine (m6A) and poor survival in HCC patients. Mechanistically, circMDK sponged miR-346 and miR-874-3p to upregulate ATG16L1 (Autophagy Related 16 Like 1), resulting to the activation of PI3K/AKT/mTOR signaling pathway to promote cell proliferation, migration and invasion. Poly (β-amino esters) (PAEs) were synthesized to assist the delivery of circMDK siRNA (PAE-siRNA), which effectively inhibited tumor progression without obvious adverse effects in four liver tumor models including subcutaneous, metastatic, orthotopic and patient-derived xenograft (PDX) models.CircMDK could serve as a potential tumor biomarker that promotes the progression of HCC via the miR-346/874-3p-ATG16L1 axis. The PAE-based delivery of siRNA improved the stability and efficiency of siRNA targeting circMDK. The PAE-siRNA nanoparticles effectively inhibited HCC proliferation and metastasis in vivo. Our current findings offer a promising nanotherapeutic strategy for the treatment of HCC. 

/pdf/m6a-mediated-upregulation-of-circmdk-promotes-tumorigenesis-1eweueus.pdf

M6A-mediated upregulation of circMDK promotes tumorigenesis and acts as a nanotherapeutic target in hepatocellular carcinoma

https://molecular-cancer.biomedcentral.com/track/pdf/10.1186/s12943-022-01575-z

BACKGROUND
Disulfidptosis has been discovered as a mechanism of cell death mediating by SLC7A11. Nonetheless, little is known about the relationship between disulfidptosis-related genes (DRG) and hepatocellular carcinoma (HCC).


METHODS
7 datasets including 1,302 HCC patients and 62,530 cells were downloaded. We adopted consensus clustering algorithm to construct the consensus matrix and cluster the samples' DRG related expression profile data. Then, weighted gene co-expression network analysis (WGCNA) was conducted to identify hub gene modules associated with the identified clusters and determine the correlation between modules. A DRG.score was constructed based on genes through differential analysis and WGCNA of the 2 clusters.


RESULTS
Univariate and multivariate Cox regression analysis show that SLC7A11 and LRPPRC can be used as an independent factor in HCC. Then, two molecular subgroups with significantly different survival were identified based on 10 DRG. The cluster.A was showed a worse prognosis, higher immune infiltration, and higher immune checkpoint expression. Then, by differential analysis and WGCNA of the 2 clusters, we identified 5 hub genes, and constructed a DRG.score. Univariate and multivariate Cox regression analysis show that DRG.score can be used as an independent factor to predict the prognosis in HCC. Furthermore, high DRG.score group had a worse prognosis, and was validated in TCGA-LIHC, LIRI-JP, GSE14520, GSE36376, and GSE76427. Preclinically, patients with higher DRG.score demonstrated significant immunotherapy therapeutic advantages and transcatheter arterial chemoembolization clinical benefits.


CONCLUSIONS
SLC7A11 and LRPPRC play an essential role in HCC prognosis prediction. The DRG.score might become useful biomarkers for novel therapeutic targets.

/pdf/identification-and-characterization-of-a-novel-molecular-2th9csm1.pdf

Identification and characterization of a novel molecular classification based on disulfidptosis-related genes to predict prognosis and immunotherapy efficacy in hepatocellular carcinoma.

Chinese herb Radix sophorae tonkinensis extract oxymatrine shows anticancer effects. This study evaluated the role of oxymatrine in colorectal cancer (CRC) and the underlying molecular events in vitro and in vivo. CRC cells were treated with different doses of oxymatrine to assess cell viability, reactive oxygen species production, gene expression, and gene alterations. Meanwhile, mouse xenograft and liver metastasis models were used to assess the effects of oxymatrine using histology examination, transmission electron microscopy, and Western blot, respectively. Our results showed that oxymatrine treatment triggered CRC cell mitophagy to inhibit CRC cell growth, migration, invasion, and metastasis in vitro and in vivo. At the gene level, oxymatrine inhibited LRPPRC to promote Parkin translocation into the mitochondria and reduce the mitophagy-activated NLRP3 inflammasome. Thus, oxymatrine had an anticancer activity through LRPPRC inhibition, mitophagy induction, and NLRP3 inflammasome suppression in the CRC cell xenograft and liver metastasis models. In conclusion, the study demonstrates the oxymatrine anti- CRC activity through its unique role in regulating CRC cell mitophagy and NLRP3 inflammasome levels in vitro and in vivo.

