A nomogram for predicting prognosis of multiple myeloma patients based on a ubiquitin-proteasome gene signature.

BACKGROUND: Multiple myeloma (MM) is a malignant hematopoietic disease that is usually incurable. However, the ubiquitin-proteasome system (UPS) genes have not yet been established as a prognostic predictor for MM, despite their potential applications in other cancers. METHODS: RNA sequencing data and corresponding clinical information were acquired from Multiple Myeloma Research Foundation (MMRF)-COMMPASS and served as a training set (n=787). Validation of the prediction signature were conducted by the Gene Expression Omnibus (GEO) databases (n=1040). To develop a prognostic signature for overall survival (OS), least absolute shrinkage and selection operator regressions, along with Cox regressions, were used. RESULTS: A six-gene signature, including KCTD12, SIAH1, TRIM58, TRIM47, UBE2S, and UBE2T, was established. Kaplan-Meier survival analysis of the training and validation cohorts revealed that patients with high-risk conditions had a significantly worse prognosis than those with low-risk conditions. Furthermore, UPS-related signature is associated with a positive immune response. For predicting survival, a simple to use nomogram and the corresponding web-based calculator (https://jiangyanxiamm.shinyapps.io/MMprognosis/) were built based on the UPS signature and its clinical features. Analyses of calibration plots and decision curves showed clinical utility for both training and validation datasets. CONCLUSIONS: As a result of these results, we established a genetic signature for MM based on UPS. This genetic signature could contribute to improving individualized survival prediction, thereby facilitating clinical decisions in patients with MM.

Silencing LINC00491 Inhibits Pancreatic Cancer Progression through MiR-188-5p-induced Inhibition of ZFP91.

Background: Pancreatic cancer is recognized as one of the most malignant tumors with poor prognosis. Recently, long noncoding RNAs (lncRNAs) are considered as a potential prognostic biomarker of PC. However, the concrete biological effect of lncRNAs in PC remains unmasked. Herein, we explored the mechanism of LINC00491 in PC. Methods: Quantitative real-time PCR (qRT-PCR) was administrated to detected the expression of LINC00491 in PC tissues and cell lines. Loss-of-function experiment in vitro and in vivo was carried out to figure out the biological effects of LINC00491 on PC carcinogenesis. Luciferase reporter assay, subcellular fractionation, western blotting, pull-down assay and RNA immunoprecipitation assay were further used to explore the mechanism of PC tumorigenesis of LINC00491. Results: An increase of LINC00491 was detected in PC cell lines and tissues. Silencing LINC00491 in vitro and in vivo subsequently hindered cell migration, invasion, proliferation and tumor growth, respectively. Further research confirmed a negative and a positive connection of LINC00491 with microRNA 188-5p (miR-188-5p) level and Zinc finger protein 91 (ZFP91), a target of miR-188-5p, respectively. qRT-PCR and western blotting found that miR-188-5p was upregulated while LINC00491 was downregulated, concomitant with ZFP91 decreasing in PC cells or node mouse tumors, which could be significantly restored by inhibiting miR-188-5p. Besides, overexpression of miR-188-5p partially restored the inhibitory effect of LINC00491 diminution on proliferation, migration, and invasion of PC cells. Conclusion: LINC00491 promotes PC proliferation, migration, invasion via the miR-188-5p/ZFP91 axis, suggesting LINC00491 could be a new therapeutic target for PC.

LINC01128 facilitates the progression of pancreatic cancer through up-regulation of LDHA by targeting miR-561-5p.

