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In this article, we describe the gene-directed enzyme prodrug therapy, also known as the "Trojan Horse" therapy mediated by exosomes - small extracellular vesicles (sEVs) secreted from mesenchymal stem/stromal cells (MSCs) and cancer cells. MSC-EVs possess strong migrating tropism toward tumor sites. EVs derived from tumor cells mimic the parental cells in an invasive metastatic growth trait and the capability to reprogram the recipient cells. The behavior of these EVs when modified with the suicide gene predestinates them to be a drug with guided intracellular action. EVs with therapeutic suicide gene are prepared from cells with integrated retrovirus vector containing its genetic message. These EVs are internalized by tumor cells and the product of the gene converts the non-toxic prodrug into a cytotoxic drug inside the cell causing its suicide. The action of two suicide gene systems are described: the yCD::UPRT-MSC/5-FC system and the HSVTK-MSC-GCV system. Suicide gene EVs either MSCs or tumor cell origin due to their intrinsic targeting capabilities, high modification flexibility, as well as biological barrier permeability represent potential drugs for tumors untreatable with present standard cancer therapies.

The role of radiotherapy in borderline resectable (BRPC) and locally advanced pancreatic carcinoma (LAPC) remains controversial. In our study, we retrospectively evaluated 48 patients with BRPC (14; 29.2%) and LAPC (34; 70. 8%) who underwent 6-8 cycles of induction mFOLFIRINOX chemotherapy alone (23; 47.9%) or 4-6 cycles of mFOLFIRINOX followed by hypofractionated radiotherapy (up to the total dose of 39.9 Gy in 15 fractions) (25; 52.1%). Survival parameters were evaluated using the Gehan-Breslow-Wilcoxon Test and compared by using the long-rank test. The addition of radiotherapy was not associated with better survival (16.9 months for chemotherapy only versus 15.9 months for the combined therapy; p=0.486), as well as for both subgroups (13.5 months vs. 18.3 months; p=0.679) and (20.7 months vs. 13.8 months; p=0.425) for BRPC and LAPC, respectively. A higher resection rate was seen in the BRPC group compared to the LAPC group (43% vs. 17.6%, respectively). Our study revealed a significantly higher rate of lung metastases in patients after the combination therapy compared to those treated by chemotherapy only (19% vs. 0%, respectively; p=0.045). Such a borderline result, however, prevents us from drawing clear conclusions about whether this is an artifact caused by the low number of patients or whether radiotherapy leads to a selection of stem cells with a predilection to the generalization to the lungs.

Hepatocellular carcinoma (HCC) is a malignant tumor, which seriously threatens the life of patients. LncRNA SLC7A11-AS1 was reported to be abnormally expressed in HCC. Here, the functions and relative molecular regulatory mechanism of SLC7A11-AS1 in HCC were investigated. Nude mice and HCC cells were used as the experimental subjects. Knockdown or overexpression of exogenous genes was conducted in HCC cells. RT-qPCR, IHC, and western blot were employed to evaluate the abundance of genes and proteins. The malignant behaviors were evaluated using CCK-8, clone formation, wound-healing, and Transwell. The locations of SLC7A11-AS1 and KLF9 in cells were determined by FISH and IF assays. The total m6A level was evaluated by dot-blot assay. m6A modification of SLC7A11-AS1 was detected using RNA MeRIP. The interactions among molecules were validated by RIP, ChIP, dual luciferase reporter assay, and co-IP. SLC7A11-AS1 was elevated apparently in HCC cells and HCC tissues from mice. SLC7A11-AS1 silencing could suppress HCC progression, which was validated in in vivo and in vitro experiments. Furthermore, METTL3 mediated m6A modification of SLC7A11-AS1 to elevate its expression. In addition, SLC7A11-AS1 downregulated KLF9 expression by affecting STUB1-mediated ubiquitination degradation and KLF9 enhanced PHLPP2 expression to inactivate the AKT pathway. Eventually, rescue experiments revealed that KLF9 knockdown abolished SLC7A11-AS1 silencing-mediated suppression of HCC progression in vivo and in vitro. Our results unveiled that m6A-modified SLC7A11-AS1 promoted HCC progression by regulating the STUB1/KLF9/PHLPP2/AKT axis, indicating that targeting SLC7A11-AS1 might alleviate HCC progression.

