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Systematic and dynamic humoral immune reconstitution is little-known for patients with relapsed/refractory (R/R) multiple myeloma (MM) who received anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy. We investigated the kinetics of B-cell, normal plasma cell, and immunoglobulin recovery in 40 patients who achieved ongoing response after anti-BCMA CAR T-cell therapy. All patients developed B-cell aplasia and the median duration of B-cell aplasia was 70 days (range, 23-270). The B-cell count reached its nadir on median day 7 and returned to baseline level on median day 97. BCMA+ cells in bone marrow turned undetectable on median day 28 (13-159) in 94.87% (37 of 39) of patients. Normal plasma cells in bone marrow were first redetected on median day 212. All patients developed a significant decrease in serum IgG, IgA, and IgM on median day 60. At year 1, recovery of serum IgG, IgM, and IgA was observed in 53.33% (8 of 15; non-IgG MM), 73.08% (19 of 26; non-IgM MM), and 23.81% (5 of 21;non-IgA MM) of the patients, respectively. Median time to IgG, IgM, and IgA recovery were days 386, 254, and not reached during follow-up, respectively. Virus-specific IgG levels decreased with loss of protection. Twenty-three of 40 (57.5%) patients had a total of 44 infection events. There were no infection-related deaths. These results reveal a 7-month aplasia of bone marrow normal plasma cells and longer period of hypogammaglobulinemia, suggesting a profound and lasting humoral immune deficiency after anti-BCMA CAR T-cell therapy, especially for IgA.

Metastatic renal carcinoma is a kind of tumor with high degree of malignancy, but there are no effective treatment methods and strategies at present. In this study, we designed a folate-grafted PEI600-CyD (H1) nanoparticle-mediated DNA vaccine containing an adjuvant of high mobility group box 1 protein (HMGB1) and a tumor-specific antigen of B7H3 (CD276) for renal carcinoma therapy. Mice bearing subcutaneous human B7H3 (hB7H3)-Renca tumor were immunized with H1-pHMGB1/pB7H3, H1-pB7H3, H1-pHMGB1, or Mock vaccine. Compared to other control groups, the growth of the tumor was significantly inhibited in H1-pHMGB1/pB7H3 vaccine group. The increased proportion and mature of CD11c+ DCs were observed in the spleen of H1-pHMGB1/pB7H3 treated mice. Likewise, HMGB1 promoted B7H3 vaccine to induce tumor-specific CD8+ T cell proliferation and CTL responses. Beyond that, H1-pHMGB1/pB7H3 vaccine strengthened the induction of functional CD8+ T cells. With the depletion of CD8+ T cells, the anti-tumor effect of H1-pHMGB1/pB7H3 also disappeared, indicating that CD8+ T cells are the key factor of the anti-tumor activity of the vaccine. So, to sum up, H1-pHMGB1/pB7H3 vaccine could achieve the desired anti-tumor effect by enhancing the response of tumor-specific functional CD8+ T cell responses. H1 nanoparticle-based vaccines may have great potential and prospect in the treatment of primary solid tumors.

Acute liver injury is a common but urgent clinical condition, and its underlying mechanism remains to be further elucidated. Concanavalin A (ConA)-induced liver injury was investigated in the study. Different from the caspase-dependent cell apoptosis in lipopolysaccharide/D-aminogalactose (LPS/D-GalN) induced liver injury, ConA-induced hepatocyte death was independent on caspase. Increased hepatocytic expressions of mixed lineage kinase domain like (MLKL) and receptor-interacting protein kinase 1 (RIPK1), and higher serum concentration of tumor necrosis factor-α (TNF-α) were noticed in mice with ConA-induced liver injury. Inhibition of RIPK1 protein or deletion of MLKL gene could significantly attenuate the acute liver injury and improve mice survival. Besides, the ConA treatment induced severe hepatic inflammation in wide type (WT) mice in comparison with Mlkl−/− mice, suggesting the RIPK1-MLKL-mediated hepatocellular necroptosis might participate in the process of liver injury. Moreover, mitochondrial damage associated molecular patterns (DAMPs) were subsequently released after the hepatocyte death, and further activated the p38 mitogen-activated protein kinase (MAPK) pathway, which could be reduced by deletion or inhibition of Toll-like receptor 9 (TLR9). Taken together, our research revealed that ConA-induced acute liver injury was closely related to TNF-α-mediated cell necroptosis, and inhibiting RIPK1 or deleting MLKL gene could alleviate liver injury in mice. The mitochondrial DNA released by dead hepatocytes further activated neutrophils through TLR9, thus resulting in the exacerbation of liver injury.

Long non-coding RNAs (lncRNAs) play key roles in various human cancers. We aimed to determine the key lncRNAs mediating colorectal cancer (CRC) progression. We identified some lncRNAs aberrantly expressed in CRC tissues by using lncRNA microarrays and demonstrated that SH3PXD2A-AS1 was one of the most highly overexpressed lncRNAs in CRC. We further aimed to explore the roles and possible molecular mechanisms of SH3PXD2A-AS1 in CRC. RNA ISH revealed that SH3PXD2A-AS1 was overexpressed in CRC compared with adjacent normal colon tissues and indicated poor prognosis in CRC. Functional analyses showed that SH3PXD2A-AS1 enhanced cell proliferation, angiogenesis, and metastasis. Mechanistically, SH3PXD2A-AS1 can directly interact with p53 protein and regulate p53-mediated gene transcription in CRC. We provided mechanistic insights into the regulation of SH3PXD2A-AS1 on p53-mediated gene transcription and suggested its potential as a new prognostic biomarker and target for the clinical management of CRC.

Aurora-A has attracted a great deal of interest as a potential therapeutic target for patients with CRC. However, the outcomes of inhibitors targeting Aurora-A are not as favorable as expected, and the basis behind the ineffectiveness remains unknown. Here, we found that signal transducer and activator of transcription 1 (STAT1) was highly expressed in colorectal cancer (CRC) xenograft mouse models that were resistant to alisertib, an Aurora-A inhibitor. Unexpectedly, we found that alisertib disrupted Aurora-A binding with ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1), leading to UHRF1 mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1), which in turn resulted in demethylation of CpG islands of STAT1 promoter and STAT1 overexpression. Simultaneous silencing Aurora-A and UHRF1 prevented STAT1 overexpression and effectively inhibited CRC growth. Hence, concomitant targeting Aurora-A and UHRF1 can be a promising therapeutic strategy for CRC.

Enhancer of zeste homolog 2 (EZH2), as a main component of Polycomb Repressive Complex 2, catalyzes histone H3K27me3 to silence its target gene expression. EZH2 upregulation results in cancer development and poor prognosis of cancer patients. Post-translational modifications (PTMs) are important biological events in cancer progression. PTMs regulate protein conformation and diversity functions. Recently, mounting studies have demonstrated that EZH2 stability, histone methyltransferase activity, localization, and binding partners can be regulated by PTMs, including phosphorylation,O-GlcNAcylation, acetylation, methylation and ubiquitination. However, the detailed molecular mechanisms of the EZH2-PTMs and whether other types of PTMs occur in EZH2 remain largely unclear. This review presents an overview of different roles of EZH2 modification and EZH2-PTMs crosstalk during tumorigenesis and cancer metastasis. We also discussed the therapeutic potential of targeting EZH2 modifications for cancer therapy.