BACKGROUND: Long non-coding RNAs (lncRNAs) regulate tumor development and metastasis in several types of cancers through various molecular mechanisms. However, the biological role of most lncRNAs in pancreatic cancer (PC) remains unclear. Here, we explored the expression, biological functions, and molecular mechanism of LINC01128 in PC. METHODS: Quantitive reverse transcription PCR was used to detect the expression level of LINC01128 in PC tissues and different PC cell lines. A loss-of-function and gain-of-function experiment was used to explore the biological effects of LINC01128 on PC carcinogenesis in vitro and in vivo. Western blot analysis, subcellular fractionation experiment, luciferase reporter gene assay, and MS2-RNA immunoprecipitation experiment were used to study the potential molecular mechanism of LINC01128 during carcinogenesis. RESULTS: The expression of LINC01128 was upregulated in PC tissues and cell lines, and overexpression of LINC01128 was significantly related to the poor prognosis of patients with PC. Furthermore, silencing LINC01128 significantly inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of PC cells in vitro and tumor growth in vivo, while LINC01128 overexpression promoted these processes. Further research showed that LINC01128 acted as a sponge for microRNA miR-561-5p, and lactate dehydrogenase A (LDHA) was the downstream target gene of miR-561-5p. It was also revealed that the expression of miR-561-5p in PC was decreased, and a negative correlation between miR-561-5p and LINC01128 was revealed. Based on rescue experiments, LDHA overexpression partially restored the inhibitory effect of LINC01128 knockdown on proliferation, migration, and invasion of PC cells. CONCLUSIONS: LINC01128 promotes the proliferation, migration, invasion, and EMT of PC by regulating the miR-561-5p/LDHA axis, suggesting LINC01128 may be a new prognostic marker and therapeutic target in PC.

Long non-coding RNA LINC01224 promotes progression and cisplatin resistance in non-small lung cancer by sponging miR-2467.

Copious evidence reveals that long non-coding RNAs (lncRNAs) exert great regulatory functions in various human cancers. LINC01224 is a novel lncRNA, identified as a cancer regulator of HCC. However, the underlying mechanisms and clinical significance of LINC01224 in other types of cancers need further researches to explore. In this study, we aimed to elucidate the biological role of LINC01224 in NSCLC progression. Presently, LINNC01224 expression was elevated and miR-2467 expression was down-regulated in NSCLC, compared with standard control. Then we described the reciprocal correlation between LINC01224 and miR 2467. Afterward, the dual-luciferase reporter assay, RIP assay and RNA pull-down assay validated the base-pair interaction between LINC01224 and miR-2467. Moreover, our findings demonstrated that the silence of LINC01224 inhibited cell proliferation and invasion in NSCLC and enhanced cisplatin (CDDP) sensitivity in vitro. Besides, rescue assays verified that miR-2467 inhibitor could reverse the effects on cell biological activities and CDDP resistance caused by knockdown of LINC01224. Finally, in vivo experiments implicated that knockdown of LINC01224 could inhibit NSCLC tumor growth. To sum up, LINC01224 can promote tumor progression and CDDP resistance in NSCLC via sponging miR-2467, suggesting a promising therapeutic target for better diagnosis and prognosis of NSCLC patients.

Silencing UCHL3 enhances radio-sensitivity of non-small cell lung cancer cells by inhibiting DNA repair.

UCHL3 belongs to the UCH family and is involved in multiple biological processes. However, the biological functions and underlying mechanisms of action of UCHL3 in radio-sensitivity of non-small cell lung cancer (NSCLC) remain unknown. Here, we reported that the expression of UCHL3 was significantly up-regulated in NSCLC tissues and cell lines, and associated with poor prognosis of NSCLC patients. The expression of UCHL3 of NSCLC cells was increased after exposure to ionizing radiation (IR). Moreover, we found that knockdown of UCHL3 enhanced the radio-sensitivity of NSCLC cells both in vitro and in vivo. Furthermore, γH2AX foci staining and Western blot analysis showed that knockdown of UCHL3 increased IR-induced DNA damage. Knockdown of UCHL3 in NSCLC cells decreased homologous recombination (HR) repair efficiency and RAD51 foci formation. Collectively, our study revealed that knockdown of UCHL3 enhanced the radio-sensitivity of NSCLC cells and increased IR-induced DNA damage via impairing HR repair.

Long noncoding RNA LINC00520 accelerates lung adenocarcinoma progression via miR-1252-5p/FOXR2 pathway.

