Long-term effect of transurethral partial cystectomy with a 2-micrometer continuous-wave laser for non-muscle-invasive bladder cancer.

Purpose: We have reported the efficacy and safety of 2-micrometer continuous-wave laser cystectomy of non-muscle invasive bladder tumor (NMIBC) (J Urol. 2009;182:66-9). In this study, we evaluated the long-term outcomes of patients with NMIBC who underwent transurethral partial cystectomy with a 2-micrometer continuous-wave laser, and explored the risk factors for tumor recurrence. Methods: This was a retrospective study of patients with NMIBC planned to undergo transurethral partial cystectomy with a 2-micrometer continuous-wave laser at the Fourth Medical Center of the PLA General Hospital between January 2012 and December 2014. The primary outcome was bladder cancer recurrence. Results: A total of 75 patients were enrolled. Sixty-two (82.7%) were male. The patients were 59.8 ± 12.9 years of age. The mean operation time was 38.7 ± 20.4 min. No Clavien grade >2 complications occurred. The duration of catheter indwelling was 3.6 ± 1.8 days. The hospital stay was 6.0 ± 2.3 days. The median follow-up was 80 months. A total of 17 patients had a recurrence during follow-up, and the recurrence-free survival (RFS) rate was 77.3%. In the multivariable analysis, the tumor risk group were independently associated with the recurrence of NMIBC (p = 0.026). Conclusions: After TURBT with a 2-micrometer continuous-wave laser, RFS was 77.3% at the median follow-up of 80 months. All complications were mild. Only tumor risk group was independently associated with the recurrence of NMIBC.

GTSE1 promotes tumor growth and metastasis by attenuating of KLF4 expression in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors and is characterized by a poor prognosis. Although G2- and S -phase expressed-1 (GTSE1) is known to be involved in the progression and metastasis of various cancers, its significance and mechanism in ccRCC remain unknown. In the present study, we found that GTSE1 was overexpressed in ccRCC tissues, especially in metastatic samples. Moreover, high GTSE1 expression was positively correlated with higher pT stage, tumor size, clinical stage, and WHO/ISUP grade and worse prognosis. And GTSE1 expression served as an independent prognostic factor for overall survival (OS). In addition, GTSE1 knockdown inhibited ccRCC cell proliferation, migration, and invasion, and enhanced cell apoptosis in vitro and in vivo. GTSE1 was crucial for epithelial-mesenchymal transition (EMT) in ccRCC. Mechanistically, GTSE1 depletion could upregulate the expression of Krüppel-like factor 4 (KLF4), which acts as a tumor suppressor in ccRCC. Downregulation of KLF4 effectively rescued the inhibitory effect induced by GTSE1 knockdown and reversed the EMT process. Overall, our results revealed that GTSE1 served as an oncogene regulating EMT through KLF4 in ccRCC, and that GTSE1 could also serve as a novel prognostic biomarker and may represent a promising therapeutic target for ccRCC.

Loss of CMTM6 promotes DNA damage-induced cellular senescence and antitumor immunity.

Recent studies have revealed that chemokine-like factor-like MARVEL transmembrane domain-containing family member 6 (CMTM6) promotes tumor progression and modulates tumor immunity by regulating programmed death-ligand 1 stability; however, its intrinsic functions and regulatory mechanisms in clear cell renal cell carcinoma (ccRCC) remain poorly understood. Here, we show that CMTM6 is upregulated in ccRCC tissues and is strongly associated with advanced tumor grades, early metastases, and a worse prognosis. CMTM6 depletion significantly impaired the proliferation, migration, and invasion of ccRCC cells in vitro and in xenograft mouse models in vivo. In addition, targeting CMTM6 promotes anti-tumor immunity, represented by increased infiltration of CD4+ and CD8+ T cells in syngeneic graft mouse models. Further research revealed that loss of CMTM6 triggered aberrant activation of DNA damage response, resulting in micronucleus formation and G2/M checkpoint arrest, finally leading to cellular senescence with robust upregulation of numerous chemokines and cytokines. Our findings show for the first time the novel role of CMTM6 in maintaining cancer genome stability and facilitating tumor-mediated immunosuppression, linking DNA damage signaling to the secretion of inflammatory factors. Targeting CMTM6 may improve the treatment of patients with advanced ccRCC.

