Involvement of aberrantly expressed microRNAs in the pathogenesis of head and neck squamous cell carcinoma.

MicroRNAs (miRNAs) are small noncoding RNAs that act as fine-tuners of the post-transcriptional control of protein-coding or noncoding RNAs by repressing translation or cleaving RNA transcripts in a sequence-dependent manner in cells. Accumulating evidence have been indicated that aberrantly expressed miRNAs are deeply involved in human pathogenesis, including cancers. Surprisingly, these small, single-stranded RNAs (18-23 nucleotides) have been shown to function as antitumor or oncogenic RNAs in several types of cancer cells. A single miRNA has regulating hundreds or thousands of different mRNAs, and individual mRNA has been regulated by multiple different miRNAs in normal cells. Therefore, tightly controlled RNA networks can be disrupted by dysregulated of miRNAs in cancer cells. Investigation of novel miRNA-mediated RNA networks in cancer cells could provide new insights in the field of cancer research. In this review, we focus on head and neck squamous cell carcinoma (HNSCC) and discuss current findings of the involvement of aberrantly expressed miRNAs in the pathogenesis of HNSCC.

Impact of novel oncogenic pathways regulated by antitumor miR-451a in renal cell carcinoma.

Recent analyses of our microRNA (miRNA) expression signatures obtained from several types of cancer have provided novel information on their molecular pathology. In renal cell carcinoma (RCC), expression of microRNA-451a (miR-451a) was significantly downregulated in patient specimens and low expression of miR-451a was significantly associated with poor prognosis of RCC patients (P = .00305) based on data in The Cancer Genome Atlas. The aims of the present study were to investigate the antitumor roles of miR-451a and to identify novel oncogenic networks it regulated in RCC cells. Ectopic expression of miR-451a significantly inhibited cancer cell migration and invasion by RCC cell lines, suggesting that miR-451a had antitumor roles. To identify oncogenes regulated by miR-451a in RCC cells, we analyzed genome-wide gene expression data and examined information in in silico databases. A total of 16 oncogenes and were found to be possible targets of miR-451a regulation. Interestingly, high expression of 9 genes (PMM2, CRELD2, CLEC2D, SPC25, BST2, EVL, TBX15, DPYSL3, and NAMPT) was significantly associated with poor prognosis. In this study, we focused on phosphomannomutase 2 (PMM2), which was the most strongly associated with prognosis. Overexpression of PMM2 was detected in clinical specimens and Spearman's rank test indicated a negative correlation between the expression levels of miR-451a and PMM2 (P = .0409). Knockdown of PMM2 in RCC cells inhibited cancer cell migration and invasion, indicating overexpression of PMM2 could promote malignancy. Analytic strategies based on antitumor miRNAs is an effective tool for identification of novel pathways of cancer.

Regulation of antitumor miR-144-5p targets oncogenes: Direct regulation of syndecan-3 and its clinical significance.

In the human genome, miR-451a, miR-144-5p (passenger strand), and miR-144-3p (guide strand) reside in clustered microRNA (miRNA) sequences located within the 17q11.2 region. Low expression of these miRNAs is significantly associated with poor prognosis of patients with renal cell carcinoma (RCC) (miR-451a: P = .00305; miR-144-5p: P = .00128; miR-144-3p: P = 9.45 × 10-5 ). We previously reported that miR-451a acted as an antitumor miRNA in RCC cells. Involvement of the passenger strand of the miR-144 duplex in the pathogenesis of RCC is not well understood. Functional assays showed that miR-144-5p and miR-144-3p significantly reduced cancer cell migration and invasive abilities, suggesting these miRNAs acted as antitumor miRNAs in RCC cells. Analyses of miR-144-5p targets identified a total of 65 putative oncogenic targets in RCC cells. Among them, high expression levels of 9 genes (FAM64A, F2, TRIP13, ANKRD36, CENPF, NCAPG, CLEC2D, SDC3, and SEMA4B) were significantly associated with poor prognosis (P < .001). Among these targets, expression of SDC3 was directly controlled by miR-144-5p, and its expression enhanced cancer cell aggressiveness. We identified genes downstream by SDC3 regulation. Data showed that expression of 10 of the downstream genes (IL18RAP, SDC3, SH2D1A, GZMH, KIF21B, TMC8, GAB3, HLA-DPB2, PLEK, and C1QB) significantly predicted poor prognosis of the patients (P = .0064). These data indicated that the antitumor miR-144-5p/oncogenic SDC3 axis was deeply involved in RCC pathogenesis. Clustered miRNAs (miR-451a, miR-144-5p, and miR-144-3p) acted as antitumor miRNAs, and their targets were intimately involved in RCC pathogenesis.