It has been corroborated that long noncoding RNA (lncRNA) played fundamental function in various human malignancies development including lung adenocarcinoma (lung ADC). In our study, LINC00520 roles in lung ADC tumorigenesis were explored. We found that LINC00520 level was elevated in lung ADC tissues and cell lines. Besides, the LINC00520 expression had a negative connection with miR-1252-5p level in lung ADC tissues. Additionally, our results demonstrated the reciprocal repression influence between LINC00520 and miR-1252-5p. Moreover, luciferase reporter assays, RIP (RNA-binding protein immunoprecipitation) and pull down assays revealed that miR-1252-5p regulated LINC00520 in RISC-dependent. Furthermore, knockdown of LINC00520 inhibited lung ADC cells proliferation, migration and invasion, while co-transfection with a miR-1252-5p inhibitor inverted these influences. Additionally, the findings also demonstrated that FOXR2 was a target of miR-1252-5p; thus, LINC00520 could regulate FOXR2 level. Moreover, LINC00520 silencing suppressed the tumor growth of lung ADC in vivo. In summary, our data indicated that LINC00520 may act as a ceRNA to modulated FOXR2 level by sponging miR-1252-5p, which might bring a potential and effective biomarker to lung ADC treatment.

LDLRAD2 promotes pancreatic cancer progression through Akt/mTOR signaling pathway.

Low-density lipoprotein receptor class A domain containing 2 (LDLRAD2) acts as a protein-coding gene in a large number of human diseases. However, the potential roles and underlying mechanism in pancreatic cancer remains unclear. Therefore, this study was conducted to address this question. Herein, we found that the expression of LDLRAD2 was elevated in pancreatic cancer tissues and cell lines. LDLRAD2 knockdown inhibited pancreatic cancer cell proliferation, migration, and invasion in vitro. Besides, silencing LDLRAD2 impaired tumor growth and metastasis in vivo and up-regulated the E-Cadherin level, whereas down-regulated the expression of N-Cadherin and Vimentin levels, which indicating that LDLRAD2 knockdown suppresses EMT. Additionally, LDLRAD2 knockdown decreased the Warburg effect and glycolytic enzymes expression. Pathway scan assay and western blotting assay indicated that LDLRAD2 knockdown significantly down-regulated the expression of phosphorylation of Akt and phosphorylation of mTOR, which suggested that knockdown of LDLRAD2 inhibits Akt/mTOR signaling pathway. Taken together, these findings suggested that LDLRAD2 may be an oncogene in pancreatic cancer via modulating Akt/mTOR signaling pathway.

Long noncoding RNA LINC00514 accelerates pancreatic cancer progression by acting as a ceRNA of miR-28-5p to upregulate Rap1b expression.

BACKGROUND: Pancreatic cancer (PC) is one of the most aggressive cancers and has an extremely poor prognosis worldwide. Long noncoding RNA (lncRNA) has been reported to be a potential prognostic biomarker in the initiation and prognosis of PC. Nevertheless, the biological functions and the detailed molecular mechanism of LINC00514 in PC remain unclear. METHODS: We measured the expression level of LINC00514 in PC tissues and cell lines by quantitative real-time PCR. Gain- and loss-of-function experiments were performed to explore the bioeffects of LINC00514 on PC development both in vitro and in vivo. Subcellular fractionation, luciferase reporter assay, RNA immunoprecipitation assay, pull-down assay and western blotting were performed to investigate the oncogenic molecular mechanisms of LINC00514. RESULTS: In this study, LINC00514 was shown to be upregulated in PC tissues and cell lines. Increased LINC00514 expression was significantly associated with the clinical progression and prognosis of PC patients. In addition, silencing LINC00514 inhibited PC cell proliferation, migration and invasion, while LINC00514 overexpression promoted these processes. Moreover, LINC00514 knockdown remarkably inhibited PC development and metastasis in vivo. Deeper investigations indicated that LINC00514 acted as a sponge for microRNA-28-5p (miR-28-5p) in PC and that Rap1b was a downstream target of miR-28-5p. Furthermore, the positive correlation of LINC00514 and Rap1b and the negative correlation between miR-28-5p and LINC00514 (or Rap1b) were revealed. Based on the rescue assays, Rap1b inhibition partially suppressed the oncogenic effect of LINC00514 overexpression on PC cell proliferation, migration and invasion. CONCLUSIONS: This study is the first to characterize the oncogenic function of the long noncoding RNA LINC00514 in pancreatic cancer progression by acting as a competing endogenous RNA (ceRNA) of miR-28-5p to upregulate Rap1b expression. Understanding this molecular mechanism might contribute to further discoveries of better diagnostic and therapeutic options for pancreatic cancer.