Resistance Mechanism to Metsulfuron-Methyl in Polypogon fugax.

Polypogon fugax is a common winter weed in China and other Asia countries. We have previously found a P. fugax biotype (R) resistant to acetyl co-enzyme A carboxylase (ACCase) herbicides also cannot be effectively controlled by some acetolactate synthase (ALS) herbicides. This study evaluated the level of resistance to four ALS herbicides (metsulfuron-methyl, chlorsulfuron, monosulfuron, pyribambenz isopropyl) in the R biotype and the associated resistance mechanism. The R biotype exhibited moderate level of resistance to metsulfuron-methyl (6.0-fold) compared with the sensitive biotype (S). Sequence analysis of ALS gene revealed that two ALS genes existed in P. fugax. However, no substitution associated with ALS resistance mechanism were found in ALS genes between the S and R biotypes. The activity of ALS enzyme isolated from the R biotype was inherently higher and less sensitive to metsulfuron-methyl than the S biotype. Glutathione S-transferases (GST) activity was also less sensitive to metsulfuron-methyl in the R than as the S biotypes. Malathion, a cytochrome P450 (CYP) monooxygenase inhibitor, had much greater synergistic effect with metsulfuron-methyl on the R than as the S plants, reducing the ED50 value (herbicide dose to inhibit growth by 50%) of metsulfuron-methyl by 23- and 6-fold, respectively, suggesting that CYP mediated enhanced metabolism might contribute to the resistance to ALS herbicides. These results suggest that metsulfuron-methyl resistance in the R biotype was associated with the up-regulated ALS enzymatic activity and the GST and CYP-mediated enhanced herbicide metabolism.

The Correlation Between Platelet-to-Lymphocyte Ratio and Neutrophil-to-Lymphocyte Ratio with Hepatic Echinococcosis.

OBJECTIVE: To explore the correlation between neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) with hepatic hydatid diseases. METHODS: The clinical data of 420 patients with hydatid disease who were treated in our hospital from October 2015 to October 2018 were collected from the database of our hospital. According to the postoperative pathological diagnosis, 200 patients were assigned into the alveolar echinococcosis (AE) group, and 220 patients were assigned into the cystic echinococcosis (CE) group. A total of 160 healthy examinees were enrolled as the control group. The main observation indexes included preoperative PLR and NLR. Pearson's correlation was used to analyze the correlation between PLR and NLR with clinical indicators in HE patients, and the receiver operator characteristic (ROC) curve was used to evaluate the clinical values of PLR and NLR in diagnosing different types of hydatid diseases. RESULTS: The results revealed that the expressions of PLR and NLR were significantly higher in the AE group than in the CE and control groups (P<0.05). The results of multiple linear regression analysis revealed that PLR was positively correlated with aspartate aminotransferase, alanine aminotransferase, total bilirubin, direct bilirubin, alkaline phosphatase and γ-glutamyltranspeptidase (P<0.05). NLR was correlated with albumin content (P<0.05). ROC curve analysis results revealed that the area under the curve (AUC) of PLR and NLR for AE was 0.800 and 0.700 respectively, and the AUC for CE was 0.78 and 0.75 respectively. CONCLUSION: The NLR and PLR of AE patients were higher than those of CE patients, and the high inflammation of CE patients may be correlated to the reproductive mode of Echinococcus multilocularis. PLR and NLR have certain diagnostic values for disease classification, but PLR has higher specificity when compared with NLR.

Comparative Transcriptome Analysis Revealing the Different Germination Process in Aryloxyphenoxypropionate-Resistant and APP-Susceptible Asia Minor Bluegrass (Polypogon fugax).