Introduction Anti-CD19 chimeric antigen receptor (CAR) -T cells, which recognize and kill both B lymphoblasts and normal B cells, result in B cell aplasia and humoral immunodeficiency. However, there were only a few detailed reports on the profile of immune reconstitution after anti-CD19 CAR-T cell therapy. Methods Thirty nine patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL) receiving anti-CD19 CAR-T cell therapy were enrolled. Subjects died, relapsed, received other treatment, or lost to follow-up within 60 days post-infusion were excluded. 21 patients were finally selected. Laboratory and clinical data were collected for analysis of immune reconstitution. Results CD8+ cells were the first to recover with a median time on day 21(7-87), followed by CD16/CD56+ cells on day 28(14-87), and finally CD4+ cells with only 5(23.81%) patients recovered within 60 days post-infusion. CD4/CD8 ratio was inverted, sustaining for at least 1 year. B cell aplasia occurred in all patients and CD19+ cells returned to normal on a median time of day 79(41-118). All patients developed hypogammaglobulinemia with a median onset time of 2 weeks post-infusion. IgG recovered in 6 patients with a median time on day 184(89-346). IgM recovered on days 212, 242, and 346 in 3 patients. IgA recovered most slowly and remained low >1 year postinfusion. A total of 9 infections occurred in 6(28.57%) patients. Conclusions Our data showed prolonged reconstitution of immune function, especially humoral immunity, in R/R B cell ALL patients receiving anti-CD19 CAR-T cell therapy.

Enhancer of zeste homolog 2 (EZH2), a key histone methyltransferase and EMT inducer, is overexpressed in diverse carcinomas, including breast cancer. However, the molecular mechanisms of EZH2 dysregulation in cancers are still largely unknown. Here, we discover that EZH2 is asymmetrically dimethylated at R342 (meR342-EZH2) by PRMT1. meR342-EZH2 was found to inhibit the CDK1-mediated phosphorylation of EZH2 at T345 and T487, thereby attenuating EZH2 ubiquitylation mediated by the E3 ligase TRAF6. We also demonstrate that meR342-EZH2 resulted in a decrease in EZH2 target gene expression, but an increase in breast cancer cell EMT, invasion and metastasis. Moreover, we confirm the positive correlations among PRMT1, meR342-EZH2 and EZH2 expression in the breast cancer tissues. Finally, we report that high expression levels of meR342-EZH2 predict a poor clinical outcome in breast cancer patients. Our findings may provide a novel diagnostic target and promising therapeutic target for breast cancer metastasis.

Purpose Anti‐CD19 chimeric antigen receptor T (CAR‐T) cell therapy has demonstrated remarkable efficacy for refractory and relapsed diffuse large B cell lymphoma (R/R DLBCL). However, this therapy failed in nearly 25% patients mainly due to antigen loss. The authors performed a phase Ⅱ trial by coadministration of anti‐CD19 and anti‐CD20 CAR‐T cells treatment for R/R DLBCL and evaluated its efficacy and toxicity. Methods Totally 21 patients with DLBCL were enrolled in this study. The patients were conditioned with fludarabine and cyclophosphamide before the infusion of anti‐CD19 and anti‐CD20 CAR‐T cells. Treatment response, toxicity, and persistence were monitored continuously. Results Of the 21 patients received the treatment, the objective response rate (ORR) is 81.0% (95% confidence interval [CI], 58.1%‐94.6%) with four cases of bulk (4/5) and one case of testis involvement; 52.4% (95% CI, 29.8%‐74.3%) had a complete response (CR). Peak levels of anti‐CD19 and anti‐CD20 CAR cells were associated with response (P = .007 and .002). Grade 3‐4 cytokine release syndrome (CRS) and neurologic events occurred in 28.5% and 9.5% patients, respectively. Median overall survival (OS) and progression‐free survival (PFS) were 8.1 and 5.0 months, respectively. The maximum standard uptake value (SUVmax) of CD4/CD8 ratio before and after infusion were associated with responses, and the total lesion glycolysis (TLG) before infusion correlates with cytokines level. Conclusions Coadministration of anti‐CD19 and CD20 CAR‐T cells therapy for DLBCL is feasible with manageable toxicity. Cytokine markers are related to toxicity and SUVmax could predict efficacy. This trial was registered at www.clinicaltrials.gov as NCT03207178., In this study, we confirmed that combination of anti‐CD19 and anti‐CD20 CAR‐T cells therapy strategy was efficient (81% ORR and 52.4% CR respectively) for R/R DLBCL, and that the toxicities was transient and manageable. To our knowledge, this is the first report that combination of anti‐CD19 and anti‐CD20 double‐target CAR‐T cell therapy for R/R DLBCL, and our data demonstrated the feasibility of combination of anti‐CD19 and anti‐CD20 CAR‐T cells therapy for R/R DLBCL.

Cancers develop within complex tissue environments consisting of diverse innate and adaptive immune cells, along with stromal cells, vascular networks, and many other cellular and noncellular components. The high heterogeneity within the tumor microenvironment (TME) remains a key obstacle in understanding and treating cancer. Understanding the dynamic functional interplay within this intricate ecosystem will provide important insights into the design of effective combinatorial strategies against cancer. Here, we present recent technical advances to explore the complexity of the TME. Then, we discuss how innate immune sensing machinery, genetic alterations of oncogenic signaling, cellular metabolism, and epigenetic factors are involved in modulating the TME. Finally, we summarize the potential strategies to boost antitumor immunity by therapeutically exploiting the TME.

Acute viral infection causes illness and death. In addition, an infection often results in increased susceptibility to a secondary infection, but the mechanisms behind this susceptibility are poorly understood. Since its initial identification as a marker for resident memory CD8+ T cells in barrier tissues, the function and regulation of CD103 integrin (encoded by ITGAE gene) have been extensively investigated. Nonetheless, the function and regulation of the resident CD103+CD8+ T cell response to acute viral infection remain unclear. Although TGFβ signaling is essential for CD103 expression, the precise molecular mechanism behind this regulation is elusive. Here, we reveal a TGFβ-SKI-Smad4 pathway that critically and specifically directs resident CD103+CD8+ T cell generation for protective immunity against primary and secondary viral infection. We found that resident CD103+CD8+ T cells are abundant in both lymphoid and nonlymphoid tissues from uninfected mice. CD103 acts as a costimulation signal to produce an optimal antigenic CD8+ T cell response to acute viral infection. There is a reduction in resident CD103+CD8+ T cells following primary infection that results in increased susceptibility of the host to secondary infection. Intriguingly, CD103 expression inversely and specifically correlates with SKI proto-oncogene (SKI) expression but not R-Smad2/3 activation. Ectopic expression of SKI restricts CD103 expression in CD8+ T cells in vitro and in vivo to hamper viral clearance. Mechanistically, SKI is recruited to the Itgae loci to directly suppress CD103 transcription by regulating histone acetylation in a Smad4-dependent manner. Our study therefore reveals that resident CD103+CD8+ T cells dictate protective immunity during primary and secondary infection. Interfering with SKI function may amplify the resident CD103+CD8+ T cell response to promote protective immunity.

Protein arginine methyltransferase 1 (PRMT1) is able to promote breast cancer cell proliferation. However, the detailed mechanisms of PRMT1-mediated breast cancer cell proliferation are largely unknown. In this study, we reveal that PRMT1-mediated methylation of EZH2 at the R342 site (meR342-EZH2) has a great effect on PRMT1-induced cell proliferation. We also demonstrate that meR342-EZH2 can accelerate breast cancer cell proliferation in vitro and in vivo. Further, we show that meR342-EZH2 promotes cell cycle progression by repressing P16 and P21 transcription expression. In terms of mechanism, we illustrate that meR342-EZH2 facilitates EZH2 binding with SUZ12 and PRC2 assembly by preventing AMPKα1-mediated phosphorylation of pT311-EZH2, which results in suppression of P16 and P21 transcription by enhancing EZH2 expression and H3K27me3 enrichment at P16 and P21 promoters. Finally, we validate that the expression of PRMT1 and meR342-EZH2 is negatively correlated with pT311-EZH2 expression. Our findings suggest that meR342-EZH2 may become a novel therapeutic target for the treatment of breast cancer.