Ruscogenin induces ferroptosis in pancreatic cancer cells.

Pancreatic cancer is characterized by aggressive and highly metastatic phenotypes. This disease exhibits a poor patient prognosis and is considered a challenge due to the limited treatment options encountered in clinical practice. Previous studies have shown that ruscogenin, a saponin found in the root of Ophiopogon japonicus, exerts a wide range of biological functions including anticancer activity. In the present study, the effects of ruscogenin were investigated on pancreatic cancer cells and the potential molecular mechanism of this compound was explored. Cell viability was assessed using the 3­(4,5­dimethylthiazol­2­yl)­2,5­diphenyltetrazolium bromide (MTT) assay. Cell death was measured by trypan blue staining and by flow cytometry. The number of iron oxide nanoparticles was measured using Prussian blue staining. Reactive oxygen species (ROS) production was assessed using flow cytometry with dihydroethidium staining. Protein expression of the associated genes was assayed by western blotting. Furthermore, in vivo experiments were conducted to confirm the antitumor effects and assay the potential toxicity of ruscogenin in a nude mouse xenograft model. The results indicated that ruscogenin significantly repressed cell viability and induced cell death of pancreatic cancer cells in vitro in a dose­ and time­dependent manner. Furthermore, ruscogenin increased the concentration of intracellular ferrous irons and the production of ROS. This effect was inhibited by deferoxamine (DFO). Ruscogenin induced ferroptosis by regulating the levels of transferrin and ferroportin. These two proteins were involved in ruscogenin­induced pancreatic cancer cell death. Finally, in vivo experiments demonstrated the antitumor effect of ruscogenin on pancreatic cancer xenografts in the absence of apparent toxicity. Taken collectively, the data demonstrated that ruscogenin exhibited anticancer effects in pancreatic cancer cells by inducing ferroptosis. The findings suggested that this compound may be further developed as a promising anticancer candidate for the treatment of pancreatic cancer.

UCHL3 promotes pancreatic cancer progression and chemo-resistance through FOXM1 stabilization.

The dysregulation of deubiquitinating enzymes has been reported to be important in the development of many human cancers, including pancreatic cancer. However, the precise role and potential mechanism of action of the deubiquitinating enzyme UCHL3 in pancreatic cancer progression and chemo-resistance, are poorly elucidated. In the current study, the consequences of UCHL3 knockdown in pancreatic cancer cells were evaluated via cell viability and colony formation assays. In vivo experiments were also conducted to confirm the effect of UCHL3 and FOXM1 depletion on tumor growth in nude mouse xenograft models. Cell migration and invasion were assessed by wound-healing and transwell assays, respectively. Co-immunoprecipitation (co-IP) and in vitro deubiquitination assays were performed to investigate the interactions between UCHL3 and FOXM1. Immunohistochemical (IHC) staining was utilized to examine the expression of UCHL3 and FOXM1 in pancreatic cancer tissues. Our results demonstrate that UCHL3 deubiquitinated and stabilized FOXM1, thereby potentiating proliferation, migration, and invasion of pancreatic cancer cells. Furthermore, knockdown of UCHL3 increased FOXM1 ubiquitination, which enhanced FOXM1 turnover and promoted pancreatic cancer cells' sensitivity to gemcitabine. High UCHL3 expression was positively associated with FOXM1 expression level in pancreatic cancer patient samples. Collectively, our study established the UCHL3-FOXM1 axis as a pivotal driver of pancreatic cancer progression and gemcitabine resistance and provided evidence for the potential therapeutic benefit of targeting the UCHL3-FOXM1 axis for pancreatic cancer treatment.

LINC01133 inhibits breast cancer invasion and metastasis by negatively regulating SOX4 expression through EZH2.