Herbicide-resistant mutations are predicted to exhibit fitness cost under herbicide-free conditions. Asia minor bluegrass (Polypogon fugax) is a common weed species in the winter crops. Our previous study established a P. fugax accession (LR) resistant to aryloxyphenoxypropionate (APP) herbicides, which also exhibited germination delay relative to the susceptible accession (LS). A comparative transcriptome was conducted to analyze the gene expression profile of LS and LR at two germination time points. A total of 11,856 and 23,123 differentially expressed genes (DEGs) were respectively identified in LS and LR. Most DEGs were involved in lipid metabolism, carbohydrate metabolism, amino acid metabolism, and secondary metabolites biosynthesis. Twenty-four genes involved in carbohydrate and fatty acid metabolism had higher relative expression levels in LS than LR during germination. Nine genes involved in gibberellin (GA) and abscisic acid (ABA) signal transduction showed different expression patterns in LS and LR, consistent with their different sensitivity to exogenous hormones treatments. This study first provided insight into transcriptional changes and interaction in the seed germination process of P. fugax. It compared the differential expression profile between APP herbicides resistance and susceptible accessions during germination, which contributed to understanding the association between herbicide resistance and fitness cost.

Kidney ventrally rotation technique in retroperitoneal robot-assisted partial nephrectomy for posterior hilar tumor: technical feasibility and preliminary results.

PURPOSE: The retroperitoneal robotic assisted partial nephrectomy (RAPN) is suitable for tumors locating on the posterior side of the kidney. However, the posterior hilar tumor poses an additional surgical challenge due to the special location and poor tumor exposure. We developed a novel kidney ventrally rotation technique to overcome this difficulty during retroperitoneal RAPN and evaluated its efficacy in a retrospective case-control comparative study. METHODS: From March 2016 to April 2019, a total of 39 patients with posterior renal hilar tumor underwent retroperitoneal RAPN. The kidney ventrally rotation technique, which improved the tumor exposure by opening the peritoneum and rotating the kidney ventrally, was applied in 24 cases, and the conventional RAPN was performed in the other 15 cases (control group). Perioperative data was analyzed to evaluate the efficacy of the kidney ventrally rotation technique. RESULTS: In kidney rotation group, the 24 patients underwent RAPN successfully without converting to open surgery or radical nephrectomy. The warm ischemia time was 17.4 ± 6.6 min, which was significantly shorter than 24.5 ± 8.3 min in control group. The mean operation time (80 ± 24 min) and estimated blood loss (104 ± 65 ml) were not different from the control group. No sever complications occurred, and no positive surgical margin was found in all the malignant cases. After 14 months follow-up, no recurrence or metastasis occurred in all cases. CONCLUSION: Kidney ventrally rotation technique is safe and feasible for improving the exposure of posterior renal hilar tumor during retroperitoneal RAPN. It could be regarded as an efficient option for the management of posterior hilar tumor.

Overexpression of microRNA-9 enhances cisplatin sensitivity in hepatocellular carcinoma by regulating EIF5A2-mediated epithelial-mesenchymal transition.

We investigated the role of microRNA (miR)-9 in modulating chemoresistance in hepatocellular carcinoma (HCC) cells. MiR-9 was overexpressed or knocked down in HCC cell lines. Cell viability, cell proliferation, the expression of EIF5A2 and the epithelial-mesenchymal transition (EMT)-related proteins were examined. HCC cells overexpressing miR-9 were more sensitive to cisplatin; miR-9 knockdown yielded the opposite result. The in vivo nude mouse HCC xenograft tumors yielded the same results. EIF5A2 was identified as a potential target of miR-9, where miR-9 regulated EIF5A2 expression at mRNA and protein level. EIF5A2 knockdown reversed miR-9 inhibition-mediated cisplatin resistance. Altering miR-9 and EIF5A2 expression changed E-cadherin and vimentin expression. Furthermore, EIF5A2 mediated miR-9 EMT pathway regulation, indicating that miR-9 can enhance cisplatin sensitivity by targeting EIF5A2 and inhibiting the EMT pathway. Targeting miR-9 may be useful for overcoming drug resistance in HCC.