Molecular pathogenesis of pancreatic ductal adenocarcinoma: Impact of passenger strand of pre-miR-148a on gene regulation.

We previously used RNA sequencing to establish the microRNA (miRNA) expression signature of pancreatic ductal adenocarcinoma (PDAC). We found that both strands of pre-miR-148a (miR-148a-5p: the passenger strand and miR-148a-3p: the guide strand) were downregulated in cancer tissues. Ectopic expression of miR-148a-5p and miR-148a-3p significantly inhibited cancer cell migration and invasion, indicating that both strands of pre-miR-148a had tumor-suppressive roles in PDAC cells. In silico database and genome-wide gene expression analyses identified a total of 15 genes that were putative targets regulated by these miRNAs. High expression of miR-148a-5p targets (PHLDA2, LPCAT2 and AP1S3) and miR-148a-3p targets (SMA, ENDOD1 and UHMK1) was associated with poor prognosis of patients with PDAC. Moreover, knockdown of PHLDA2 expression inhibited cancer cell aggressiveness, suggesting PHLDA2 acted as an oncogene in PDAC cells. Involvement of the passenger strand of pre-miR-148a (miR-148-5p) is a new concept in cancer research. Novel approaches that identify tumor-suppressive miRNA regulatory networks in lethal PDAC might provide new prognostic markers and therapeutic targets for this disease.

Regulation of HMGB3 by antitumor miR-205-5p inhibits cancer cell aggressiveness and is involved in prostate cancer pathogenesis.

Our recent determination of a microRNA (miRNA) expression signature in prostate cancer (PCa) revealed that miR-205-5p was significantly reduced in PCa tissues and that it acted as an antitumor miRNA. The aim of this study was to identify oncogenic genes and pathways in PCa cells that were regulated by antitumor miR-205-5p. Genome-wide gene expression analyses and in silico miRNA database searches showed that 37 genes were putative targets of miR-205-5p regulation. Among those genes, elevated expression levels of seven in particular (HMGB3, SPARC, MKI67, CENPF, CDK1, RHOU, and POLR2D) were associated with a shorter disease-free survival in a large number of patients in the The Cancer Genome Atlas (TCGA) database. We focused on high-mobility group box 3 (HMGB3) because it was the most downregulated by ectopic expression of miR-205-5p in PC3 cells and its expression was involved in PCa pathogenesis. Luciferase reporter assays showed that HMGB3 was directly regulated by miR-205-5p in PCa cells. Knockdown studies using si-HMGB3 showed that expression of HMGB3 enhanced PCa cell aggressiveness. Overexpression of HMGB3/HMGB3 was confirmed in naive PCa and castration-resistant PCa (CRPC) clinical specimens. Novel approaches to analysis of antitumor miRNA-regulated RNA networks in PCa cells may provide new insights into the pathogenic mechanisms of the disease.

Dual strands of the miR-223 duplex (miR-223-5p and miR-223-3p) inhibit cancer cell aggressiveness: targeted genes are involved in bladder cancer pathogenesis.

