Emerging diabetes therapies: Regenerating pancreatic ß cells.

The incidence of diabetes mellitus (DM) is steadily increasing annually, with 537 million diabetic patients as of 2021. Restoring diminished ß cell mass or impaired islet function is crucial in treating DM, particularly type 1 diabetes mellitus (T1DM). However, the regenerative capacity of islet ß cells, which primarily produce insulin, is severely limited, and natural regeneration is only observed in young rodents or children. Hence, there is an urgent need to develop advanced therapeutic approaches that can regenerate endogenous ß cells or replace them with stem cell (SC)-derived or engineered ß-like cells. Current strategies for treating insulin-dependent DM mainly include promoting the self-replication of endogenous ß cells, inducing SC differentiation, reprogramming non-ß cells into ß-like cells, and generating pancreatic-like organoids through cell-based intervention. In this Review, we discuss the current state of the art in these approaches, describe associated challenges, propose potential solutions, and highlight ongoing efforts to optimize ß cell or islet transplantation and related clinical trials. These effective cell-based therapies will generate a sustainable source of functional ß cells for transplantation and lay strong foundations for future curative treatments for DM.

Wnt signaling: Modulating tumor-associated macrophages and related immunotherapeutic insights.

Wnt signaling pathways are highly conserved cascades that mediate multiple biological processes through canonical or noncanonical pathways, from embryonic development to tissue maintenance, but they also contribute to the pathogenesis of numerous cancers. Recent studies have revealed that Wnt signaling pathways critically control the interplay between cancer cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) and potentially impact the efficacy of cancer immunotherapy. In this review, we summarize the evidence that Wnt signaling pathways boost the maturation and infiltration of macrophages for immune surveillance in the steady state but also polarize TAMs toward immunosuppressive M2-like phenotypes for immune escape in the TME. Both cancer cells and TAMs utilize Wnt signaling to transmit signals, and this interaction is crucial for the carcinogenesis and progression of common solid cancers, such as colorectal, gastric, hepatocellular, breast, thyroid, prostate, kidney, and lung cancers; osteosarcoma; and glioma. Specifically, compared with those in solid cancers, Wnt signaling pathways play a distinct role in the pathogenesis of leukemia. Efforts to develop Wnt-based drugs for cancer treatment are still ongoing, and some indeed enhance the anticancer immune response. We believe that the combination of Wnt signaling-based therapy with conventional or immune therapies is a promising therapeutic approach and can facilitate personalized treatment for most cancers.

Serine hydroxymethyltransferase 2 knockdown induces apoptosis in ccRCC by causing lysosomal membrane permeabilization via metabolic reprogramming.

Serine hydroxymethyltransferase 2 (SHMT2) plays an important role in converting serine to glycine and supplying carbon to one-carbon metabolism to sustain cancer cell proliferation. However, the expression, function, and underlying mechanisms of SHMT2 in clear cell renal cell carcinoma (ccRCC) remain largely unknown. In this study, we demonstrated that SHMT2 was upregulated in ccRCC tissues compared with controls and associated with patient survival. SHMT2 knockdown inhibited proliferation, migration, and invasion in ccRCC cells. Overexpression of SHMT2 promoted tumor progression. Mechanistically, SHMT2 depletion disrupted one-carbon metabolism, increased reactive oxygen species (ROS) levels, and decreased ATP levels via metabolic reprogramming, which destroyed cell homeostasis. The SHMT2 knockdown-induced stress activated autophagy. A mass of autophagosomes fused with lysosomes, resulting in lysosomal membrane permeabilization (LMP) and leakage of lysosomal contents into the cytoplasm, which eventually led to apoptosis. Our work reveals that SHMT2 functions as an oncogenic gene to promote ccRCC progression. SHMT2 depletion induces apoptosis by causing LMP through excessive activation of the autophagy-lysosome pathway via metabolic reprogramming.

Circ-SAR1A Promotes Renal Cell Carcinoma Progression Through miR-382/YBX1 Axis.

BACKGROUND: Accumulating evidence points to a role for circular RNAs (circRNAs) in important regulatory function in tumor advancement. We explored the effect and function of circ-SAR1A in renal cell carcinoma (RCC). METHODS: circ-SAR1A expression in RCC tissues and cell lines was explored by qRT-PCR. The roles of circ-SAR1A on RCC progression were explored by in vitro function assays. Moreover, we determined the underlying mechanism of circ-SAR1A in RCC progression through bioinformatics analysis and dual-luciferase reporter assays. RESULTS: Our data reveal that circ-SAR1A is significantly high in RCC tissues and cell lines. High circ-SAR1A levels are correlated to advanced Fuhrman grade, and lymph-node metastasis in RCC patients. Functional experiments indicate that circ-SAR1A suppression decreased RCC cell growth and invasion abilities in vitro. Mechanistically, circ-SAR1A upregulated YBX1 expression by sponging miR-382, resulting in promoting the growth and invasion in RCC cells. CONCLUSION: Our data indicate that the circ-SAR1A/miR-382/YBX1 axis plays a critical role in RCC progression, which serve as a potential novel treatment strategy of RCC.