Regulatory mechanisms of nitrogen (N) on cadmium (Cd) uptake and accumulation in plants: A review.

Cadmium (Cd) is a heavy metal that is toxic to plants and animals. Nitrogen (N), the most significant macro-nutrient and a common input for crop production, is often excessively applied than plants' demands by farmers to obtain more economic benefits. Understanding the regulatory mechanisms of N that control Cd uptake, translocation, and accumulation may enable the development of solutions regarding Cd pollution in the trophic chain, a major and global threat to agricultural sustainability and human health. In this review, we clarified that an increased amount of N, regardless of its form, enhances Cd uptake, translocation, and accumulation in plants, and nitrate promotes Cd uptake more than any other N form. We also described that N fertilizer alters the Cd exchange capacity and the bio-available Cd content in soil; regulates nitric oxide induced divalent cation gene expression of Nramp1, HMA2, and IRT1; and changes cell wall isolation, chelation capacity, and oxidative resistance to regulate Cd accumulation in plants. By revealing the integrated interaction effects between Cd accumulation and N fertiliser use, we propose new challenges to investigate the functions and mechanisms of N in Cd-contaminated croplands and develop suitable N-fertilisation protocols to practically reduce food health risks in agricultural food production.

Robot-assisted laparoscopic antegrade versus open inguinal lymphadenectomy: a retrospective controlled study.

BACKGROUND: To investigate the surgical methods and clinical results of robot-assisted laparoscopic antegrade inguinal lymphadenectomy. METHODS: A retrospective study was performed on clinical data from 19 patients with penile cancer admitted from March 2013 to October 2017. Among them, nine patients underwent robot-assisted laparoscopic antegrade inguinal lymphadenectomy (robot-assisted group) and 10 patients underwent open inguinal lymphadenectomy (open group). In the robot-assisted group, preoperative preparation, patient position, robot placement, design of operating channel and establishment of operating space are described. Key surgical procedures and techniques are also summarized. In addition, the number of lymph nodes removed, postoperative complications and follow-up in both groups were statistically analyzed. RESULTS: For the 9 patients in the robot-assisted group, surgery was successfully accomplished at 17 sides without intraoperative conversion to open surgery. The surgery time for each side was 45~90 min using laparoscope with an average of 68.5 ± 13.69 min/side. The intraoperative blood loss was estimated to be < 10 ml/side, and the number of removed lymph nodes was not significantly different from that of the open group (12 ± 4.2/side vs.11 ± 5.8/side, P = 0.84). There were no postoperative complications such as skin necrosis, delayed wound healing and cellulitis in the robot-assisted group. Skin-related complications occurred in 9 (45%) of the 20 sides in the open group. During a median follow-up of 25 months in robot-assisted group and 52.5 mouths in open group, was not significantly different there were no statistical differences in recurrence-free survival between the groups (75% vs 60%, p = 0.536). CONCLUSION: Robot-assisted laparoscopic antegrade inguinal lymphadenectomy achieved the desired surgical outcomes with fewer intraoperative and postoperative complications. The robotic arms of the surgical system were placed between the lower limbs of each patient. There was no need to re-position the robotic arms during bilateral inguinal lymphadenectomy. This simplified the procedure and reduced the use of trocars. If necessary, pelvic lymphadenectomy could be performed simultaneously using the original trocar position.

Retraction Note: Antisense oligonucleotides targeting midkine induced apoptosis and increased chemosensitivity in hepatocellular carcinoma cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

COUP­TFII promotes epithelial­mesenchymal transition by inhibiting miR­34a expression in colorectal cancer.