Characterized as a complex of extracellular DNA fibers and granule proteins, neutrophil extracellular traps (NETs) are generated specifically by neutrophils which play a critical role in host defense and immune regulation. NETs have been initially found crucial for neutrophil anti-microbial function. Recent studies suggest that NETs are involved in tumorigenesis and cancer progression. However, the function of NETs in cancer remains unclear, which might be due to the variation of research models and the heterogeneity of cancers. Although most of malignant tumors have similar biological behaviors, significant differences indeed exist in various systems. Malignant tumors of the digestive system cause the most incidence and mortality of cancer worldwide. In this review, we would focus on research developments on NETs in digestive cancers to provide insights on their role in digestive cancer progression and future research directions.

Prostate cancer (PCa) is the third leading malignancy engendering mortality among men globally. The present study aimed at determining the expression of hepatocellular carcinoma-related protein-1 (HCRP-1) in PCa, to explore its potential role in prostate tumorigenesis in vitro and in vivo. We evaluated HCRP-1 protein with immunohistochemistry (IHC) technology and found HCRP-1 expression was significantly low in PCa tissues (PCTs); In addition, the decreased HCRP-1 was significantly associated with TNM (tumor node metastasis) stage, advanced histology grade and gleason score. Transwell, tube formation, Western blot and co-immunoprecipitation (Co-IP) assays were utilized to determine the role of down-regulating HCRP-1 in PCa cell migration, invasion and angiogenesis. Meanwhile, we found HCRP-1 depletion induced Src and focal adhesion kinase (FAK) phosphorylation, which could be reversed by Src inhibitor PP2 or FAK inhibitor. Furthermore, down-regulated HCRP-1 evidently induced lung metastasis of PCa cells in xenograft mode. Taken together, our study indicates HCRP-1 plays an important role in PCa metastasis. HCRP-1 may serve as a potential therapeutic target for PCa.

PIN2/TRF1-interacting telomerase inhibitor 1 (PinX1) is a tumor suppressor in various tumors. However, the molecular mechanism underlying PinX1’s role in cancer development and progression remains unclear. In this study, we aimed to uncover the new molecular mechanism and role of PinX1 in renal cell carcinoma (RCC) progression. We used miRNA microarray to detect the different expressed miRNAs upon PinX1 knockdown. Chromatin immunoprecipitation and Luciferase reporter assays were taken to identify the molecular mechanism of PinX1 in regulating mir-125-3p. In situ hybridization was performed to analyze the expression of mir-125a-3p in RCC using tissue microarray. The correlations between the mir-125a-3p expression level and clinicopathological features were evaluated using the χ2 test. The role and molecular mechanism of PinX1 in RCC angiogenesis were investigated through a series of in vitro and in vivo experiments. In this study, we discovered a new molecular mechanism of PinX1, in which PinX1 transcriptionally activated mir-125a-3p expression, thereby inhibiting the expression of vascular endothelial growth factor (VEGF), which is the target gene of mir-125a-3p. PinX1 also repressed tumor angiogenesis by increasing the mir-125a-3p expression in renal cancer. Moreover, the loss of mir-125a-3p expression was manifested in patients with RCC, and low miR-125a-3p levels correlated with poor survival of these patients. PinX1 represses renal cancer angiogenesis through mir-125a-3p/VEGF signal pathway. The miR-125a-3p may be a candidate clinical prognostic marker and a novel therapeutic target in RCC.

Human homolog of mouse double minute 2 (HDM2) is an oncogene frequently overexpressed in cancers with poor prognosis, but mechanisms of controlling its abundance remain elusive. In an unbiased biochemical search, we discovered Skp1-Cullin 1-FBXO22-ROC1 (SCF(FBXO22)) as the most dominating HDM2 E3 ubiquitin ligase from human proteome. The results of protein decay rate analysis, ubiquitination, siRNA-mediated silencing, and coimmunoprecipitation experiments support a hypothesis that FBXO22 targets cellular HDM2 for ubiquitin-dependent degradation. In human breast cancer cells, FBXO22 knockdown (KD) increased cell invasiveness, which was driven by elevated levels of HDM2. Moreover, mouse 4T1 breast tumor model studies revealed that FBXO22 KD led to a significant increase of breast tumor cell metastasis to the lung. Finally, low FBXO22 expression is correlated with worse survival and high HDM2 expression in human breast cancer. Altogether, these findings suggest that SCF(FBXO22) targets HDM2 for degradation and possesses inhibitory effects against breast cancer tumor cell invasion and metastasis.

Background Increasing studies have shown that long noncoding RNAs (lncRNAs) are pivotal regulators participating in carcinogenic progression and tumor metastasis in colorectal cancer (CRC). Although lncRNA long intergenic noncoding RNA 460 (LINC00460) has been reported in CRC, the role and molecular mechanism of LINC00460 in CRC progression still requires exploration. Methods The expression levels of LINC00460 were analyzed by using a tissue microarray containing 498 CRC tissues and their corresponding non-tumor adjacent tissues. The correlations between the LINC00460 expression level and clinicopathological features were evaluated. The functional characterization of the role and molecular mechanism of LINC00460 in CRC was investigated through a series of in vitro and in vivo experiments. Results LINC00460 expression was increased in human CRC, and high LINC00460 expression was correlated with poor five-year overall survival and disease-free survival. LINC00460 overexpression sufficiently induced the epithelial–mesenchymal transition and promoted tumor cell proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo. In addition, LINC00460 enhanced the protein expression of high-mobility group AT-hook 1 (HMGA1) by directly interacting with IGF2BP2 and DHX9 to bind the 3′ untranslated region (UTR) of HMGA1 mRNA and increased the stability of HMGA1 mRNA. In addition, the N6-methyladenosine (m6A) modification of HMGA1 mRNA by METTL3 enhanced HMGA1 expression in CRC. Finally, it suggested that HMGA1 was essential for LINC00460-induced cell proliferation, migration, and invasion. Conclusions LINC00460 may be a novel oncogene of CRC through interacting with IGF2BP2 and DHX9 and bind to the m6A modified HMGA1 mRNA to enhance the HMGA1 mRNA stability. LINC00460 can serve as a promising predictive biomarker for the diagnosis and prognosis among patients with CRC.

The tumor suppressor p53 transactivates the expression of multiple genes to exert its multifaceted functions and ultimately maintains genome stability. Thus, cancer cells develop various mechanisms to diminish p53 expression and bypass the cell cycle checkpoint. In this study, we identified the gene encoding RNA-binding protein cytoplasmic polyadenylation element-binding protein 2 (CPEB2) as a p53 target. In turn, CPEB2 decreases p53 messenger RNA stability and translation to fine-tune p53 level. Specifically, we showed that CPEB2 binds the cytoplasmic polyadenylation elements in the p53 3′-untranslated region, and the RNA recognition motif and zinc finger (ZF) domains of CPEB2 are required for this binding. Furthermore, we found that CPEB2 was upregulated in renal cancer tissues and promotes the renal cancer cell proliferation and migration. The oncogenic effect of CPEB2 is partially dependent on negative feedback regulation of p53. Overall, we identify a novel regulatory feedback loop between p53 and CPEB2 and demonstrate that CPEB2 promotes tumor progression by inactivating p53, suggesting that CPEB2 is a potential therapeutic target in human renal cancer.

DNA methylation plays a pivotal role in regulating cellular processes, and altered DNA methylation pattern is a general hallmark of cancer. However, DNA methylome in circulating tumor cells (CTCs) is still a mystery due to the lack of proper analytical techniques. We introduced an efficient workflow, LCM–µWGBS, which can efficiently profile the DNA methylation of microdissected CTC samples. LCM–µWGBS combines the laser capture microdissection (LCM)-based CTC capture method and whole-genome bisulfite sequencing in very small CTC population (µWGBS) to gain insight into the DNA methylation landscape of CTCs. We herein profiled the DNA methylome of CTCs from lung cancer patients. Deriving from a comprehensive analysis of CTC methylome, a unique “CTC DNA methylation signature” that is distinct from primary lung cancer tissues was identified. Further analysis showed that promoter hypermethylation of epithelial genes is a hallmark of stable epithelial–mesenchymal transition process. Moreover, it has been suggested that CTCs are endowed with a stemness-related feature during dissemination and metastasis. This work constitutes a unique DNA methylation analysis of CTCs at single base-pair resolution, which might facilitate to propose noninvasive CTC DNA methylation biomarkers contributing to clinical diagnosis.