Pretreatment elevated prognostic nutritional index predicts a favorable prognosis in patients with prostate cancer.

BACKGROUND: The prognostic nutritional index (PNI), an immunity and nutrition based prognostic score, was correlated with clinical outcomes in different tumors. However, the prognostic significance of PNI has not been investigated in hormone sensitive prostate cancer (PCa). The objective of this study was to determine the prognostic significance of PNI in hormone sensitive PCa. METHODS: Two hundred eighty PCa patients undergoing androgen deprivation therapy (ADT) as first line therapy at three centers were enrolled. The serum albumin levels and peripheral lymphocyte count were measured at the time of diagnosis. PNI was calculated as 10 * serum albumin (g/dL) + 0.005 * total lymphocyte count (per mm3). Patients were categorized in two groups using a cut-off point of 50.2 as calculated by the receiver-operating curve analysis. Univariate and multivariate cox regression analyses were performed to evaluate PNI as a favorable prognostic factor for progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Prognostic accuracy was evaluated with the Harrell concordance index. RESULTS: Multivariate analyses identified PNI as an independent prognostic indicator with respect to PFS (hazard ratio (HR) = 0.521, p = 0.001), CSS (HR = 0.421, p = 0.002) and OS (HR = 0.429, p = 0.001). Patients with elevated PNI had better clinical outcomes. The addition of PNI to the final models improved predictive accuracy (c-index: 0.758, 0.830 and 0.782) for PFS, CSS and OS compared with the clinicopathological base models (c-index: 0.736, 0.801 and 0.752), which included Gleason score and incidence of metastasis. CONCLUSIONS: Elevated pretreatment PNI was a favorable prognostic indicator for PCa patients treated with ADT.

Screening and identification of key biomarkers in prostate cancer using bioinformatics.

Prostate cancer (PCa) is the second most common cancer amongst males worldwide. In the current study, microarray datasets GSE3325 and GSE6919 from the Gene Expression Omnibus database were screened to identify candidate genes that are associated with the progression of PCa. A total of 273 differentially expressed genes (DEGs) were identified, which included 173 downregulated genes and 100 upregulated genes, and a protein­protein interaction network was constructed using Search Tool for the Retired of Interacting Genes. The enriched functions and pathways of the identified DEGs included cell adhesion, the negative regulation of cell proliferation, protein binding and focal adhesion. A total of 8 hub genes were identified, of which PDZ binding kinase, Krüppel­like factor 4, collagen type XII α­1 chain, RAP1A and RAP39B were indicated to be associated with the progression and recurrence of PCa. In conclusion, the DEGs and hub genes identified in the present study may aid in determining the molecular mechanisms associated with PCa carcinogenesis and progression.

MALAT1 silencing suppresses prostate cancer progression by upregulating miR-1 and downregulating KRAS.

BACKGROUND: Prostate cancer (PC) is the second leading cause of cancer-related deaths among men. Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) performed as an oncogene in multiple cancers including PC. However, the molecular mechanisms of MALAT1 implicated in PC progression have not been thoroughly elaborated. MATERIALS AND METHODS: Reverse transcription-quantitative polymerase chain reaction assay was used to detect the expressions of MALAT1 and microRNA-1 (miR-1). Protein levels of cleaved poly (ADP-ribose) polymerase, cleaved caspase-3, BAX, bcl-2, and KRAS were determined using a western blot assay. Cell proliferation was assessed by colony formation and MTS assays. Cell migration capacity was examined by transwell migration assay (Corning Incorporated, Corning, NY, USA). Apoptosis rate was measured by flow cytometry via double staining of annexin V-FITC and propidium iodide. Luciferase and RNA immunoprecipitation assays were employed to explore the relationship among miR-1, MALAT1, and KRAS. RESULTS: MALAT1 expression was upregulated and miR-1 expression was downregulated in PC tissues and cell lines. MALAT1 knockdown inhibited cell proliferation and migration, and promoted cell apoptosis in androgen receptor-negative DU145 and PC3 cells. Molecular mechanism explorations disclosed that MALAT1 acted as a molecular sponge of miR-1 in DU145 cells. Moreover, miR-1 downregulation partly abrogated MALAT1 silencing-mediated anti-proliferative, antimigratory, and proapoptotic effects in DU145 and PC3 cells. Further investigation revealed that KRAS was a target of miR-1 in DU145 cells. MALAT1 acted as a competing endogenous RNA of miR-1, resulting in the increase of KRAS expression in DU145 and PC3 cells. Furthermore, miR-1 overexpression hampered proliferation and migration and promoted apoptosis in DU145 and PC3 cells, while these effects were markedly weakened following KRAS upregulation. CONCLUSION: MALAT1 knockdown inhibited proliferation and migration and facilitated apoptosis by upregulating miR-1 and downregulating KRAS in androgen receptor-negative PCa cells, providing a new insight into the molecular basis of MALAT1 and a potential biomarker or therapeutic target for suppressing castration-resistant PC.