Chicken ovalbumin upstream promoter­transcription factor II (COUP­TFII) expression is upregulated in colorectal cancer and is associated with its progression and a poor prognosis. The aim of the present study was to determine whether COUP­TFII regulates colorectal cancer cell (CRC) invasion and migration by inhibiting microRNA (miR)­34a. Transwell system and wound healing assays were performed to examine cell invasiveness and migration, respectively. Reverse transcription polymerase chain reaction and western blotting were used to detect the RNA and protein levels of target molecules, respectively. The results revealed that COUP­TFII knockdown significantly inhibited CRC invasion and migration. In addition, the expression of miR­34a, a well­known tumor suppressor was revealed to be inversely correlated with COUP­TFII expression. The miR­34a mimic significantly reduced CRC invasion and migration abilities, while the miR­34a inhibitor enhanced CRC invasion and migration activity. There was no significant difference between the negative small interfering RNA and miR­34a inhibitor groups following knockdown of COUP­TFII. Furthermore, western blotting demonstrated that miR­34a mimics inhibited the epithelial­mesenchymal transition (EMT) process of CRCs, while the miR­34a inhibitor had the opposite effect. Taken together, the results demonstrate that miR­34a regulates CRC invasion and migration by examining the mechanism by which COUP­TFII regulates EMT.

Effect of midkine on gemcitabine resistance in biliary tract cancer.

Gemcitabine­based chemotherapy is one of the most effective and commonly used chemotherapeutic regimens for biliary tract cancer (BTC). However, development of resistance to this drug limits its efficacy. The present study aimed to explore the effects of midkine (MDK) on the resistance of BTC cells to gemcitabine. Cell viability and proliferation were measured by a Cell Counting Kit­8 assay and 5­ethynyl­2'­deoxyuridine staining, respectively. Western blot analysis was used to detect the expression of E­cadherin and vimentin. The results indicated that BTC cell lines were more resistant to gemcitabine plus MDK compared with gemcitabine alone. In terms of the underlying mechanism, MDK promoted the epithelial to mesenchymal transition (EMT) of BTC cells and the enhancing effect of MDK on gemcitabine resistance was abrogated when the EMT was blocked with small interfering (si)RNA targeting Twist. In addition, MDK promoted the expression of Notch­1, while knockdown of Notch­1 by siRNA blocked the EMT process in the BTC cell lines. Taken together, these results indicated that MDK promoted gemcitabine resistance of BTC through inducing EMT via upregulating Notch­1. It was suggested that inhibition of the EMT is a promising strategy to overcome MDK­induced drug resistance.

Gene signatures associated with drug resistance to irinotecan and oxaliplatin predict a poor prognosis in patients with colorectal cancer.

The identification of novel survival predictors may help to improve the appropriate management of colorectal cancer (CRC). In the present study, two gene sets associated with irinotecan or oxaliplatin resistance in CRC cell lines were first identified and subsequently applied to the clinical CRC microarray dataset GSE14333. Subsequently, a 60-gene irinotecan resistance-associated signature and a 13-gene oxaliplatin resistance-associated signature were established, which were able to classify CRC patients into high- and low-risk subgroups with varied clinical outcomes [irinotecan-resistance gene signature: hazard ratio (HR)=0.4607, 95% confidence interval (CI)=0.3369-0.6300, P<0.0001; oxaliplatin-resistance gene signature: HR=0.6119, 95% CI=0.4547-0.8233, P=0.0008]. The performance of these two gene expression signatures in predicting outcome risk were also validated in two other independent CRC gene expression microarray datasets, GSE17536 (irinotecan-resistance gene signature: HR=0.5318, 95% CI=0.3359-0.8419, P=0.0079; oxaliplatin-resistance gene signature: HR=0.5383, 95% CI=0.3400-0.8521, P=0.0114) and GSE17537 (irinotecan-resistance gene signature: HR=0.2827, 95% CI=0.1173-0.6813, P=0.0088; oxaliplatin-resistance gene signature: HR=0.2378, 95% CI=0.09773-0.5784, P=0.0023). Furthermore, the combination of these two gene classifiers demonstrated a superior performance in CRC prognosis prediction than either used individually. Therefore, this study proposed novel gene classifier models for CRC prognosis prediction, which may be potentially useful to inform treatment decisions for patients with CRC in clinical settings.

Blocking hepatic metastases of colon cancer cells using an shRNA against Rac1 delivered by activatable cell-penetrating peptide.

