Hongqian Guo

TGFβ1 secreted by cancer-associated fibroblasts induces epithelial-mesenchymal transition of bladder cancer cells through lncRNA-ZEB2NAT

Urinary bladder cancer (UBC) patients at muscle invasive stage have poor clinical outcome, due to high propensity for metastasis. Cancer-associated fibroblasts (CAFs), one of the principal constituents of the tumor stroma, play an important role in tumor development. However, it is unclear whether CAFs from UBC induce cell invasion and which signaling pathway is involved. Herein, we found that conditional medium from UBC CAFs (CAF-CM) enhanced the invasion of UBC cells. CAF-CM induced the epithelial-mesenchymal transition (EMT) by regulating expression levels of EMT-associated markers in UBC cells. Higher concentration of TGFβ1 in CAF-CM, comparing with the CM from adjacent normal fibroblast, led to phosphorylation of Smad2 in UBC cells. Additionally, inhibition of TGFβ1 signaling decreased the EMT-associated gene expression, and cancer cell invasion. Interestingly, a long non-coding RNA, ZEB2NAT, was demonstrated to be essential for this TGFβ1-dependent process. ZEB2NAT depletion reversed CAF-CM-induced EMT and invasion of cancer cells, as well as reduced the ZEB2 protein level. Consistently, TGFβ1 mRNA expression is positively correlated with ZEB2NAT transcript and ZEB2 protein levels in human bladder cancer specimens. Our data revealed a novel mechanism that CAFs induces EMT and invasion of human UBC cells through the TGFβ1-ZEB2NAT-ZEB2 axis.

Laparoscopic Radiofrequency Ablation of Renal Tumors: 32-Month Mean Follow-up Results of 106 Patients

OBJECTIVE To report our experience of laparoscopic radiofrequency ablation (RFA) on patients with renal tumors. RFA has been increasingly applied in the management of small renal tumors. However, it was performed mostly via percutaneous approach, with limited cases and a short follow-up period. METHODS From February 2006 to March 2008, laparoscopic RFA was performed on 106 renal tumors (size range: 0.9-5.5 cm) in 106 selected patients (74 men and 32 women, age range: 25-81 years). Initial contrast-enhanced computed tomography (CT) examination was performed seven days after the procedure, with subsequent CT assessment at three months, six months, and every six months thereafter. Serum creatinine measurement was conducted along with each time CT examination. RESULTS The mean follow-up period was 32 months (range: 12-48). All 106 tumors were biopsied before RFA, of which 90 were diagnosed as renal cell carcinoma (RCC) (84.90%). There was one incomplete ablation. One case with radiographic local recurrence was then proved by pathologic analysis of the nephrectomy specimen to have no cancer cells. The local tumor control rate was 98.1% (104/106). Of the 90 RCC cases, the disease-free survival rate was 97.8% (88/90); both the cancer-specific and the overall survival rate were 100%. No death or renal failure after the procedure has yet been found. CONCLUSIONS Our results showed that the laparoscopic RFA on small renal mass was safe, with outcomes of patients comparable with those by partial nephrectomy and percutaneous RFA. Further research and a longer follow-up period are needed to confirm our results.

Radio Frequency Ablation versus Partial Nephrectomy for Clinical T1b Renal Cell Carcinoma: Long-Term Clinical and Oncologic Outcomes

PURPOSE We compared outcomes in patients treated with radio frequency ablation or partial nephrectomy for clinical cT1b renal cell carcinoma. MATERIALS AND METHODS We retrospectively reviewed the records of all patients who underwent radio frequency ablation or nephrectomy between February 2006 and December 2010. Radiographic followup with contrast imaging was performed 7 days, 3 and 6 months, and every 6 months thereafter after radio frequency ablation sequentially. The followup protocol for partial nephrectomy was every 6 months in the initial 3 years and annually thereafter. The Kaplan-Meier method was used to generate survival curves, which were compared with the log rank test. Multivariable regression analysis was done to determine predictors of survival. RESULTS A total of 56 patients who met selection criteria were included in study. Patients in the radio frequency ablation group had relatively higher mean age and a higher mean ASA® score than those in the partial nephrectomy group. Mean tumor diameter was significantly larger in the partial nephrectomy cohort. For radio frequency ablation vs partial nephrectomy 5-year overall, cancer specific and disease-free survival was 85.5% (95% CI 72.2-98.8) vs 96.6% (95% CI 95.9-97.3), 92.6% (95% CI 82.4-98.1) vs 96.6% (95% CI 95.9-97.3) and 81.0% (95% CI 66.2-95.8) vs 89.7% (95% CI 78.5-97.9), respectively. The percent decrease in the glomerular filtration rate was significantly lower in the radio frequency ablation group at early and last followup. CONCLUSIONS In appropriately selected patients with stage cT1b renal cell carcinoma radio frequency ablation is an effective treatment option that provides 5-year overall, cancer specific and disease-free survival comparable to that of partial nephrectomy as well as better renal function preservation than partial nephrectomy.