Tumor-associated macrophages (TAMs) are important monocytes in the breast cancer microenvironment. They facilitate the distant metastasis of breast cancer. However, the detailed mechanisms of TAM-derived cancer metastasis have not been clearly elucidated. Here, we demonstrate that PRMT1 is essential for TAM-mediated breast cancer cell migration and metastasis. TAMs increase EZH2 stability by stimulating PRMT1-mediated meR342-EZH2 formation through the secretion of interleukin-6 (IL-6) cytokine. Moreover, high expression levels of TAMs are positively correlated with PRMT1, meR342-EZH2, and EZH2 expression in breast cancer patients. Our study presents a novel mechanism of TAM-induced breast cancer metastasis via the IL-6-PRMT1-meR342-EZH2 axis.

Mitochondria as the cellular energy powerhouses provide a common site for multiple metabolic reactions in order to cover energy and biomolecule demands, thus integrating the diverse metabolic pathways to endow cells with metabolic adaptation. Mitochondrial plasticity is normally regulated by mitochondrial dynamics, mitochondrial metabolism and mitochondrial biogenesis. Given that tumor cells and T cells share the metabolic similarities of survival, proliferation, expansion as well as effector function, manipulation of mitochondrial plasticity would change the metabolic competition between “foe” and “friend” during tumor malignant progression. On the one hand, for “foe” tumor cells, mitochondrial plasticity provides the enhancement of tumor metastasis and the development of resistance to‘ diverse antitumor drugs. On the other hand, for “friend” T cells, mitochondrial plasticity promotes the generation of long-term memory T (TM) cells and alleviates the exhaustion of tumor-infiltrating lymphocytes (TILs). Therefore, downregulation of mitochondrial plasticity of tumor cells through engineering tumor-targeting nanoparticles may effectively potentiate metabolic vulnerability and re-sensitize tumor to relevant therapeutic treatment. On the contrary, upregulation of mitochondrial plasticity of T cells through optimizing adoptive cellular immunotherapy (ACI) or chimeric antigen receptor (CAR)-T cell therapy would provide T cells with the robust metabolic fitness and the persistent immune function, thus blocking tumor metastasis and reoccurrence.

An efficient electrotransformation system that includes electrocompetent cells is a critical component for the success of large‐scale gene transduction and replication. The conditions of TG1 competent cell preparation and optimal electrotransformation were evaluated by investigating different parameters. Certain parameters for preparation of TG1 competent cells (≥8 × 1010 colony forming units (cfu)/μg DNA) include optimum culture time of monoclonal bacteria (8–10 hr), amplification growth concentration (approximately OD600 = 0.45), and culture volume (400 ml in 2 L conical flask). With increased storage of competent cells at −80°C, electrotransformation efficiency gradually decreased, but it remains greater than ≥ 1010 cfu/μg DNA 3 months later. Moreover, the recovery time of electrotransformation also influenced electrotransformation efficiency (1.5–2 hr for optimization). The optimized transformation efficiency of TG1 (≥8 × 1010 cfu/μg DNA) was observed under suitable electric voltage (2.5 kV), electric intensity (15 kV/cm), and electric time (3.5 ms) of electricity for plasmid transformation. Optimized DNA amount (0.01–100 ng) dissolved in water led to the high efficiency of plasmid transformation (≥8 × 1010 cfu/μg DNA), but had low efficiency when dissolved in T4 ligation buffer (≤3 × 1010 cfu/μg DNA). These results indicated that an optimized TG1 transformation system is useful for high electrotransformation efficiency under general laboratory conditions. The optimized TG1 transformation system might facilitate large‐scale gene transduction for phage display library construction., Certain parameters for the preparation of TG1 competent cells include optimum culture time of monoclonal bacteria, amplification growth concentration, and culture volume. The optimized transformation efficiency of TG1 (≥8 × 1010 cfu/μg DNA) was observed under suitable electric voltage (2.5 kV), electric intensity (15 kV/cm), and electric time (3.5 ms) of electricity for plasmid transformation. Optimized DNA amount (0.01–100 ng) dissolved in water led to the high efficiency of plasmid transformation but had low efficiency when dissolved in the T4 ligation buffer.

The selective formation of nanomedicines around cancer cells is very important for cancer therapy because it increases the inhibitory capacity and decreases the systemic toxicity. However, successful examples are rare. Taking advantage of the overexpression of both the enzyme alkaline phosphatase (ALP) and the cell membrane receptor (CCK2R), we demonstrated in this study the selective formation of supramolecular nanofibers and hydrogels in the pericellular space of two cancer cell lines (HeLa and HepG2 cells). Both cell lines showed high expression levels of extracellular ALP and membrane-bound CCK2R. ALP efficiently converted Comp. 1 to a self-assembling molecule (Comp. 2). Comp. 2 interacted with CCK2R, thereby facilitating the self-assembly and formation of hydrogels around the cancer cells. The selective pericellular hydrogelations efficiently inhibited cancer cells. Pericellular hydrogelation around cancer cells is a promising strategy to control the formation of nanomedicines spatiotemporally in cellular microenvironments for cancer therapy and diagnostics.

CUL1 is an essential component of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex. Our previous study has showed that CUL1 is positively associated with poor overall and disease-specific survival of breast cancer patients. Here, we further explored its roles in breast cancer metastasis. Our data showed that CUL1 significantly promoted breast cancer cell migration, invasion, tube formation in vitro, as well as angiogenesis and metastasis in vivo. In mechanism, the human gene expression profiling was used to determine global transcriptional changes in MDA-MB-231 cells, and we identified autocrine expression of the cytokines CXCL8 and IL11 as the target genes of CUL1 in breast cancer cell migration, invasion, metastasis, and angiogenesis. CUL1 regulated EZH2 expression to promote the production of cytokines, and finally significantly aggravating the breast cancer cell metastasis and angiogenesis through the PI3K–AKT–mTOR signaling pathway. Combined with the previous report about CUL1, we proposed that CUL1 may serve as a promising therapeutic target for breast cancer metastasis.

Absent in melanoma 2 (AIM2) as a tumor suppressor is recently recognized to play an important role in many human solid tumors. However, the biological significance and function of AIM2 in renal cell carcinoma (RCC) remain unknown. In this study, we proposed to investigate the clinicopathological and prognostic significance of AIM2 in RCC patient specimens, to analyze the correlation between AIM2 expression and disease progression, and to further investigate the role and mechanism of AIM2 in malignant behaviors of renal carcinoma by cellular and animal models. The correlation analysis showed that low AIM2 expression was significantly correlated with lymph node metastasis, poor 5-year overall (P 0.05) and disease-specific survival (P 0.05) in RCC patients. Over-expression of AIM2 in 786-O or OSRC-2 cells suppressed the cell proliferation, migration and invasion as compared with control. The increased AIM2 expression enhanced the expression of autophagy-related genes (Bcl-2, Beclin-1, LC3-Ⅱ, and ATG-5) and increased the ratio of LC3-Ⅱ/LC3-Ⅰin renal carcinoma cells. Of note, the blockade of autophagy by 3-Methyladenine (3-MA) abrogated the inhibition of cell migration and invasion by over-expressing AIM2, indicated that AIM2 suppressed the malignant behaviors of renal carcinoma by enhancing the induction of autophagy. Furthermore, 3-MA abolished the prevention of tumor growth on nude mouse established by AIM2-OSRC-2 cells. Our results suggested that AIM2 might serve as a novel prognostic indicator as well as a potential therapeutic target for renal carcinoma treatment.