Oxymatrine suppresses colorectal cancer progression by inhibiting NLRP3 inflammasome activation through mitophagy induction in vitro and in vivo.

Hepatocellular carcinoma (HCC) has a poor prognosis and new effective treatments are needed. SLC12A5 plays important roles in multiple complex pathological states and is overexpressed in a variety of malignancies. However, the effects of SLC12A5 in HCC have not been determined.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cam4.5605

SLC12A5 promotes hepatocellular carcinoma growth and ferroptosis resistance by inducing ER stress and cystine transport changes

Reactive oxygen species (ROS) which are continuously generated mainly by mitochondria, have been proved to play an important role in the stress signaling of cancer cells. Moreover, pentatricopeptide repeat (PPR) proteins have been suggested to take part in mitochondrial metabolism. However, the mechanisms integrating the actions of these distinct networks in urothelial carcinoma of the bladder (UCB) pathogenesis are elusive. In this study, we found that leucine rich pentatricopeptide repeat containing (LRPPRC) was frequently upregulated in UCB and that it was an independent prognostic factor in UCB. We further revealed that LRPPRC promoted UCB tumorigenesis by regulating the intracellular ROS homeostasis. Mechanistically, LRPPRC modulates ROS balance and protects UCB cells from oxidative stress via mt-mRNA metabolism and the circANKHD1/FOXM1 axis. In addition, the SRA stem-loop interacting RNA binding protein (SLIRP) directly interacted with LRPPRC to protect it from ubiquitination and proteasomal degradation. Notably, we showed that LRPPRC modulated the tumorigenesis of UCB cells in a circANKHD1-FOXM1-dependent manner. In conclusion, LRPPRC exerts critical roles in regulating UCB redox homeostasis and tumorigenesis, and is a prognostic factor for UCB; suggesting that LRPPRC may serve as an exploitable therapeutic target in UCB.

LRPPRC regulates redox homeostasis via the circANKHD1/FOXM1 axis to enhance bladder urothelial carcinoma tumorigenesis

Clinically, patients with urothelial carcinoma of the bladder (UCB) with tumor metastasis are incurable. To find new therapeutic strategies, the mechanisms underlying UCB invasion and metastasis should be further investigated. In this study, zinc finger and homeobox 3 (ZHX3) was first screened as a critical oncogenic factor associated with poor prognosis in a UCB dataset from The Cancer Genome Atlas (TCGA). These results were also confirmed in a large cohort of clinical UCB clinical samples. Next, we found that ZHX3 could promote the migration and invasion capacities of UCB cells both in vitro and in vivo. Mechanistically, coimmunoprecipitation (coIP) and mass spectrometry (MS) analysis indicated that ZHX3 was a target of tripartite motif 21 (TRIM21), which mediates its ubiquitination, and subsequent degradation. Notably, RNA-seq analysis showed that ZHX3 repressed the expression of regulator of G protein signaling 2 (RGS2). Generally, our results suggest that ZHX3 plays an oncogenic role in UCB pathogenesis and might serve as a novel therapeutic target for UCB.

ZHX3 promotes the progression of urothelial carcinoma of the bladder via repressing of RGS2 and is a novel substrate of TRIM21.