Circular RNA (circ)_0000326 has been reported in bladder cancer and cervical cancer and is concerned to be involved with the development of cancerous cells. Whereas, there have been no reports concentrating on the influences of circ_0000326 in breast cancer (BC). Therefore, the latent modulatory mechanisms of circ_0000326 in BC are researched. circ_0000326 expression in BC tissues and correlative cells was evaluated via RT-qPCR, and the relevance between circ_0000326 expression and overall survival and the clinicopathological feature was also investigated. After a series of transfection, the effects of circ_0000326, microRNA-9-3p (miR-9-3p), and Yes-associated protein 1 (YAP1) in BC cell growth, invasion, and stemness were studied by CCK-8, flow cytometry, Transwell, and sphere-forming assays. The binding sites and correlation of circ_0000326, miR-9-3p, and YAP1 were certified via starBase website, luciferase reporter assay, and Pearson's χ2 test. The in vivo experiment was evaluated by establishing a subcutaneous tumorigenesis model. High-expressed circ_0000326 in BC tissues and cells was discovered, which was connected with an undesirable prognosis. Silencing of circ_0000326 visibly inhibited MCF-7 and BT549 cell growth, invasion, stemness, meanwhile declining the protein levels of SRY-related high-mobility group box gene 2 (SOX2) and octamer binding transcription factor 4 (OCT4). miR-9-3p was a sponger of circ_0000326, which was negatively regulated by circ_0000326. Moreover, YAP1 was confirmed as a target gene of miR-9-3p. circ_0000326 affected BC cell behaviors via mediating miR-9-3p and YAP1. Furthermore, circ_0000326 silencing prohibited tumor growth of BC in vivo. The research uncovered that circ_0000326 facilitated BC development via mediating the miR-9-3p/YAP1 axis.

We have identified that NUDT21 plays a vital role in MDS transformations, while the transcription factor RUNX1 is essential for normal hematopoiesis, which is a high expression in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), and we aim to explore the linkage between the two genes and new pathways for MDS transformation to AML. Prediction of RUNX1 expression levels and its relationship with NUDT21 in AML and MDS patients was performed using bioinformatics techniques and validated in patients. Using lentiviral packaging technology, NUDT21 knockdown and overexpression models were developed in AML and MDS cell lines. These models were validated using quantitative polymerase chain reaction (qPCR) and western blotting. The cell cycle, apoptosis, differentiation, and cytokines were examined by flow cytometry, CCK-8 analyzed proliferation, and the intracellular localization of NUDT21 and RUNX1 was examined by immunofluorescence. mRNA transcriptome sequencing was performed on THP-1, MUTZ-1, and Dapars analyzed SKM-1 cell lines and the sequencing data to observe the knockdown effect of NUDT21 on RUNX1. qPCR and western blot revealed a positive correlation between NUDT21 and RUNX1; both were located in the nucleus. Overexpression of NUDT21 reduced apoptosis, promoted cell proliferation, and possibly increased the invasive ability of cells. It also altered the APA site in the RUNX1 3'-UTRs region. NUDT21 regulates RUNX1 gene expression and promotes AML transformation in MDS through an APA mechanism.

Six cycles of docetaxel in addition to androgen deprivation therapy (ADT) are currently one of the treatment options for patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC). Since the outcomes in patients with high-volume (HV) disease remain modest, we aimed to identify patients for more intensified treatment. We report a cohort of 73 consecutive patients with de novo mHSPC treated with early docetaxel at the Department of Oncology and Radiotherapy, University Hospital of Split, Croatia, from October 2015 until March 2020. The outcomes analyzed were the occurrence of castration-resistant disease (CRPC) and death from any cause (OS). The median follow-up was 54 (50-73) months. Forty-six (63%) patients developed CRPC and 34 (47%) died during the follow-up. The median time to CRPC and median OS were 16.2 and 58.4 months, respectively. The risk of CRPC was higher for patients with high (above median) values of serum alkaline phosphatase (ALP) (HR=2.4; 95% CI [1.4-4.5]), lactate dehydrogenase (LDH) (HR=1.98; 95% CI [1.1-3.7]), prostate-specific antigen (PSA) (HR=1.8; 95% CI [1.1-3]), ECOG performance status >1 (HR=2; 95% CI [1.2-3.3]) and HV disease (HR=1.9; 95% CI [1.1-3.1]). The risk of any-cause death was higher in patients with high values of ALP, LDH, and ECOG performance status >1. The predictive value of LDH was independent of disease volume. A set of baseline characteristics could be used in conjunction with disease volume in deciding on the optimal treatment strategy for patients with de novo mHSPC.