Hepatic metastasis is one of the critical progressions of colon cancer. Blocking this process is key to prolonging survival time in cancer patients. Studies on activatable cell-penetrating peptides (dtACPPs) have demonstrated their potential as gene carriers. It showed high tumor cell-targeting specificity and transfection efficiency and low cytotoxicity in the in vitro settings of drug delivery. However, using this system to silence target genes to inhibit metastasis in colorectal cancer cells has not been widely reported and requires further investigation. In this study, we observed that expression of Rac1, a key molecule for cytoskeletal reorganization, was higher in hepatic metastatic tumor tissue compared with prime colon cancer tissue and that patients with high Rac1-expressing colon cancer showed shorter survival time. Base on these findings, we created dtACPP-PEG-DGL (dtACPPD)/shRac1 nanoparticles and demonstrated that they downregulated Rac1 expression in colon cancer cells. Moreover, we observed inhibitory effects on migration, invasion and adhesion in HCT116 colorectal cancer cells in vitro, and our results showed that Rac1 regulated colon cancer cell matrix adhesion through the regulation of cytofilament dynamics. Moreover, mechanically, repression of Rac1 inhibiting cells migration and invasion by enhancing cell to cell adhesion and reducing cell to extracellular matrix adhesion. Furthermore, when atCDPPD/shRac1 nanoparticles were administered intravenously to a HCT116 xenograft model, significant tumor metastasis to the liver was inhibited. Our results suggest that atCDPP/shRac1 nanoparticles may enable the blockade of hepatic metastasis in colon cancer.

WISP3 is highly expressed in a subset of colorectal carcinomas with a better prognosis.

Outlier genes with marked overexpression in subsets of cancers like ERBB2 have potential for the identification of gene classifiers and therapeutic targets for the appropriate subpopulation. In this study, using the cancer outlier profile analysis strategy, we identified WNT1-inducible-signaling pathway protein 3 (WISP3) as an outlier gene that is highly expressed in a subset of colorectal cancers (CRCs) from The Cancer Genome Atlas dataset. A meta-cancer outlier profile analysis and immunohistochemistry experiment to validate the outlier expression model of WISP3 in CRC was then performed. Our immunohistochemical results indicated that WISP3 was more frequently seen in the small tumors, and there was a significant association between its overexpression with a good prognosis. Furthermore, in the multivariable model, WISP3 outlier expression retained significance for overall survival. In summary, in this study, we identified an outlier gene WISP3 overexpressed in a subset of CRC having less aggressive characteristics and a better prognosis. We suggest WISP3 may provide more accurate and precise information regarding CRC population classification.

Phospholipid Scramblase 1 Interacts with Midkine and Regulates Hepatic Cancer Cell Proliferation and Migration.

BACKGROUND: Mounting evidence indicates that nuclear targeting by growth factors plays an indispensable role on their biological activities. Midkine (MK) is a multifunctional growth factor and has been discovered to play important roles in carcinogenesis. MK has been reported to localize to the nucleus and nucleolus of HepG2 cells and is involved in cell proliferation and apoptosis. METHODS: The interaction was reconfirmed by in vitro pull down and in vivo coimmunoprecipitation (Co-IP), also by the colocalization in the HepG2 cells. The proliferation and migration was determined by MTT and trans-well assay. RESULTS: PLSCR1 was identified as a novel MK-interacting protein. Notably, PLSCR1 interacted with MK in the cell nucleus and regulated hepatic carcinoma cell proliferation and migration. CONCLUSIONS: This study suggests that PLSCR1 positively regulates hepatic carcinoma cell proliferation and migration through interacting with MK, thus deepening our understanding on the regulation of midkine during hepatic carcinoma growth and metastasis.

Eukaryotic translation initiation factor 5A2 (eIF5A2) regulates chemoresistance in colorectal cancer through epithelial mesenchymal transition.