Gender disparity of living donor renal transplantation in East China

Gender disparity among living kidney donors is common world wide, which demonstrates different social and economic problems in different countries. However, few data are available for China. Therefore, we retrospectively analyzed all 139 living donor renal transplants performed in our center between 2003 and 2010. The annual number of living donor renal transplants increased from six to 26 cases per year during the observation period. Among them, 69.2% of all kidney donors were females, whereas 79.5% of the recipients were male. The average age of recipients was 34.1 ± 7.6 yr and 94% (110/117) were younger than 44 yr. In contrast, 53% (62/117) of all donors were “middle‐aged” (45–59 yr) with an average donor age of 47.8 ± 9.2 yr. The first‐degree relatives accounted for the majority of the donor pool, as the most common donor‐recipient combination consisted of mother to son. In conclusion, there was a male and young preponderance among recipients, and a female and middle‐aged one among donors of living kidney transplants in our transplant center, which might be related to socio‐cultural as well as economic factors.

Single-center comparison of complications in laparoscopic and percutaneous radiofrequency ablation with ultrasound guidance for renal tumors.

OBJECTIVE To report on postoperative complications associated with laparoscopic radiofrequency ablation (LRFA) and percutaneous radiofrequency ablation (PRFA) in a single-center experience. METHODS We conducted a retrospective review of medical records for patients undergoing LRFA or PRFA between February 2006 and March 2010 at our center. Demographics, radiographic variables, and complication rates were compared between the 2 groups. Risk factors for postoperative complications after operation were analyzed with multivariate logistic regression. RESULTS Of a total 191 patients included in this study, 132 underwent LRFA and 59 underwent PRFA. There were no significant differences between the 2 groups with respect to age, gender, biopsy data, American Society of Anesthesiologists classification, body mass index, single kidney, tumor size, tumor number, glomerular filtration rate, follow-up, or RENAL nephrometry score. We observed complications in 16 LRFA procedures (12.1%) and 10 PRFA procedures (16.9%) (P = .369). There was no difference in the distribution of the complications between LRFA and PRFA groups. The complication (grades 1 and 2) rate in the LRFA group (7.6%) was not significantly different from that in the PRFA group (10.2%) (P = .550). The complication (grade 3a) rate in the LRFA group (4.5%) was not significantly different from that in the PRFA group (6.8%) (P = .522). A multivariate analysis disclosed that extra ablation time was the only predictor of postoperative complications. CONCLUSION Significantly more anterior tumors were approached laparoscopically, and significantly more posterior tumors were approached percutaneously. Complication rate was not significantly different between LRFA and PRFA. Extra ablation time was a significant risk factor associated with postoperative complications.

In Situ Floating Hydrogel for Intravesical Delivery of Adriamycin Without Blocking Urinary Tract

Drug solution is commonly used in conventional intravesical instillation. However, most of them would be easily eliminated by voiding, which significantly limit their efficacy. Recent advances in intravesical drug delivery are to use hydrogels as drug reservoir to extend the drug residence time in bladder. However, because of the high viscosity of hydrogel, urinary obstruction is usually existed during the intravesical instillation. To overcome these, we developed a floating hydrogel for the delivery of Adriamycin (ADR). The floating hydrogel was made of ADR, thermosensitive polymer (Poloxamer 407) and NaHCO₃, which was liquid at low temperature, whereas formed gel at high temperature. In the presence of H⁺, NaHCO₃ decomposed and produced CO₂ that attached on the surface of hydrogel and helped the hydrogel float on the urine. Hence, the urinary tract will not be blocked. Meanwhile, the encapsulated ADR released in a controlled manner. These results suggest that the floating gel may have promising applications in intravesical therapy for bladder cancer.

Steroid Receptor Coactivator-3 Regulates Glucose Metabolism in Bladder Cancer Cells through Coactivation of Hypoxia Inducible Factor 1α