Posttranscriptional Regulation of Human Antigen R by miR-133b Enhances Docetaxel Cytotoxicity Through the Inhibition of ATP-Binding Cassette Subfamily G Member 2 in Prostate Cancer Cells.

Docetaxel (DTX)-based chemotherapy is a first-line therapy in patients with castration-resistant prostate cancer. However, development of DTX resistance remains a challenge in cancer treatment. miRNAs have been shown to be involved in drug resistance in tumors. Nevertheless, little is known about the function and detailed molecular mechanism of miR-133b in DTX resistance of prostate cancer cells. The current study showed that miR-133b was downregulated, while human antigen R (HuR) was upregulated in prostate cancer cells. HuR was identified as a target of miR-133b, and miR-133b could suppress HuR expression. Ectopic expression of miR-133b and HuR knockdown suppressed cell viability and promoted DTX-induced apoptosis in DTX-treated prostate cancer cells, which were restored by HuR overexpression. Furthermore, HuR overexpression partially abolished the inhibitory effect of miR-133b overexpression on ATP-binding cassette (ABC) subfamily G member 2 (ABCG2) expression in prostate cancer cells. ABCG2 overexpression relieved DTX and miR-133b cytotoxicity in prostate cancer cells. In conclusion, posttranscriptional regulation of HuR by miR-133b enhances DTX cytotoxicity through inhibition of ABCG2, revealing a novel miR-133b/HuR/ABCG2 regulatory pathway to overcome chemoresistance in prostate cancer cells.

Effects of exogenous hydrogen sulfide on the proliferation and invasion of human Bladder cancer cells.

OBJECTIVE: The objective of this study is to evaluate the effects of exogenous hydrogen sulfide (H2S) on the proliferation and invasion of human bladder cancer cells. METHODS: Human bladder cancer EJ cells were cultured and then treated with sodium bisulfide (NaHS) (100 µmol/L for low dosage, 200 µmol/L for moderate dosage, 400 µmol/L for high dosage). The differences on proliferation and invasion of EJ cells were detected among different groups with MTT and transwell invasion assays. The differences in the expression levels of matrix metalloproteinase 2 (MMP2) and MMP9 among the groups were detected with Western blot. RESULTS: Cell proliferation activity was elevated by exogenous NaHS, with significantly statistical difference compared to the blank control group (P < 0.05). With the increased NaHS concentration, the EJ cell proliferation activity presented a statistically significant trend of increase, showing comparative differences among different groups (P < 0.05). Exogenous NaHS could also improve the invasion ability of bladder cancer EJ cells, which was significantly enhanced with increased NaHS dose (P < 0.001). The levels of MMP2 and MMP9 in EJ cells were significantly upregulated with the increased NaHS dose (P < 0.001). CONCLUSION: Exogenous H2S may promote cell proliferation and invasion by upregulating the expression level of MMP2 and MMP9 in human bladder cancer EJ cells.

Long non-coding RNA PCAT-1 contributes to tumorigenesis by regulating FSCN1 via miR-145-5p in prostate cancer.

Prostate cancer associated lncRNA transcript 1 (PCAT-1) has been identified as an oncogenic long non-coding RNA (lncRNA) in some solid tumors, including prostate cancer (PC). However, the molecular mechanism of PCAT-1 involved in PC is poorly defined. In this study, we found that PCAT-1 expression was up-regulated and miR-145-5p expression was down-regulated in PC tissues and cells. Function analysis indicated that PCAT-1 overexpression promoted proliferation, migration, invasion and inhibited apoptosis of PC cells. Rescue experiments demonstrated that miR-145-5p restoration attenuated the promotive effects of PCAT1 on PC progression, while Fascin-1 (FSCN1) upregulation relieved the anti-cancer role of miR-145-5p in PC. Mechanical analysis discovered that PCAT-1 could act as a miR-145-5p sponge to modulate FSCN1 expression. In conclusion, these findings suggested that PCAT-1 accelerated PC cell proliferation, migration, invasion and suppressed apoptosis by up-regulating FSCN1 mediated via miR-145-5p, hinting a potential therapeutic strategy for PC patients.