BACKGROUND: Chemoresistance is a major obstacle to successful chemotherapy for colorectal cancer. Eukaryotic translation initiation factor 5A2 (eIF5A2), one of the two isoforms in the eIF5A family, has been reported to be a new oncogene in many types of human cancer. In the present study, we aimed to investigate whether eIF5A2 was involved in the chemoresistance to doxorubicin in colorectal cancer. METHODS: Cell viability was measured by CCK-8 assay with or without doxorubicin treatment. Protein expression was detected by western blot. Tumor cells were transfected with eIF5A2 siRNA or plasmid encoding eIF5A2 to down- or up regulate the expression of eIF5A2. RESULTS: We found that eIF5A2-negtive colon cancer cells (HCT116 and HT29) were more sensitive to doxorubicin compare with the eIF5A2-positive cells (LOVO and SW480). Downregulation of eIF5A2 in LOVO and SW480 cells enhanced the chemosensitivity to doxorubicin. On the contrary, overexpression of eIF5A2 reduced doxorubicin sensitivity in colon cancer cells. In addition, eIF5A2 knockdown increased the protein level of E-cadherin and reduced vimentin expression in LOVO and SW480 cells. Meanwhile, upregulation of eIF5A2 potentiated epithelial mesenchymal transition (EMT) in colon cancer cells. Moreover, blockade of EMT with Twist siRNA abolished eIF5A2-regulated chemoresistance in colon cancer cells. CONCLUSION: Our present study demonstrated that eIF5A2 promoted the chemoresistance to doxorubicin via regulation of EMT in colon cancer cells. Therefore, eIF5A2 inhibition may be a new potential strategy for the reversal of drug resistance in colorectal cancer therapy.

Role of midkine-progranulin interaction during angiogenesis of hepatocellular carcinoma.

Midkine (MK) is a heparin-binding growth factor involved in growth, survival, migration, and differentiation of various target cells and dysregulation of MK signaling is implicated in a variety of inflammatory diseases and cancers. Although MK has been reported to act on endothelial cells and to have proangiogenic effects, the exact role of MK in angiogenesis is poorly defined. Progranulin (PGRN) is a secreted glycoprotein that functions as an important regulator of development, cell cycle progression, cell motility, tumorigenesis, angiogenesis. We screened the PGRN from the hepatic cancer cell cDNA library which was interacted with MK, and confirmed the binding by co-immunoprecipitation and co-localization. During our study, the interaction between MK and PGRN had the important role on the HUVECs proliferation, migration, and tubulogenesis, which indicated the interaction may regulate the angiogenesis, also the in vivo angiogenesis model CAM showed the promotion effect stimulated by MK and PGRN. These findings provide the first evidence linking the association of MK and PGRN and may identify the mechanism of MK during the hepatocellular carcinoma angiogenesis.

Inhibitory effect of midkine-binding peptide on tumor proliferation and migration.

BACKGROUND: To investigate the inhibitory effect of midkine-binding peptides on human umbilical vein endothelial cells (HUVECs) proliferation and angiogenesis of xenograft tumor. METHODS: The midkine-binding peptides were panned by Ph.D.-7(™) Phage Display Peptide Library Kit, and the specific binding activities of positive clones to target protein were examined by phage ELISA. The effect of midkine-binding peptides on proliferation of HUVECs was confirmed by MTT test. The xenograft tumor model was formed in BALB/c mice with the murine hepatocarcinoma cells H22 (H22). Microvessel density (MVD) was analyzed by immunohistochemistry of factor VIII staining. RESULTS: Midkine-binding peptides have the inhibitory effects on tumor angiogenesis, a proliferation assay using human umbilical vein endothelial cells (HUVECs) indicated that particular midkine-binding peptides significantly inhibited the proliferation of the HUVECs. Midkine-binding peptides were also observed to efficiently suppress angiogenesis induced by murine hepatocarcinoma H22 cells in BALB/c nude mice. CONCLUSION: The midkine-binding peptides can inhibit solid tumor growth by retarding the formation of new blood vessels. The results indicate that midkine-binding peptides may represent potent anti-angiogenesis agents in vivo.