Background: Steroid receptor coactivator-3 (SRC-3) is frequently overexpressed in human urinary bladder cancer. Results: SRC-3 promotes urinary bladder cancer (UBC) cells proliferation through coactivating HIF1α and up-regulating the expression of genes involved in the glycolytic pathway. Conclusion: SRC-3 plays an important role in UBC development through enhancing glycolysis. Significance: Targeting SRC-3 or enzymes in glycolytic pathway could be an attractive approach in UBC therapy. Cancer cell proliferation is a metabolically demanding process, requiring high glycolysis, which is known as “Warburg effect,” to support anabolic growth. Steroid receptor coactivator-3 (SRC-3), a steroid receptor coactivator, is overexpressed and/or amplified in multiple cancer types, including non-steroid targeted cancers, such as urinary bladder cancer (UBC). However, whether SRC-3 regulates the metabolic reprogramming for cancer cell growth is unknown. Here, we reported that overexpression of SRC-3 accelerated UBC cell growth, accompanied by the increased expression of genes involved in glycolysis. Knockdown of SRC-3 reduced the UBC cell glycolytic rate under hypoxia, decreased tumor growth in nude mice, with reduction of proliferating cell nuclear antigen and lactate dehydrogenase expression levels. We further revealed that SRC-3 could interact with hypoxia inducible factor 1α (HIF1α), which is a key transcription factor required for glycolysis, and coactivate its transcriptional activity. SRC-3 was recruited to the promoters of HIF1α-target genes, such as glut1 and pgk1. The positive correlation of expression levels between SRC-3 and Glut1 proteins was demonstrated in human UBC patient samples. Inhibition of glycolysis through targeting HK2 or LDHA decelerated SRC-3 overexpression-induced cell growth. In summary, overexpression of SRC-3 promoted glycolysis in bladder cancer cells through HIF1α to facilitate tumorigenesis, which may be an intriguing drug target for bladder cancer therapy.

Minimally invasive percutaneous cystolithotomy: an effective treatment for bladder stones in infants aged <1 year

Study Type – Therapy (case series)
Level of Evidence 4

Honokiol inhibits bladder tumor growth by suppressing EZH2/miR-143 axis

The oncoprotein EZH2, as a histone H3K27 methyltransferase, is frequently overexpressed in various cancer types. However, the mechanisms underlying its role in urinary bladder cancer (UBC) cells have not yet fully understood. Herein, we reported that honokiol, a biologically active biphenolic compound isolated from the Magnolia officinalis inhibited human UBC cell proliferation, survival, cancer stemness, migration, and invasion, through downregulation of EZH2 expression level, along with the reductions of MMP9, CD44, Sox2 and the induction of tumor suppressor miR-143. Either EZH2 overexpression or miR-143 inhibition could partially reverse honokiol-induced cell growth arrest and impaired clonogenicity. Importantly, it was first revealed that EZH2 could directly bind to the transcriptional regulatory region of miR-143 and repress its expression. Furthermore, honokiol treatment on T24 tumor xenografts confirmed its anticancer effects in vivo, including suppression tumor growth and tumor stemness, accompanied by the dysregulation of EZH2 and miR-143 expressions. Our data suggest a promising therapeutic option to develop drugs targeting EZH2/miR-143 axis, such as honokiol, for bladder cancer treatment.

TGFβƒ1 Promotes Gemcitabine Resistance Through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

High tumor recurrence is frequently observed in patients with urinary bladder cancers (UBCs), with the need for biomarkers of prognosis and drug response. Chemoresistance and subsequent recurrence of cancers are driven by a subpopulation of tumor initiating cells, namely cancer stem-like cells (CSCs). However, the underlying molecular mechanism in chemotherapy-induced CSCs enrichment remains largely unclear. In this study, we found that during gemcitabine treatment lncRNA-Low Expression in Tumor (lncRNA-LET) was downregulated in chemoresistant UBC, accompanied with the enrichment of CSC population. Knockdown of lncRNA-LET increased UBC cell stemness, whereas forced expression of lncRNA-LET delayed gemcitabine-induced tumor recurrence. Furthermore, lncRNA-LET was directly repressed by gemcitabine treatment-induced overactivation of TGFβ/SMAD signaling through SMAD binding element (SBE) in the lncRNA-LET promoter. Consequently, reduced lncRNA-LET increased the NF90 protein stability, which in turn repressed biogenesis of miR-145 and subsequently resulted in accumulation of CSCs evidenced by the elevated levels of stemness markers HMGA2 and KLF4. Treatment of gemcitabine resistant xenografts with LY2157299, a clinically relevant specific inhibitor of TGFβRI, sensitized them to gemcitabine and significantly reduced tumorigenecity in vivo. Notably, overexpression of TGFβ1, combined with decreased levels of lncRNA-LET and miR-145 predicted poor prognosis in UBC patients. Collectively, we proved that the dysregulated lncRNA-LET/NF90/miR-145 axis by gemcitabine-induced TGFβ1 promotes UBC chemoresistance through enhancing cancer cell stemness. The combined changes in TGFβ1/lncRNA-LET/miR-145 provide novel molecular prognostic markers in UBC outcome. Therefore, targeting this axis could be a promising therapeutic approach in treating UBC patients.