Aurora kinase A (Aurora-A), a member of the Aurora family of serine/threonine kinases, plays a critical role in multiple steps of mitotic progression, including microtubule stability during the G1 phase of the cell cycle, chromosome alignment and segregation, and cytokinesis and is aberrantly expressed in various types of human cancers. In addition to its classic functions, recent studies have indicated that Aurora-A is critical for controlling self-renewal of embryonic stem cells through negative regulation of p53. Additionally, aberrant expression of Aurora-A contributes to oncogenic transformation and induces stem cell-like properties in estrogen receptor α-positive breast cancer cells. Silencing of Aurora-A has been implicated in elimination of leukemia stem cells in vivo. Therefore, Aurora-A is an attractive target for cancer therapeutics and a growing number of small molecule inhibitors of Aurora-A have been developed. In the present review, we will address the role of Aurora-A in cancer stem cells, as well as the outcomes of clinical trials assessing Aurora-A-specific small molecular inhibitors.

In recent years, the chimeric antigen receptor modified T cells (Chimeric antigen receptor T cells, CAR-T) immunotherapy has developed rapidly, which has been considered the most promising therapy. Efforts to enhance the efficacy of CAR-based anti-tumor therapy have been made, such as the improvement of structures of CAR-T cells, including the development of extracellular antigen recognition receptors, intracellular co-stimulatory molecules and the combination application of CARs and synthetic small molecules. In addition, effects on the function of the CAR-T cells that the space distance between the antigen binding domains and tumor targets and the length of the spacer domains have are also being investigated. Given the fast-moving nature of this field, it is necessary to make a summary of the development of CAR-T cells. In this review, we mainly focus on the present design strategies of CAR-T cells with the hope that they can provide insights to increase the anti-tumor efficacy and safety.

Long noncoding RNAs (lncRNAs), with length of more than 200 nucleotides, are not translated into proteins but involved in multiple diverse diseases, especially tumorigenesis. The dysregulation of lncRNAs greatly contributes to the progression of various tumors through specific signaling pathways, including Wnt/β-catenin signaling pathway, which is associated with malignant features of tumors. The interactions between lncRNAs, which have specific expression characteristics in diverse cancer tissues, and Wnt/β-catenin signaling pathway, exhibit potential as novel biomarkers and therapeutic targets. In this review, we aim to present research findings on the roles of Wnt pathway-related lncRNAs and their effects on Wnt/β-catenin signaling to regulate tumorigenesis in different cancer types. Results may be used as basis to develop or improve strategies for treatment of different carcinomas.

Decorin (DCN), an extracellular matrix (ECM) protein, belongs to the small leucine-rich proteoglycan family. As a pluripotent molecule, DCN regulates the bioactivities of cell growth factors and participates in ECM assembly. Accumulating evidence has shown that DCN acts as a ligand of various cytokines and growth factors by directly or indirectly interacting with the corresponding signalling molecules involved in cell growth, differentiation, proliferation, adhesion and metastasis and that DCN especially plays vital roles in cancer cell proliferation, spread, pro-inflammatory processes and anti-fibrillogenesis. The multifunctional nature of DCN thus enables it to be a potential therapeutic agent for a variety of diseases and shows good prospects for clinical and research applications. DCN, an extracellular matrix (ECM) protein that belongs to the small leucine-rich proteoglycan family, is widely distributed and plays multifunctional roles in the stroma and epithelial cells. Originally, DCN was known as an effective collagen-binding partner for fibrillogenesis [1] and to modulate key biomechanical parameters of tissue integrity in the tendon, skin and cornea [2]; thus, it was named decorin (DCN). Since being initially cloned in 1986, DCN was discovered to be a structural constituent of the ECM [3]. However, the paradigm has been shifted; it has become increasingly evident that in addition to being a matrix structural protein, DCN affects a wide range of biological processes, including cell growth, differentiation, proliferation, adhesion, spread and migration, and regulates inflammation and fibrillogenesis [4-7]. Two main themes for DCN functions have emerged: maintenance of cellular structure and regulation of signal transduction pathways, culminating in anti-tumourigenic effects. Here, we review the interaction network of DCN and emphasize the biological correlations between these interactions, some of which are expected to be therapeutic intervention targets.

// Feng-Lei Wu 1, 9, * , Jian Zhang 2, * , Wei Li 3, * , Bao-Xiang Bian 1 , Yi-Dong Hong 4 , Zi-Yan Song 1 , Hui-Yu Wang 5 , Fang-Bo Cui 6 , Ru-Tian Li 7 , Qin Liu 7 , Xiao-Dong Jiang 1 , Xiao-Min Li 8 and Jun-Nian Zheng 9 1 Department of Onology, Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu 222000, China 2 Department of General Surgery, Huai'an First People's Hospital, Nanjing Medical University, Huai’an, Jiangsu 223000, China 3 Center of Research Laboratory, Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu 222000, China 4 Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212001, China 5 Department of Oncology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214000, China 6 Department of Oncology, The People’s Hospital of Ma’anshan, Ma’anshan, Anhui 243000, China 7 The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 210008, China 8 Department of Emergency, Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu 222000, China 9 Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China * These are the corporate first authors Correspondence to: Jun-Nian Zheng, email: zhengjunnian1968@126.com Xiao-Min Li, email: lyglxm1@163.com Keywords: microRNA, gastric cancer, HER2, trastuzumab, nanoparticles Received: January 25, 2017 Accepted: April 12, 2017 Published: May 22, 2017 ABSTRACT MiR-21 is an oncogenic miR frequently elevated in gastric cancer. Overexpression of miR-21 decreases the sensitivity of gastric cancer cells to trastuzumab, which is a humanized monoclonal antibody targeting human epidermal growth factor receptor 2. However, optimization of miRNA or its anti-miRNA oligonucleotides (AMOs) for delivery is a challenge. Receptor-mediated endocytosis plays a crucial role in the delivery of biotherapeutics including AMOs. This study is a continuation of our earlier findings involving poly(e-caprolactone) (PCL)-poly (ethylene glycol) (PEG) nanoparticles (PEG-PCL NPs), which were coated with trastuzumab to target gastric cancer cells with HER2 receptor over-expression using anti-miRNA-21 antisense oligonucleotides (AMO-21). The antibody conjugates (HER-PEG-PCL NPs) act against target cells via antibody-dependent mechanisms and also based on encapsutalated AMO-21. X-ray photoelectron spectroscopy validated the presence of trastuzumab on NP surface. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed a stable antibody expression. The cell line specificity, cellular uptake, AMO-21 delivery, and cytotoxicity of the HER-PEG-PCL NPs were investigated. We found that the antibody conjugates significantly enhanced the cellular uptake of NPs. The HER-PEG-PCL NPs effectively suppressed the target miRNA expression in gastric cancer cells, which further up-regulated phosphatase and tensin homolog (PTEN). As a result, the sensitivity of HER2-expressing gastric cancer cells to trastuzumab was enhanced. The approach enhances the targeting by trastuzumab as well as antibody-dependent cellular cytotoxicity of immune effector cells. The antitumor effects of AMO-21-HER-PEG-PCL NPs were compared with trastuzumab in xenograft gastric cancer mice. The results provide insight into the biological and clinical potential of targeted AMO-21 delivery using modified trastuzumab for gastric cancer treatment.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis and high mortality. At present, vaccination with tumor cell lysate (TCL) loaded dendritic cells (DC) has been shown to be an effective therapy against HCC. However, the ability of promoting the specific T cell immune response is rather weak, influencing the antitumor response. Thus, it is necessary to find a strategy to improve the antitumor effect of TCL-loaded DC. Activation of signal transducer and activator of transcription 3 (STAT3) significantly inhibits antitumor immune response and DC maturity. Nifuroxazide, an antidiarrheal agent, has been proved to directly inhibit STAT3 activation. Thus, we investigated whether nifuroxazide could improve the antitumor immune response in mice vaccinated with TCL-loaded DC. The study provides the theoretical and experimental basis for developing an effective adjuvant for DC vaccine to treat HCC. Our results showed that the administration of nifuroxazide and DC-loaded TCL could significantly improve the survival rate, inhibit the tumor growth, and prompt the antitumor immune responses in mice with orthotopically implanted hepatocarcinomas, thus, possibly providing a new combination strategy to treat HCC.