Analyses of microRNA (miRNA) expression signatures obtained by RNA sequencing revealed that some passenger miRNAs (miR-144-5p, miR-145-3p, miR-149-3p, miR-150-3p, and miR-199a-3p) acted as anti-tumor miRNAs in several types of cancer cells. The involvement of passenger strands in the pathogenesis of human cancer is a novel concept. Based on the miRNA signature of bladder cancer (BC) obtained by RNA sequencing, we focused on both strands of the miR-223-duplex (miR-223-5p and miR-223-3p) and investigated their functional significance in BC cells. Ectopic expression of these miRNAs showed that both miR-223-3p (the guide strand) and miR-223-5p (the passenger strand) inhibited cancer cell migration and invasion of BC cells. The role of miR-223-5p (the passenger strand) has not been well studied. Combining gene expression studies and in silico database analyses, we demonstrated the presence of 20 putative target genes that could be regulated by miR-223-5p in BC cells. Among these targets, high expression of five genes (ANLN, INHBA, OIP5, CCNB1, and CDCA2) was significantly associated with poor prognosis of BC patients based on The Cancer Genome Atlas (TCGA) database. Moreover, we showed that a gene (ANLN) encoding a multifunctional actin-binding protein was directly regulated by miR-223-5p in BC cells. Overexpression of ANLN was observed in BC clinical specimens and high expression of ANLN was significantly associated with poor prognosis of BC patients. We suggest that studies of regulatory cancer networks, including the passenger strands of miRNAs, may provide new insights into the pathogenic mechanisms of BC.

Molecular pathogenesis of interstitial cystitis based on microRNA expression signature: miR-320 family-regulated molecular pathways and targets.

Interstitial cystitis (IC), also known as bladder pain syndrome, is a chronic inflammatory disease that affects the bladder. The symptoms of IC vary, including feeling an urgent need for immediate urination and of needing to urinate often, as well as bladder or pelvic pain. Despite its high incidence, no molecular diagnostic methods are available for IC, and the molecular pathogenesis is unknown. microRNAs (miRNA) can regulate expression of RNA transcripts in cells and aberrant expression of miRNAs is associated with several human diseases. Here, we investigated the molecular pathogenesis of IC based on miRNA expression signatures. RNA sequencing of miRNA levels in IC tissues and comparison with levels in normal bladder tissue and bladder cancer revealed dysregulated expression of 366 miRNAs (203 and 163 down- and upregulated miRNAs, respectively). In particular, miR-320 family miRNAs(miR-320a, miR-320b, miR-320c, miR-320d and miR-320e) had downregulated expression in IC tissues. Genome-wide gene expression analyses and in silico database analyses showed that three transcription factors, E2F-1, E2F-2 and TUB, are regulated by miR-320 family miRNAs. Immunostaining of IC tissues confirmed that these transcription factors are overexpressed in IC tissues. Novel approaches that identify aberrantly expressed miRNA regulatory networks in IC could provide new prognostic markers and therapeutic targets for this disease.

Molecular pathogenesis of renal cell carcinoma: Impact of the anti-tumor miR-29 family on gene regulation.

OBJECTIVES: To identify key oncogenes and proteins that are controlled by the microRNA miR-29 family (miR-29a, miR-29b and miR-29c) in renal cell carcinoma pathogenesis. METHODS: Genome-wide gene expression and in silico database analyses were carried out. The Cancer Genome Atlas database was used to investigate the clinical significance of gene expression data in renal cell carcinoma patients. Loss-of-function assays were applied to investigate the function of target genes. RESULTS: We identified 47 possible target genes that might be regulated by the miR-29 family in renal cell carcinoma cells. Among the targets of the miR-29 family, high expression of 10 genes (ADAMTS14, TRIB13, SERPINH1, FCGR1B, COL1A1, LAIR2, WISP2, TREM1, TNKS1BP1 and GBP2) significantly predicted poor patient prognosis (P < 0.001). SERPINH1 was directly regulated by the miR-29 family, and its overexpression was detected in renal cell carcinoma surgical specimens and tyrosine kinase inhibitor failure autopsy specimens. High expression of SERPINH1 was significantly associated with tumor stage, pathological grade and poor prognosis (P < 0.0001). Knockdown assays showed that its expression enhanced cancer cell migration and invasive abilities. CONCLUSIONS: Genes regulated by the anti-tumor miR-29 family are closely involved in the molecular pathogenesis of renal cell carcinoma. Our approach based on anti-tumor microRNAs might contribute to the development of new diagnostic markers and therapeutic strategies.

Regulation of ITGA3 by the anti-tumor miR-199 family inhibits cancer cell migration and invasion in head and neck cancer.