The regulation of protein kinase B (AKT) phosphorylation by Tripartite motif-containing protein 31 (TRIM31) is implicated as an essential mechanism in the progression of many malignant tumors. Nevertheless, the function of the TRIM31/AKT pathway in oral squamous cell carcinoma (OSCC) remains elusive. Here, immunohistochemistry analysis of human OSCC tissue microarrays indicated significantly higher levels of TRIM31 and phosphorylated AKT (p-AKT) in OSCC tumors than in adjacent tissue samples. Also, we detected a positive association between TRIM31 expression and clinical OSCC development. In in vitro studies, TRIM31 knockdown severely impaired OSCC cell growth, invasion, and migration. By contrast, TRIM31 overexpression improved these cell behaviors, while subsequent AKT inhibition abrogated the effect. In vivo tumorigenesis experiments using nude mice also validated the effects of TRIM31/AKT signaling in tumor growth. Furthermore, TRIM31 upregulation facilitated glucose uptake, as well as lactate and adenosine triphosphate production of OSCC cells, while such positive effects on glycolysis and malignant cell phenotypes were reversed by treatment with AKT or glycolysis inhibitors. In conclusion, TRIM31 may improve OSCC progression by enhancing AKT phosphorylation and subsequent glycolysis. Hence, TRIM31 has the potential as a treatment target in OSCC.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality. Our previous study has confirmed that XPD acts as an anti-oncogene and is downregulated in HCC. The mechanism of XPD downregulation in HCC is unclear. In this work, we obtained the datasets related to HCC patients from GSE76427, LIRI-JP, and TCGA-LIHC cohorts. Among 15 m5C regulators (NSUN2, NSUN3, NSUN4, NSUN5, NSUN6, NSUN7, DNMT1, TRDMT1, DNMT3A, DNMT3B and NOP2, TET1, TET2, and TET3, ALYREF), 14 m5C regulators were upregulated in tumor tissues of HCC patients, except for TET2. HCC patients were divided into Cluster A and B with different m5C methylation patterns. Cluster B was enriched in metabolism-related signaling pathways, and Cluster A was prominently associated with the cell cycle signaling pathway. Moreover, XPD was positively correlated with NOP2. Cluster B exhibited upregulation of XPD and had an obvious survival advantage with respect to Cluster A. Additionally, NOP2 and XPD were downregulated in HCC tumors and cells. In vitro assays revealed that NOP2 overexpression enhanced XPD expression by elevating the m5C methylation of XPD, which contributed to inhibit proliferation, migration, and invasion of HCC cells. In conclusion, this work demonstrated that XPD mRNA stability was elevated by NOP2-mediated m5C methylation modification and then inhibited the malignant progression of HCC, suggesting that XPD may be a potential target for HCC treatment.

We retrospectively compared long-term biochemical recurrence rates (BCR) in pN1 PCa patients that underwent adjuvant radiotherapy (aRT) vs. no aRT/early salvage (esRT) after robot-assisted radical prostatectomy and extended pelvic lymphadenectomy. All PCa pN1 M0 patients treated at a single high-volume center between 2010 and 2020 were analyzed. Patients with <10 LNs yield, or >10 positive LNs, or persistently detectable PSA after RARP were excluded. Kaplan-Meier (KM) plots depicted BCR rates. Multivariable Cox regression models (MCRMs) focused on predictors of BCR. The cumulative incidence plot depicted BCR rates after propensity score (PS) matching (ratio 1:1). 220 pN1 patients were enrolled, 133 (60.4%) treated with aRT and 87 (39.6%) with no-aRT/esRT. aRT patients were older, with higher rates of postoperative ISUP grade group 4-5, and higher rates of pT3b stage. The actuarial BCR was similar (aRT 39.8% vs. no-aRT/esRT 40.2%; p=1). Median time to BCR was 62 vs. 38 months in aRT vs. no-aRT/esRT patients (p=0.001). In MCRMs, patients managed with no-aRT/esRT were associated with higher rates of BCR over time (hazard ratio [HR]: 3.27, p<0.001). ISUP grade group 5 (HR: 2.18, p<0.01) was an independent predictor of BCR. In PS-matched cumulative incidence plots, the BCR rate was significantly higher in the aRT group (76.4 vs. 40.4%; p<0.01). Patients managed with no-aRT/esRT experienced BCR approximately two years before the aRT group. Despite, the important BCR benefit after aRT, this treatment strategy is underused in daily practice.