MDM2 regulates p53 degradation by functioning as an E3 ubiquitin ligase. The role of MDMX, an MDM2 homolog that lacks E3 ligase activity, in the regulation of p53 degradation remains incompletely understood and sometime controversial. This confusion is due at least in part to studies of p53 degradation mainly carried out in in vitro settings, as elimination of either MDM2 or MDMX from mice results in p53-dependent embryonic lethality, thus obfuscating in vivo studies of the individual roles of MDM2 and MDMX in p53 degradation. To overcome this problem, we generated mice expressing an inducible p53 allele under various MDM2 and MDMX deletion and mutation statuses and studied in vivo p53 degradation. Degradation of p53 in vivo was largely prevented in mice and mouse embryonic fibroblast retaining MDM2 but lacking MDMX. Although MDM2 and MDMX interacted with p53 in the absence of each other, they bound p53 more efficiently as a heterodimer. MDMX, but not MDM2, interacted with ubiquitin-conjugating enzyme UbcH5c, an interaction that was essential for MDMX to enable MDM2 E3 ligase activity for p53 degradation. Grafting the C-terminal residues of MDMX to the C-terminus of MDM2 allowed MDM2 to interact with UbcH5c and enhanced MDM2-mediated p53 degradation in the absence of MDMX. Together, these data indicate that MDMX plays an essential role for p53 degradation in vivo by recruiting UbcH5c to facilitate MDM2 E3 ligase function. Significance: This study provides the first in vivo evidence of MDMX facilitating MDM2-mediated p53 degradation, clarifying its role in the regulation of this critical tumor suppressor.

Circular RNAs (circRNAs) are a new class of non-coding RNAs formed by covalently closed loops through backsplicing. Recent methodologies have enabled in-depth characterization of circRNAs for identification and potential functions. CircRNAs play important roles in various biological functions as microRNA sponges, transcriptional regulators and combining with RNA binding proteins. Recent studies indicated that some cytoplasmic circRNAs can be effectively translated into detectable peptides, which enlightened us on the importance of circRNAs in cellular physiology function. Internal Ribosome Entry site (IRES)- and N6-methyladenosines (m6A)-mediated cap-independent translation initiation have been suggested to be potential mechanism for circRNA translation. To date, several translated circRNAs have been uncovered to play pivotal roles in human cancers. In this review, we introduced the properties and functions of circRNAs, and characterized the possible mechanism of translation initiation and complexity of the translation ability of circRNAs. We summarized the emerging functions of circRNA-encoded proteins in human cancer. The works on circRNA translation will open a hidden human proteome, and enhance us to understand the importance of circRNAs in human cancer, which has been poorly explored so far.

Transketolase (TKT), which is a metabolic enzyme in the nonoxidative phase of the pentose phosphate pathway (PPP), plays an important role in providing cancer cells with raw materials for macromolecular biosynthesis. The ectopic expression of TKT in hepatocellular carcinoma (HCC) was reported previously. However, the role of TKT in the initiation of liver cancer is still obscure. In our previous study, we found that TKT deficiency protects the liver from DNA damage by increasing levels of ribose 5-phosphate and nucleotides. What’s more interesting is that we found TKT deficiency reduced bile acids and loss of TKT promoted the farnesoid receptor (FXR) expression. We further showed that TKT translocated into the nucleus of HCC cell lines through interacting with the signal transducer and activator of transcription 1 (STAT1), and then the complex inhibited FXR expression by promoting the binding of histone deacetylase 3 (HDAC3) to FXR promoter.

As a hallmark of immunological aging, low-grade, chronic inflammation with accumulation of effector memory T cells contributes to increased susceptibility to many aging-related diseases. While the proinflammatory state of aged T cells indicates a dysregulation of immune homeostasis, whether and how aging drives regulatory T cell (Treg) aging and alters Treg function are not fully understood owing to a lack of specific aging markers. Here, by a combination of cellular, molecular, and bioinformatic approaches, we discovered that Tregs senesce more severely than conventional T (Tconv) cells during aging. We found that Tregs from aged mice were less efficient than young Tregs in suppressing Tconv cell function in an inflammatory bowel disease model and in preventing Tconv cell aging in an irradiation-induced aging model. Furthermore, we revealed that DDB1- and CUL4-associated factor 1 (DCAF1) was downregulated in aged Tregs and was critical to restrain Treg aging via reactive oxygen species (ROS) regulated by glutathione-S-transferase P (GSTP1). Importantly, interfering with GSTP1 and ROS pathways reinvigorated the proliferation and function of aged Tregs. Therefore, our studies uncover an important role of the DCAF1/GSTP1/ROS axis in Treg senescence, which leads to uncontrolled inflammation and immunological aging.

Lung cancer is the most common malignancy worldwide and is characterized by rapid progression, aggressive behavior, frequent recurrence, and poor prognosis. The TCGA database indicates that chondroitin polymerizing factor (CHPF) is overexpressed in human lung cancer tissues compared with normal tissues and this overexpression corresponds to shorter overall survival in lung cancer patients. In this study, to investigate the function of CHPF in lung cancer, lentiviral vectors expressing CHPF shRNA were stably transduced into A549 and H1299 cells. Compared to shCtrl cells, CHPF knockdown cells had significantly reduced proliferation. Furthermore, the silencing of CHPF in A549 and H1299 cells resulted in apoptotic induction, which led to decreased colony formation. Wound healing and transwell invasion assays revealed that CHPF could positively regulate the migration of lung cancer cells. The tumorigenic role of CHPF was also validated in nude mouse xenograft models. Affymetrix gene chip analysis indicated that CHPF regulated the proliferation and invasion of lung cancer cells through CDH1, RRM2, MKI67, and TNFRSF10B. We thus highlight CHPF as a novel target for lung cancer treatment.

Cancer has become a major health issue worldwide, contributing to a high mortality rate. Tumor metastasis is attributed to the death of most patients. Epithelial-to-mesenchymal transition (EMT) plays a vital role in inducing metastasis. During EMT, epithelial cells lose their characteristics, such as cell-to-cell adhesion and cell polarity, and cells gain motility, migratory potential, and invasive properties to become mesenchymal stem cells. Circular RNAs (circRNAs) are closely associated with tumor metastasis and patient prognosis, as revealed by increasing lines of evidence. CircRNA is a type of single-stranded RNA that forms a covalently closed continuous loop. CircRNAs are insensitive to ribonucleases and are widespread in body fluids. This work is the first review on EMT-related circRNAs. In this review, we briefly discuss the characteristics and functions of circRNAs. The correlation of circRNAs with EMT has been reported, and we discuss the ways circRNAs can regulate EMT progression through EMT transcription factors, EMT-related signaling pathways, and other mechanisms. This work summarizes current studies on EMT-related circRNAs in various cancers and provides a theoretical basis for the use of EMT-related circRNAs in targeted management and therapy.