For patients with head and neck squamous cell carcinoma (HNSCC), survival rates have not improved due to local recurrence and distant metastasis. Current targeted molecular therapies do not substantially benefit HNSCC patients. Therefore, it is necessary to use advanced genomic approaches to elucidate the molecular mechanisms underlying the aggressiveness of HNSCC cells. Analysis of our microRNA (miRNA) expression signature by RNA sequencing showed that the miR-199 family (miR-199a-5p, miR-199a-3p, miR-199b-5p and miR-199b-3p) was significantly reduced in cancer tissues. Ectopic expression of mature miRNA demonstrated that all members of the miR-199 family inhibited cancer cell migration and invasion by HNSCC cell lines (SAS and HSC3). These findings suggested that both passenger strands and guide strands of miRNA are involved in cancer pathogenesis. In silico database and genome-wide gene expression analyses revealed that the gene coding for integrin α3 (ITGA3) was regulated by all members of the miR-199 family in HNSCC cells. Knockdown of ITGA3 significantly inhibited cancer cell migration and invasion by HNSCC cells. Moreover, overexpression of ITGA3 was confirmed in HNSCC specimens, and high expression of ITGA3 predicted poorer survival of the patients (P = 0.0048). Our data revealed that both strands of pre-miR-199a (miR-199a-5p and miR-199a-3p) and pre-miR-199b (miR-199b-5p and miR-199b-3p) acted as anti-tumor miRNA in HNSCC cells. Importantly, the involvement of passenger strand miRNA in the regulation of cellular processes is a novel concept in RNA research. Novel miRNA-based approaches for HNSCC can be used to identify potential targets for the development of new therapeutic strategies.

Regulation of spindle and kinetochore-associated protein 1 by antitumor miR-10a-5p in renal cell carcinoma.

Analysis of our original microRNA (miRNA) expression signature of patients with advanced renal cell carcinoma (RCC) showed that microRNA-10a-5p (miR-10a-5p) was significantly downregulated in RCC specimens. The aims of the present study were to investigate the antitumor roles of miR-10a-5p and the novel cancer networks regulated by this miRNA in RCC cells. Downregulation of miR-10a-5p was confirmed in RCC tissues and RCC tissues from patients treated with tyrosine kinase inhibitors (TKI). Ectopic expression of miR-10a-5p in RCC cell lines (786-O and A498 cells) inhibited cancer cell migration and invasion. Spindle and kinetochore-associated protein 1 (SKA1) was identified as an antitumor miR-10a-5p target by genome-based approaches, and direct regulation was validated by luciferase reporter assays. Knockdown of SKA1 inhibited cancer cell migration and invasion in RCC cells. Overexpression of SKA1 was observed in RCC tissues and TKI-treated RCC tissues. Moreover, analysis of The Cancer Genome Atlas database demonstrated that low expression of miR-10a-5p and high expression of SKA1 were significantly associated with overall survival in patients with RCC. These findings showed that downregulation of miR-10a-5p and overexpression of the SKA1 axis were highly involved in RCC pathogenesis and resistance to TKI treatment in RCC.

Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer.

BACKGROUND: Despite recent advancements, metastatic castration-resistant prostate cancer (CRPC) is not considered curative. Novel approaches for identification of therapeutic targets of CRPC are needed. METHODS: Next-generation sequencing revealed 945-1248 miRNAs from each lethal mCRPC sample. We constructed miRNA expression signatures of CRPC by comparing the expression of miRNAs between CRPC and normal prostate tissue or hormone-sensitive prostate cancer (HSPC). Genome-wide gene expression studies and in silico analyses were carried out to predict miRNA regulation and investigate the functional significance and clinical utility of the novel oncogenic pathways regulated by these miRNAs in prostate cancer (PCa). RESULTS: Based on the novel miRNA expression signature of CRPC, miR-145-5p and miR-145-3p were downregulated in CRPC. By focusing on miR-145-3p, which is a passenger strand and has not been well studied in previous reports, we showed that miR-145-3p targeted 4 key molecules, i.e., MELK, NCAPG, BUB1, and CDK1, in CPRC. These 4 genes significantly predicted survival in patients with PCa. CONCLUSIONS: Small RNA sequencing for lethal CRPC and in silico analyses provided novel therapeutic targets for CRPC.