Mounting evidence highlights long non-coding RNAs (lncRNAs) as crucial regulators in multiple types of biological processes and contributing to tumourigenesis. LINC01133, located in chromosome 1q23.2, was a recently identified novel lncRNA with a length of 1154nt. It was involved in the development of colorectal cancer and non-small cell lung cancer. However, its clinical relevance, biological functions and potential molecular mechanism in breast cancer are still unclear. In this study, we found that the LINC01133 expression was significantly down-regulated in breast cancer samples and was associated with progression and poor prognosis of breast cancer. Further experiments demonstrated that overexpression of LINC01133 inhibited invasion and metastasis in breast cancer both in vitro and in vivo. Mechanistic investigations revealed that LINC01133 repressed SOX4 expression by recruiting EZH2 to SOX4 promoter. Moreover, rescue experiments further confirmed that LINC01133 functional acted as an anti-oncogene, at least partly, via repressing SOX4 in breast cancer. Taken together, these findings imply that LINC01133 could serve as a novel prognostic biomarker and potential therapeutic target for breast cancer.

PD-L1 (B7-H1) Competes with the RNA Exosome to Regulate the DNA Damage Response and Can Be Targeted to Sensitize to Radiation or Chemotherapy.

Programmed death ligand 1 (PD-L1, also called B7-H1) is an immune checkpoint protein that inhibits immune function through its binding of the programmed cell death protein 1 (PD-1) receptor. Clinically approved antibodies block extracellular PD-1 and PD-L1 binding, yet the role of intracellular PD-L1 in cancer remains poorly understood. Here, we discovered that intracellular PD-L1 acts as an RNA binding protein that regulates the mRNA stability of NBS1, BRCA1, and other DNA damage-related genes. Through competition with the RNA exosome, intracellular PD-L1 protects targeted RNAs from degradation, thereby increasing cellular resistance to DNA damage. RNA immunoprecipitation and RNA-seq experiments demonstrated that PD-L1 regulates RNA stability genome-wide. Furthermore, we developed a PD-L1 antibody, H1A, which abrogates the interaction of PD-L1 with CMTM6, thereby promoting PD-L1 degradation. Intracellular PD-L1 may be a potential therapeutic target to enhance the efficacy of radiotherapy and chemotherapy in cancer through the inhibition of DNA damage response and repair.

A novel UCHL3 inhibitor, perifosine, enhances PARP inhibitor cytotoxicity through inhibition of homologous recombination-mediated DNA double strand break repair.

Triple-negative breast cancer (TNBC) treatment remains a great challenge for clinical practice and novel therapeutic strategies are urgently needed. UCHL3 is a deubiquitinase that is overexpressed in TNBC and correlates with poor prognosis. UCHL3 deubiquitinates RAD51 thereby promoting the recruitment of RAD51 to DNA damage sites and augmenting DNA repair. Therefore, UCHL3 overexpression can render cancer cells resistant to DNA damage inducing chemo and radiotherapy, and targeting UCHL3 can sensitize TNBC to radiation and chemotherapy. However, small molecule inhibitors of UCHL3 are yet to be identified. Here we report that perifosine, a previously reported Akt inhibitor, can inhibit UCHL3 in vitro and in vivo. We found low dose (50 nM) perifosine inhibited UCHL3 deubiquitination activity without affecting Akt activity. Furthermore, perifosine enhanced Olaparib-induced growth inhibition in TNBC cells. Mechanistically, perifosine induced RAD51 ubiquitination and blocked the RAD51-BRCA2 interaction, which in turn decreased ionizing radiation-induced foci (IRIF) of Rad51 and, thereby, homologous recombination (HR)-mediated DNA double strand break repair. In addition, combination of perifosine and Olaparib showed synergistic antitumor activity in vivo in TNBC xenograft model. Thus, our present study provides a novel therapeutic approach to optimize PARP inhibitor treatment efficiency.

MT1JP inhibits tumorigenesis and enhances cisplatin sensitivity of breast cancer cells through competitively binding to miR-24-3p.

Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play a key role in the development of many human cancers. MT1JP is a lncRNA that is reportedly involved in gastric cancer development, but a biological role and mechanism for MT1JP in breast cancer is unknown. Here, we found that MT1JP expression was significantly down-regulated in breast cancer tissues and cell lines, and that decreased MT1JP expression was associated with breast cancer progression and poor survival of breast cancer patients. Additionally, we found that overexpression of MT1JP in breast cancer cells significantly inhibited cell proliferation and invasion, and also enhanced the cisplatin sensitivity of breast cancer cells. We then investigated a possible mechanism for these results, finding that MT1JP binds to and negatively regulates miR-24-3p, which is known to be an oncogene in some human cancers. Our rescue experiments showed that the tumor suppressive and cisplatin-sensitizing functions of MT1JP were mediated by negative regulation of miR-24-3p. Finally, western blot results showed that MT1JP inhibited the Wnt/ß-catenin signaling pathway. Collectively, our data indicate that MT1JP functions as an anti-tumor lncRNA, enhances cisplatin sensitivity in breast cancer, and may serve as a novel diagnostic and therapeutic marker of breast cancer.

Extracellular retention of a cyclopamine nanoformulation leveraging larger size and more negative charge for improved breast cancer treatment.

Compared with intracellular drug delivery, drugs with extracellular targeting sites are rarely considered. As one of these drugs, cyclopamine (CYC) is a promising anticancer drug that functions by targeting the cell membrane receptor. For improving therapeutic effect, an albumin-based nano-system (ABN) with the capacity for extracellular retention was developed. The ABN was formulated by incorporating bovine serum albumin (BSA) into nanoparticles at the denaturing temperature of BSA, with CYC acting as a hydrophobic nucleation site, followed by stabilization upon heat-induced disulfide cross-linking. The resultant ABNs are negatively charged with a nanoparticle size that can be delicately regulated by varying the reaction time. In MDA-MB-231 cells, the size and charge of ABNs significantly affected the extracellular retention capacity, with ABN-300 nm exhibiting an enhanced cytotoxic effect. In vivo fluorescence imaging revealed obvious and persistent tumor accumulation of ABNs. A therapeutic study in an orthotopic mammary fat pad tumor model shows that ABN-300 nm possesses the most remarkable antitumor effect compared with the control groups. These results provide a new strategy for improving the efficacy of drug targeting at extracellular sites.

PHGDH is an independent prognosis marker and contributes cell proliferation, migration and invasion in human pancreatic cancer.

PURPOSE: To investigate the expression, clinical significance, biological function, and the potential mechanism of PHGDH in pancreatic cancer. METHODS: The expression of PHGDH in human pancreatic cancer tissues and corresponding adjacent normal tissues were analyzed through immunohistochemistry staining. Simultaneously, the association between the PHGDH expression and the clinicopathological parameters and OS and DFS was evaluated. Human pancreatic cancer cell line BxPC-3 and SW1990 were selected to investigate the effect of PHGDH knockdown on cell proliferation, migration, and invasion. In addition, we performed western blot to assess the expression of cyclin B1, and cyclin D1, MMP-2, and MMP-9 protein. RESULTS: Our results suggested that the expression of PHGDH is increased in pancreatic cancer compared with adjacent normal tissues and the increased expression of PHGDH is associated with tumor size, lymph node metastasis, and TNM state of pancreatic cancer patients. Moreover, the expression of PHGDH is an independent prognostic indicator for pancreatic cancer patients. In addition, we found that knockdown of PHGDH in pancreatic cancer cells inhibits the cell proliferation, migration, and invasion abilities by down-regulating the expression of cyclin B1, and cyclin D1, MMP-2, and MMP-9. CONCLUSIONS: Our data indicated that the expression of PHGDH is increased in pancreatic cancer and is an independent molecular prognostic factor for pancreatic cancer patients. In addition, PHGDH controls cell proliferation, migration and invasion abilities. Therefore, PHGDH could serve as an important prognostic indicator and therapeutic target for pancreatic cancer.

Overexpression and biological function of MEF2D in human pancreatic cancer.