Foxp3 expressing regulatory T (Treg) cells, as the central negative regulator of adaptive immune system, are essential to suppress immune response and maintain immune homeostasis. However, the function of Treg cells is frequently compromised in autoimmunity and hyper-activated in infections and tumor microenvironments. Thus, manipulating Treg cells becomes a promising therapeutic strategy for treating various diseases. Here we reported that inhibition of Cdk8/Cdk19 activity by small molecule inhibitors CCT251921 or Senexin A greatly promoted the differentiation of Treg cells and the expression of Treg signature genes, such as Foxp3, CTLA4, PD-1, and GITR. Mechanistically, we found that the augmented Treg cell differentiation was due to sensitized TGF-β signaling by Cdk8/Cdk19 inhibition, which was associated with attenuation of IFN-γ-Stat1 signaling and enhancement of phosphorylated Smad2/3. Importantly, treatment with Cdk8/Cdk19 inhibitor CCT251921 significantly increased Treg population and ameliorated autoimmune symptoms in an experimental autoimmune encephalomyelitis (EAE) model. Taken together, our study reveals a novel role of Cdk8/Cdk19 in Treg cell differentiation and provides a potential target for Treg cell based therapeutics.

Background Colorectal cancer (CRC) remains the fourth most common cause of cancer-related mortality worldwide. We aimed to identify key molecules and signalling pathways mediating CRC growth and metastasis. Polypyrimidine tract-binding protein 3 (PTBP3) is a member of PTB family. A prooncogenic role for PTBP3 has also been discovered in several kinds of tumors. However, the expression and biological functions of the PTBP3 are still unknown in CRC. Methods We analysed the expression levels of PTBP3 using tissue microarray containing 568 CRC tissues and corresponding non-tumor adjacent tissues. The correlations between the PTBP3 expression level and clinicopathological features were evaluated using the chi-square test. The functional characterization for the role and molecular mechanism of PTBP3 in CRC was investigated through a series of in vitro and in vivo experiments. Results We showed that PTBP3 expression was increased in human CRC, and high PTBP3 expression was correlated with poor five-year overall survival and disease-free survival. Moreover, PTBP3 promoted tumor cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo. PTBP3 enhanced HIF-1α protein expression by directly binding to the 5′UTR HIF-1α mRNA and activated translation of HIF-1α. Furthermore, HIF-1α was responsible for PTBP3-induced cell migration and invasion. Conclusions PTBP3 appears to be a novel oncogene of CRC through binding to the IRES region of HIF-1α mRNA, which regulates HIF-1α translation. PTBP3 can serve as a promising predictive biomarker for recurrence and prognosis in patients with CRC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1312-y) contains supplementary material, which is available to authorized users.

As a tumor-targeting and ‑penetrating peptide, iRGD binds to αv integrins and neuropilin‑1 receptors, which are expressed at high levels on tumor cells and the surfaces of vasculature. Subsequently, iRGD penetrates deep into the tumor parenchyma with antitumor drugs, imaging agents, immune modulators and biological products. These substances are either chemically linked to the peptide or co‑injected with the peptide. The iRGD peptide can be readily synthesized, exhibits significantly improved penetration, compared with traditional peptides, and can effectively inhibit tumor metastasis. Therefore, the peptide is now used widely for the diagnosis and treatment of cancer. However, whether the peptide is able to promote the entry of drugs into non‑targeted cells remains to be fully elucidated. In this review, an overview of iRGD is presented, focusing on its identification, mechanism of action and previous studies on its roles in various types of cancer. Studies in previous years have demonstrated the potential of the iRGD protein for tumors diagnosis and targeted treatment, which warrants further investigation.

// Anqun Tang 1,* , Keyu Gao 1,* , Laili Chu 1,* , Rui Zhang 1 , Jing Yang 1 and Junnian Zheng 1,2 1 Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Jiangsu, China 2 Department of Oncology, The First Affiliated Hospital, Xuzhou Medical University, Xuzhou, Jiangsu, China * These authors have contributed equally to this work Correspondence to: Junnian Zheng, email: // Jing Yang, email: // Keywords : Aurora kinases, mitosis, cancer therapy target, Aurora kinases inhibitors, combination therapy Received : November 01, 2016 Accepted : January 17, 2017 Published : January 29, 2017 Abstract Aurora kinases, a family of serine/threonine kinases, consisting of Aurora A (AURKA), Aurora B (AURKB) and Aurora C (AURKC), are essential kinases for cell division via regulating mitosis especially the process of chromosomal segregation. Besides regulating mitosis, Aurora kinases have been implicated in regulating meiosis. The deletion of Aurora kinases could lead to failure of cell division and impair the embryonic development. Overexpression or gene amplification of Aurora kinases has been clarified in a number of cancers. And a growing number of studies have demonstrated that inhibition of Aurora kinases could potentiate the effect of chemotherapies. For the past decades, a series of Aurora kinases inhibitors (AKIs) developed effectively repress the progression and growth of many cancers both in vivo and in vitro , suggesting that Aurora kinases could be a novel therapeutic target. In this review, we’ll first briefly present the structure, localization and physiological functions of Aurora kinases in mitosis, then describe the oncogenic role of Aurora kinases in tumorigenesis, we shall finally discuss the outcomes of AKIs combination with conventional therapy.

MicroRNAs (miRNAs), which are characterized by highly conserved and small non-coding RNAs, have been a hot spot regarding biological processes such as cellular proliferation, apoptosis and metabolism as well as cellular differentiation, signal transduction and carcinogenesis. MiRNA-106a (miR-106a), a member of the miR-17 family, has been validated to be aberrantly regulated in the diversity of tumors. The purpose of this review is supposed to deliver an intricate overview of miR-106a, including its role in cell proliferation, apoptosis, cell cycle, invasion and metastasis, involvement in drug resistance as well as its interactions with the target proteins and signaling pathways involved.

Lung cancer is the leading cause of cancer-associated mortality, worldwide. For this reason, novel therapies are required for the treatment of this devastating disease. Cetuximab is a monoclonal antibody against epidermal growth factor receptor (EGFR), which is overexpressed in a variety of solid tumors, including non-small cell lung cancer (NSCLC). The therapeutic efficacy of cetuximab for NSCLC is limited to use as a monotherapy or in combination with chemotherapy. The objective of the present study was to develop a novel strategy to enhance the therapeutic efficacy of cetuximab for NSCLC by a co-administration with the tumor-penetrating internalizing RGD peptide (iRGD). Human NSCLC subcutaneous xenograft models established with the A549 cell line in nude mice were treated with 30 mg/kg cetuximab, 4 mg/kg iRGD, cetuximab plus iRGD or phosphate-buffered saline. The tumor-penetration, in vivo therapeutic efficacy and involved mechanism were evaluated. The present study showed that the A549 xenograft model is sensitive to the co-administration of cetuximab and iRGD. Treatment with cetuximab plus iRGD resulted in a significant increase in the tumor-penetration of cetuximab and tumor reduction compared with cetuximab monotherapy. In conclusion, iRGD enhances the effects of co-administered cetuximab in an NSCLC model. The combined application of cetuximab and iRGD may be a novel strategy to enhance the clinical therapeutic efficacy of cetuximab for the treatment of NSCLC.

// Lin Fang 1 , Qian Cheng 1 , Jingjing Zhao 1 , Yan Ge 1 , Qi Zhu 1 , Min Zhao 1, 2 , Jie Zhang 1 , Qi Zhang 1 , Liantao Li 1, 3 , Junjie Liu 1 , Junnian Zheng 1, 3, 4 1 Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China 2 Affiliated Hospital of Taishan Medical University, Taian, Shandong Province, 271000, China 3 Cancer Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China 4 Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China Correspondence to: Junnian Zheng, email: fl@xzmc.edu.cn Keywords: adenoviral E1A, Rb, p53, cell apoptosis, hepatocellular carcinoma Received: December 03, 2015 Accepted: June 06, 2016 Published: June 22, 2016 ABSTRACT The conserved regions (CR) of adenoviral E1A had been shown to be necessary for disruption of pRb-E2F transcription factor complexes and induction of the S phase. Here we constructed a mutant adenoviral E1A with Rb-binding ability absent (E1A 30-60aa and 120-127aa deletion, mE1A) and investigated its antitumor capacities in vitro and in vivo . The mE1A suppressed the viability of tumor cells as efficiently as the wild type E1A, and there was no cytotoxic effect on normal cells. Although the mE1A arrested tumor cell cycle with the same manner as E1A, the former played a different role on cell cycle regulation compared with E1A in normal cells, which might contribute to its selective antitumor activity. E1A and mE1A had accumulated inactive p53, decreased the expression of mdm2, Cdkn1a (also named p21), increased p21’s nuclear distribution and induced tumor cell apoptosis in a p53-indenpent manner. Further, E1A or mE1A significantly suppressed tumor growth in subcutaneous hepatocellular carcinoma xenograft models. Especially, tumor-bearing mice treated with mE1A had higher survival rate than those treated with E1A. Our data demonstrated that mutant adenoviral E1A significantly induced tumor cell apoptosis in a p53-indenpednt manner and had selective tumor suppressing ability. The observations of adenoviral E1A mutant had provided a novel mechanism for E1A’s complex activities during infection.