Aberrantly expressed microRNAs in bladder cancer and renal cell carcinoma.

Bladder cancer (BC) and renal cell carcinoma (RCC) are frequently diagnosed urinary tract cancers. Recently developed molecular-targeted therapies for RCC have shown remarkable therapeutic efficacy; however, no targeted therapeutics are currently approved for the treatment of BC, and few effective treatment options exist. Current studies have shown that small noncoding RNA molecules have major roles in cancer cells. MicroRNAs (miRNAs) are endogenous small noncoding RNA molecules that regulate protein-/nonprotein-coding RNAs in human cells. A large body of evidence suggests that aberrantly expressed miRNAs are deeply involved in the pathogenesis of human cancers. In this paper, we review recently published miRNA expression signatures of BC and RCC. We focus on downregulated or upregulated miRNAs in multiple signatures and discuss putative target genes of miRNAs. Comparisons of RCC and BC expression signatures revealed that the two types of cancer showed opposite expression patterns for miR-200 family miRNAs (i.e., miR-141/200c and miR-200a/200b/429). We discuss in silico analysis of genes targeted by miR-200 family miRNAs and the molecular mechanisms underlying BC and RCC.

Regulation of SPOCK1 by dual strands of pre-miR-150 inhibit cancer cell migration and invasion in esophageal squamous cell carcinoma.

Analysis of our microRNA (miRNA) expression signatures of human cancers based on RNA sequencing have shown that both strands of pre-miR-150, miR-150-5p (the guide strand) and miR-150-3p (the passenger strand), are significantly reduced in cancer tissues. We have investigated the functional significance of both strands of pre-miR-150 in cancer cells. The aim of this study was to investigate the antitumor function of these miRNAs and how these miRNAs regulated oncogenic targets in esophageal squamous cell carcinoma (ESCC). Ectopic expression studies demonstrated that both strands of pre-miR-150 miRNA inhibited ESCC cancer cell migration and invasion, indicating that both miR-150-5p and miR-150-3p acted as antitumor miRNAs. A combination of genome-wide gene expression analyses and in silico database searches showed that SPOCK1 (SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 1) was a candidate target of miR-150-5p and miR-150-3p in ESCC cells. Luciferase reporter assays showed that SPOCK1 was directly regulated by these miRNAs. Silencing of SPOCK1 by small interfering RNA inhibited cancer cell migration and invasion. Overexpression of SPOCK1/SPOCK1 was confirmed by real-time PCR methods and immunohistochemistry. Taken together, downregulation of both strands of pre-miR-150 and overexpression of SPOCK1 are involved in ESCC pathogenesis. The involvement of passenger strand miRNAs in the regulation of cancer cell aggressiveness is a novel concept in RNA research.

Regulation of metastasis-promoting LOXL2 gene expression by antitumor microRNAs in prostate cancer.

Our recent studies of microRNA (miRNA) expression signatures of prostate cancer (PCa) showed that six miRNAs (specifically, miR-26a, miR-26b, miR-29a, miR-29b, miR-29c and miR-218) were markedly reduced in cancer tissues. Moreover, ectopic expression of these miRNAs suppressed PCa cell aggressiveness, indicating that these miRNAs acted in concert to regulate genes that promoted metastasis. Genome-wide gene expression analysis and in silico database analysis identified a total of 35 candidate genes that promoted metastasis and were targeted by these 6 miRNAs. Using luciferase reporter assays, we showed that the lysyl oxidase-like 2 (LOXL2) gene was directly controlled by these tumor-suppressive miRNAs in PCa cells. Overexpression of LOXL2 was confirmed in PCa tissues and knockdown of the LOXL2 gene markedly inhibited the migration and invasion of PCa cells. Aberrant expression of LOXL2 enhanced migration and invasion of PCa cells. Downregulation of antitumor miRNAs might disrupt the tightly controlled RNA networks found in normal cells. New insights into the novel molecular mechanisms of PCa pathogenesis was revealed by antitumor miRNA-regulated RNA networks.

The microRNA expression signature of small cell lung cancer: tumor suppressors of miR-27a-5p and miR-34b-3p and their targeted oncogenes.