To explore the expression, clinical significance, biological function, and potential mechanism of MEF2D in pancreatic cancer, the expression of MEF2D in human pancreatic cancer tissues and corresponding adjacent normal tissues was analyzed through immunohistochemical staining. The association between MEF2D expression, clinicopathological parameters, overall survival, and disease-free survival was evaluated. Human pancreatic cancer cell lines BxPC-1 and SW1990 were selected to investigate the effect of MEF2D knockdown on cell proliferation, migration, and invasion. Western blot analysis was used to assess the effect of MEF2D expression on the Akt/GSK pathway, as well as the protein expression of cyclin B1, cyclin D1, matrix metalloprotein (MMP)-2, and MMP-9. Our results revealed that the expression of MEF2D was increased in pancreatic cancer tissues compared to adjacent normal tissues and the increased expression of MEF2D was associated with tumor size, histological differentiation, and TNM stage of pancreatic cancer patients. Moreover, the expression of MEF2D was an independent prognostic indicator for pancreatic cancer patients. In addition, knockdown of MEF2D in pancreatic cancer cells inhibited cell proliferation, migration, and invasion by down-regulating the protein expression of cyclin B1, cyclin D1, MMP-2, and MMP-9. Knockdown of MEF2D reduced the levels of phosphorylated Akt and GSK-3ß. Our data indicated that MEF2D expression was increased in pancreatic cancer and was an independent molecular prognostic factor for pancreatic cancer patients. Furthermore, we showed that MEF2D controlled cell proliferation, migration, and invasion abilities in pancreatic cancer via the Akt/GSK-3ß signaling pathway.

Cyclic RGD peptide-modified liposomal drug delivery system for targeted oral apatinib administration: enhanced cellular uptake and improved therapeutic effects.

Apatinib is an oral tyrosine kinase inhibitor, which selectively targets vascular endothelial growth factor receptor 2 and has the potential to treat many tumors therapeutically. Cyclic arginylglycylaspartic acid (cRGD)- and polyethylene glycol (PEG)-modified liposomes (cRGD-Lipo-PEG) were constructed to act as a targeted delivery system for the delivery of apatinib to the human colonic cancer cell line, HCT116. These cRGD-modified liposomes specifically recognized integrin αvß3 and exhibited greater uptake efficiency with respect to delivering liposomes into HCT116 cells when compared to nontargeted liposomes (Lipo-PEG), as well as greater death of tumor cells and apoptosis. The mechanism by which cRGD-Lipo-PEG targets cells was elucidated further with competition assays. To determine the anticancer efficacy in vivo, nude mice were implanted with HCT116 xenografts and treated with apatinib-loaded liposomes or free apatinib intravenously or via intragastric administration. The active and passive targeting of cRGD-Lipo-PEG led to significant tumor treatment targeting ability, better inhibition of tumor growth, and less toxicity when compared with treatments using uncombined apatinib. The results presented strongly support the case for cRGD-Lipo-PEG representing a targeted delivery system for apatinib in the treatment of colonic cancer.

High Expression of Stromal Cell-Derived Factor 1 (SDF-1) and NF-κB Predicts Poor Prognosis in Cervical Cancer.

BACKGROUND SDF-1 and NF-κB are associated with the prognosis of a wide range of cancers, but their value in cervical cancer remains controversial. The aim of this study was to investigate the expression of SDF-1and NF-κB in cervical cancer and their significance in clinical prognosis. MATERIAL AND METHODS The expression of SDF-1and NF-κB in 105 formalin-fixed, paraffin-embedded cervical cancer tissues and the adjacent tissues was examined by immunohistochemistry (IHC). The results were semi-quantitatively scored and analyzed by chi-square test. The overall survival times (OS) were collected by follow-up and analyzed by Kaplan-Meier analysis. RESULTS The expression level of both SDF-1and NF-κB in cervical cancer are higher than that in the adjacent tissues (P<0.05). SDF-1 expression are correlated with tumor size and FIGO histology grade (P<0.05). NF-κB expression are correlated with tumor size and FIGO histology grade, and lymph node metastasis (LNM) status (P<0.05). The patients with a positive expression of SDF-1or NF-κB tended to have much shorter survival time than patients with negative expression. In addition, multivariate Cox regression analysis demonstrated that SDF-1 expression and lymph node metastasis are independent predictors of the OS in cervical cancer patients. CONCLUSIONS The expression of SDF-1 is significantly associated with tumor size and FIGO histology grade. The expression of NF-κB is significantly associated with tumor size, FIGO histology grade, and lymph node metastasis. The positive SDF-1or NF-κB expression is significantly correlated with poor prognosis. These may be valuable biomarkers for the prognosis and the potential therapeutic targets of cervical cancer.