Several studies showed that androgen deprivation therapy (ADT) plus local treatment of prostate could improve metastatic prostate cancer (mPCa) patients’ survival. To date there are few studies analyzed the value of prostate cryoablation in mPCa. The objective of our analysis is to evaluate the oncological results and clinical value of prostate cryoablation combined with ADT compared with ADT alone in newly diagnosed mPCa patients. Newly diagnosed mPCa patients undergoing cryoablation plus ADT (group A) between January 2011 and November 2018 were identified. Patients receiving ADT alone (group B) were selected from the same institutional prostate cancer database by propensity score matching based on clinical characteristics. Oncological results and clinical value in symptom control and primary lesion treatment were compared. Fifty-four patients were included in each group. Prostate cryoablation was well tolerated. The median follow-up time was 40 (27–53) and 39 (31–54) months in group A and group B, respectively. Patients in group A had a lower median prostate-specific antigen (PSA) nadir (0.025 ng/mL vs. 0.230 ng/mL, p = 0.001), longer median failure-free survival (FFS) (39 months vs. 21 months, p = 0.005), and median metastatic castration-resistant prostate cancer (mCRPC)-free survival (39 months vs. 21 months, p = 0.007). No difference in cancer-specific survival and overall survival was found between the two groups. Multivariate Cox analysis showed combination therapy reduced the risk of FFS by 45.8% (HR = 0.542 [95% CI 0.329–0.893]; p = 0.016). Patients in group A had better clinical relief of urinary symptoms (79.1 vs. 59.1%, p = 0.044) and required less treatment of primary lesions for symptomatic relief (13.0 vs. 31.5%, p = 0.021). Prostate cryoablation plus ADT decreases PSA nadir, prolongs FFS and mCRPC-free survival, relieves urinary symptoms and reduces the need for treating primary lesions in newly diagnosed mPCa patients compared to ADT alone.

/pdf/prostate-cryoablation-combined-with-androgen-deprivation-1zmvjw6zjp.pdf

Prostate cryoablation combined with androgen deprivation therapy for newly diagnosed metastatic prostate cancer: a propensity score-based study.

Solute carrier family 12 member 5 (SLC12A5) has an oncogenic role in bladder urothelial carcinoma. The present study aimed to characterize the molecular mechanisms of SLC12A5 in bladder urothelial carcinoma pathogenesis. Functional assays identified that in bladder urothelial carcinoma SLC12A5 interacts with and stabilizes SOX18, and then upregulates matrix metalloproteinase 7 (MMP7). In vivo and in vitro assays were performed to confirm the effect of SLC12A5's interaction with SOX18 on MMP7-mediated bladder urothelial carcinoma progression. SLC12A5 was upregulated in human bladder tumors, and correlated with the poor survival of patients with bladder urothelial carcinoma tumor invasion and metastasis, promoted by SLC12A5 overexpression. We demonstrated that SLC12A5 interacted with SOX18, and then upregulated MMP7, thus enhancing tumor progression. Importantly, SLC12A5 expression correlated positively with SOX18 and MMP7 expression in bladder urothelial carcinoma. Furthermore, SLC12A5 expression was suppressed by miR-133a-3p. Ectopic expression of SLC12A5 partly abolished miR-133a-3p-mediated suppression of cell migration. SLC12A5-SOX18 complex-mediated upregulation on MMP7 was important in bladder urothelial carcinoma progression. The miR-133a-3p/SLC12A5/SOX18/MMP7 signaling axis was critical for progression, and provided an effective therapeutic approach against bladder urothelial carcinoma.

SLC12A5 interacts and enhances SOX18 activity to promote bladder urothelial carcinoma progression via upregulating MMP7.

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LRPPRC regulates redox homeostasis via the circANKHD1/FOXM1 axis to enhance bladder urothelial carcinoma tumorigenesis

ZHX3 promotes the progression of urothelial carcinoma of the bladder via repressing of RGS2 and is a novel substrate of TRIM21.

Prostate cryoablation combined with androgen deprivation therapy for newly diagnosed metastatic prostate cancer: a propensity score-based study.

SLC12A5 interacts and enhances SOX18 activity to promote bladder urothelial carcinoma progression via upregulating MMP7.