Small cell lung cancer (SCLC) constitutes approximately 15% of all diagnosed lung cancers. SCLC is a particularly lethal malignancy, as the 2-year survival rate after appropriate treatment is less than 5%. The patients with SCLC have not been received a benefit of the recently developed molecular targeted treatment. Therefore, a new treatment strategy is necessary for the patients. The molecular mechanisms underlying the aggressiveness of SCLC cells and their development of treatment-resistance are still ambiguous. In this study, we newly constructed a microRNA (miRNA) expression signature of SCLC by analysis of autopsy specimens. Based on the resultant signature, four miRNAs (miR-27a-5p, miR-485-3p, miR-34-5p and miR-574-3p) were found to be candidate anti-tumor miRNAs. To investigate their functional importance, we first validated the downregulation of miR-27a-5p and miR-34b-3p in SCLC clinical specimens. Next, we demonstrated that ectopic expression of both miR-27a-5p and miR-34b-3p significantly inhibited cancer cell aggressiveness. Our in silico analyses showed that four genes (topoisomerase 2 alpha (TOP2A), maternal embryonic leucine zipper kinase (MELK), centromere protein F (CENPF) and SRY-box 1 (SOX1) were identified as miR-27a-5p- and miR-34b-3p-regulated genes. Based on immunohistochemical analysis, TOP2A, MELK and CENPF were involved in SCLC pathogenesis. These genes might contribute to high proliferation and early metastatic spread of SCLC cells. Elucidation of differentially expressed miRNA-mediated cancer pathways based on SCLC signature may provide new insights into the mechanisms of SCLC pathogenesis.

Dual Strands of Pre-miR-149 Inhibit Cancer Cell Migration and Invasion through Targeting FOXM1 in Renal Cell Carcinoma.

Our recent studies revealed that dual strands of certain pre-microRNAs, e.g., pre-miR-144, pre-miR-145, and pre-miR-150, act as antitumor microRNAs (miRNAs) in several cancers. The involvement of passenger strands of miRNAs in cancer pathogenesis is a novel concept in miRNA research. The analysis of a miRNA expression signature in clear cell renal cell carcinoma (ccRCC) has revealed that the guide strand of pre-miR-149 is significantly downregulated in cancer tissues. The aims of this study were to investigate the functional significance of miR-149's guide strand (miR-149-5p) and passenger strand (miR-149-3p), and to identify the oncogenic genes regulated by these miRNAs in ccRCC cells. The ectopic expression of these miRNAs significantly inhibited cancer cell migration and invasion in ccRCC cells. Forkhead box protein M1 (FOXM1) was directly regulated by miR-149-5p and miR-149-3p in ccRCC cells. Knockdown studies using si-FOXM1 showed that the expression of FOXM1 enhanced RCC cell aggressiveness. Interestingly, the analysis of a large number of patients in the The Cancer Genome Atlas (TCGA) database (n = 260) demonstrated that patients with high FOXM1 expression had significantly shorter survival than did those with low FOXM1 expression (p = 1.5 × 10⁻6). Taken together, dual strands of pre-miR-149 (miR-149-5p and miR-149-3p) acted as antitumor miRNAs through the targeting of FOXM1 in ccRCC cells.

Regulation of E3 ubiquitin ligase-1 (WWP1) by microRNA-452 inhibits cancer cell migration and invasion in prostate cancer.

BACKGROUND: MicroRNA-224 (miR-224) and microRNA-452 (miR-452) are closely located on the human chromosome Xq28 region. miR-224 functions as a tumour suppressor by targeting tumour protein D52 (TPD52) in prostate cancer (PCa). Here, we aimed to investigate the functional significance of miR-452 in PCa cells. METHODS: Functional studies of PCa cells were performed using transfection with mature miRNAs or siRNAs. Genome-wide gene expression analysis, in silico analysis, and dual-luciferase reporter assays were applied to identify miRNA targets. The association between miR-452 levels and overall patient survival was estimated by the Kaplan-Meier method. RESULTS: Expression of miR-452 was significantly downregulated in PCa tissues. Transfection with mature miR-452 inhibited the migration and invasion of PCa cells. Kaplan-Meier survival curves showed that low expression of miR-452 predicted a short duration of progression to castration-resistant PCa. WW domain-containing E3 ubiquitin protein ligase-1 (WWP1) was a direct target of miR-452, and knockdown of WWP1 inhibited the migration and invasion of PCa cells. WWP1 was upregulated in PCa clinical specimens. CONCLUSIONS: Regulation of the miR-452-WWP1 axis contributed to PCa cell migration and invasion, and elucidation of downstream signalling of this axis will provide new insights into the mechanisms of PCa oncogenesis and metastasis.