Tumor Protein D52 (TPD52) Inhibits Growth and Metastasis in Renal Cell Carcinoma Cells Through the PI3K/Akt Signaling Pathway.

Tumor protein D52 (TPD52) is a member of the TPD52-like protein family and plays different roles in various types of malignancies. However, its role in renal cell carcinoma (RCC) is still unclear. In this study, we investigated the role of TPD52 in RCC. The mechanism of TPD52 in RCC was also investigated. Our data demonstrated that the expression levels of TPD52 in both mRNA and protein were significantly decreased in RCC cells. Overexpression of TPD52 inhibited proliferation, migration, and invasion with decreased epithelial-mesenchymal transition (EMT) phenotype in RCC cells, as well as attenuated tumor growth in renal cancer xenografts. Mechanistically, overexpression of TPD52 significantly inhibited downregulated phosphorylation levels of PI3K and Akt in RCC cells. In conclusion, the present study demonstrated that TPD52 inhibited growth and metastasis of RCC, at least in part, by suppressing the PI3K/Akt signaling pathway. Therefore, these findings suggest that TPD52 may be a promising therapeutic target for the treatment of human RCC.

Increased expression of SPRY4-IT1 predicts poor prognosis and promotes tumor growth and metastasis in bladder cancer.

INTRODUCTION: long non-coding RNAs (lncRNAs) are emerging as new regulators in the cancer paradigm, the involvement of lncRNAs in urothelial carcinoma of the bladder (UCB) is just beginning to be studied. In this study, we focused on lncRNA SPRY4-IT1 and investigated its expression pattern, clinical significance, and biological function in UCB. METHODS: SPRY4-IT1 expression in UCB tissues was examined by quantitative Real-time PCR (qRT-PCR) and its correlation with clinicopathological features and patient prognosis was later analyzed. Moreover, in vitro assays were performed to explore its role in bladder cancer progression. RESULTS: SPRY4-IT1 expression was elevated in UCB tissues, and SPRY4-IT1 levels were highly positively correlated with histological grade, tumor stage, and lymph node metastasis and reduced overall survival. A multivariate analysis showed that SPRY4-IT1 expression is an independent prognostic factor of overall survival in patients with UCB. Additionally, the results of in vitro assays showed that the suppression of SPRY4-IT1 expression in bladder cancer cells significantly inhibit cell proliferation, migration, and invasion. CONCLUSIONS: Our data suggested that lncRNA SPRY4-IT1 is a novel molecule involved in bladder cancer progression, which provide a potential prognostic biomarker and therapeutic target.

Down-regulation of miR-497 is associated with poor prognosis in renal cancer.

INTRODUCTION: Clear cell renal cell carcinoma (ccRCC) is the most common type of cancer in the adult kidney, and the prognosis of metastatic ccRCC remains poor with high mortality. Recent study indicated that microRNAs (miRNAs) played critical roles in tumor progression. The aim of this study was to investigate the expression, biological role and clinical significance of miR-497 in ccRCC. METHODS: Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of miR-497 in renal cancer cell lines and ccRCC tissues. The association between miR-497 expression and overall survival was estimated by the Kaplan-Meier method. Gain of function assays were performed in the 786-O renal cancer cell line. RESULTS: Expression of the miR-497 was significantly decreased in renal cancer cell lines and ccRCC tissues when compared with normal human proximal tubule epithelial cells and adjacent non-tumor tissues. Decreased miR-497 expression was significantly associated with tumor stage, histological grade and lymph node metastases. Significantly shorter overall survival was observed in patients with lower expression of the miR-497. Overexpression of miR-497 significantly inhibited renal cancer cell proliferation, migration and invasion. CONCLUSIONS: Our results demonstrated that miR-497 was decreased in ccRCC tissues and may provide a potential prognostic biomarker and a potential target for therapeutic intervention.

[Application of self-made dual tubes with lateral holes in the surgical treatment of hypospadias].

OBJECTIVE: To increase the success rate of surgical treatment in patients with hypospadias. METHODS: 220 cases of hypospadias underwent one-stage urethra plasty. After the penis was straightened, urethra plasty was performed with pediculated preputial entoplastron (Duckett's method) in 195 cases; with combination of scrotal septum and pediculated preputial entoplastron in 20 cases; with free bladder mucosa transplantation in 2 cases. The self-made dual silastic tubes with lateral mini-holes were applied to support new urethra in all the cases. RESULTS: The patients were followed up for 1 - 8 years. 208 cases achieved successful results. There were 2 cases of urethral fistula, 6 cases of urethral stenosis at anastomosis site, 4 cases of stenosis at urethral orifice. CONCLUSIONS: The success rate (94.5%) suggests great advantages of the self-made dual tube with lateral mini-holes to support new urethra. It can facilitate drainage and irrigation and reduce the complications such as infection, fistula and stenosis.