ASBTARCT Adenoviruses mediated cancer gene therapies are widely investigated and show a promising effect on cancer treatment. However, efficient gene transfer varies among different cancer cell lines based on the expression of coxsakie adenovirus receptor (CAR). Hep27, a member of dehydrogenase/reductase (SDR) family, can bind to Mdm2, resulting in the attenuation of Mdm2-mediated p53 degradation. Here we constructed a fiber chimeric adenovirus carrying hep27 gene (F5/35-ZD55-Hep27), in which the fiber protein of 5-serotype adenovirus (Ad5) was substituted by that of 35-serotype adenovirus (Ad35), aiming to facilitate the infection for renal cancer cells and develop the role of hep27 in cancer therapy. We evaluated the CAR and CD46 (a membrane cofactor protein for Ad35) expression in four kinds of renal cancer cells and assessed the relationship between receptors and infection efficiency. 5/35 fiber-modified adenovirus had a much promising infectivity compared with Ad5-based vector in renal cancer cells. F5/35-ZD55-Hep27 had enhanced antitumor activity against human renal cancer cells compared to the other groups. Further, hep27 mediated p53 and cleaved-PARP upregulation and mdm2 downregulation was involved and caused increased apoptosis. Moreover, F5/35-ZD55-Hep27 significantly suppressed tumor growth in subcutaneous renal cancer cell xenograft models. Our data demonstrated that 5/35 fiber-modified adenovirus F5/35-ZD55-Hep27 transferred into renal cancers efficiently and increased p53 to induce cancer cell apoptosis. Thus 5/35 fiber-modified adenoviral vector F5/35-ZD55-Hep27 might a promising vector and antitumor reagent for renal cancer gene therapy.

Numerous studies have suggested that microRNAs (miRNAs) are vital in the development of various types of human cancers, including renal cell carcinoma (RCC), and the regulation of tumor progression and invasion. However, the effect of miRNA-27a (miR-27a) on the tumorigenesis of RCC is unclear. The aim of the present study was to investigate the function of miR-27a and identify its possible target genes in RCC cells. In the present study, cell proliferation, migration and invasion and the percentage of apoptotic cells were detected by methylthiazol tetrazolium assays, Annexin V analysis, wound-healing assays and Transwell invasion assays. Western blot analysis was performed to validate the protein expression level and assess whether the epidermal growth factor receptor (EGFR) was a target gene of miR-27a. A tumor xenograft animal model was used to detect the role of miR-27a on RCC cell growth in vivo. The present study demonstrated that miR-27a significantly suppressed human RCC 786-O cell proliferation and induced cell apoptosis. Restoration of miR-27 also resulted in 786-O cell migration and invasion inhibition. Furthermore, upregulated miR-27a attenuated RCC tumor growth in the tumor xenograft animal model. The present results suggested that miR-27a functions as a tumor suppressor in RCC. The western blot analysis assay revealed that EGFR was a novel target of miR-27a. The growth suppression of RCC cells was attributed partly to the downregulation of the cell cycle by ERFR inhibition. The present findings may aid in the understanding of the molecular mechanism of miR-27a in the tumorigenesis of RCC, and may provide novel diagnostic and therapeutic options for RCC.

Special AT-rich sequence binding protein 1 (SATB1) plays important role in the regulation of chromatin structure and gene expression. Recent studies have indicated oncogenic role of SATB1. However, the function of SATB1 in prostate cancer progression and metastasis remains unclear. In this study SATB1 expression vector or siRNA was employed to modulate the expression level of SATB1 in prostate cancer cells and xenograft tumor in nude mouse model. Immunohistochemical analysis was performed on clinical prostate cancer samples. Silencing SATB1 inhibited the growth of DU-145 cells subcutaneous tumor in nude mice, while SATB1 overexpression promoted the growth of LNCaP cells subcutaneous tumor in nude mice. Immunohistochemical and Western blot analysis of the xenografts showed that silencing SATB1 led to decreased expression of vimentin and MMP2 and increased expression of E-cadherin, while SATB1 overexpression led to increased expression of vimentin and MMP2 and decreased expression of E-cadherin. Furthermore, SATB1, vimentin and MMP2 expression was increased significantly while E-cadherin expression was reduced significantly in clinical samples of prostate carcinoma with metastasis compared to prostate carcinoma without metastasis and benign prostate hyperplasia. Taken together, these findings suggest that the modulation of epithelial–mesenchymal transition by SATB1 may contribute to prostate cancer metastasis.

Immunoglobulin D (IgD) multiple myeloma (MM) is a rare subtype of MM that carries a worse prognosis than non-IgD subtypes. Compared with non-IgD subtypes, IgD MM is associated with a shorter survival time. The application of chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed or refractory multiple myeloma (R/R MM) has increasing evidence as an efficacious treatment. This study was designed to investigate efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory IgD MM (R/R IgD MM). In this single-arm, phase 2 trial, patients diagnosed with R/R IgD MM were infused with either a combination of anti–B-cell maturation antigen and anti–CD19 CAR T-cells or anti–CD19 CAR T-cells alone, with subsequent evaluation of therapeutic response and treatment-related toxicities. At the data cutoff date, 7 patients were enrolled in our study, and all patients achieved response based on the International Myeloma Working Group Uniform Response Criteria. Six patients achieved stringent complete remission (sCR) within 60 days after CAR T-cell infusion (median time 58 days, range 18 to 90 days), and 1 patient with extramedullary disease achieved minimal response (MR) at 30 days after infusion. Bone marrow minimal residual disease (MRD) negativity was achieved in all patients, and the median time to achieve MRD negativity was 22 days (range 14 to 60 days). The most common grade 3 to 4 treatment-related toxicities were hematological toxicities. All patients experienced cytokine release syndrome (CRS), although CAR T-cell–related neurotoxicity was not observed. In our study, CAR T-cell therapy showed encouraging efficacy in the patients with R/R IgD MM, achieving high rates of sCR and MRD negativity. Aside from CRS and prolonged hematologic toxicities, other adverse reactions were mild, suggesting that this is a well-tolerated treatment with a high therapeutic potential.

CRISPR/Cas-based genetic perturbation screens have emerged as powerful tools for large-scale identification of new targets for cancer immunotherapy. Various strategies of CRISPR screen have been used for immune-oncology (IO) target discovery. The genomic sequences targeted by CRISPR/Cas system range from coding sequences to non-coding RNA/DNA, including miRNAs, LncRNAs, circRNAs, promoters, and enhancers, which may be potential targets for future pharmacological and therapeutic interventions. Rapid progresses have been witnessed in finding novel targets for enhancing tumor antigen presentation, sensitizing of tumor cells to immune-mediated cytotoxicity, and reinvigorating tumor-specific T cells by using CRISPR technologies. In combination with other strategies, the detailed characteristics of the targets for immunotherapy have been obtained by CRISPR screen. In this review, we present an overview of recent progresses in the development of CRISPR-based screens for IO target identification and discuss the challenges and possible solutions in this rapidly growing field.