LAPAROSCOPIC RADICAL NEPHRECTOMY FOR LARGE RENAL CELL CARCINOMA: RETROSPECTIVE ANALYSIS OF SAFETY AND ONCOLOGICAL OUTCOME.

(Objectives) To evaluate the safety and oncologic efficacy of laparoscopic radical nephrectomy (LRN) for renal cell carcinoma (RCC) >7 cm, we retrospectively reviewed the clinical outcome and long-term cancer control of patients who underwent LRN in comparison to open radical nephrectomy (ORN). (Patients and methods) The clinical records of 79 patients with RCC >7 cm, who underwent radical nephrectomy (37 LRN; 42 ORN) between 1993 and 2014, were reviewed. (Results) The 2 groups (LRN and ORN) were comparable regarding age, body mass index and mean tumor size (86.5 mm vs. 94.6 mm).The operative time was significantly longer in the LRN group than ORN group (204 min vs. 168 min; p<0.05) and blood loss was significantly lower in the LRN group than in the ORN group (144 ml vs. 930 ml; p<0.05).No statistically significant difference was found in complication rate (10.8% vs. 23.8%) and the 2-year recurrence-free survival rate (85.6% vs. 83.8%). (Conclusion) Despite the longer operative time, LRN for large RCC was associated with lower blood loss. This study provides evidence of the safety and efficacy of LRN for large RCC.

FGFR inhibition augments anti-PD-1 efficacy in murine FGFR3-mutant bladder cancer by abrogating immunosuppression.

The combination of targeted therapy with immune checkpoint inhibition (ICI) is an area of intense interest. We studied the interaction of fibroblast growth factor receptor (FGFR) inhibition with ICI in urothelial carcinoma (UC) of the bladder, in which FGFR3 is altered in 50% of cases. Using an FGFR3-driven, Trp53-mutant genetically engineered murine model (UPFL), we demonstrate that UPFL tumors recapitulate the histology and molecular subtype of their FGFR3-altered human counterparts. Additionally, UPFL1 allografts exhibit hyperprogression to ICI associated with an expansion of T regulatory cells (Tregs). Erdafitinib blocked Treg proliferation in vitro, while in vivo ICI-induced Treg expansion was fully abrogated by FGFR inhibition. Combined erdafitinib and ICI resulted in high therapeutic efficacy. In aggregate, our work establishes that, in mice, co-alteration of FGFR3 and Trp53 results in high-grade, non-muscle-invasive UC and presents a previously underappreciated role for FGFR inhibition in blocking ICI-induced Treg expansion.

Laparoscopic redo pyeloplasty with a buccal mucosal graft.

Introduction: Redo pyeloplasty can be difficult due to scar tissue or fibrosis. Ureteral reconstruction with a buccal mucosal graft is performed safely and successfully, but most reports of ureteral reconstruction using a buccal mucosal graft are of robot-assisted surgery, with few reports of laparoscopic-assisted surgery. A case of laparoscopic-assisted redo pyeloplasty using a buccal mucosal graft is presented. Case presentation: A 53-year-old woman was diagnosed with ureteropelvic junction obstruction, and a double-J stent was placed to relieve backache. She visited our hospital 6 months after double-J stent placement. Three months later, laparoscopic pyeloplasty was performed. At 2 months postoperatively, anatomic stenosis occurred. Holmium laser endoureterotomy and balloon dilation were performed; however, the anatomic stenosis recurred, and laparoscopic redo pyeloplasty with a buccal mucosal graft was performed. After redo pyeloplasty, obstruction was improved, and her symptoms disappeared. Conclusion: This is the first case of using a buccal mucosal graft for laparoscopic pyeloplasty in Japan.