MicroRNAs play important roles in tumor metastasis. Recently, we reported that the level of miR-520b is inversely related to the metastatic potential of breast cancer cells. In this study, we investigated the role of miR-520b in breast cancer cell migration. We found that miR-520b suppressed the migration of breast cancer cells with high metastatic potential, including MDA-MB-231 and LM-MCF-7 cells, although the inhibition of miR-520b enhanced the migration of low metastatic potential MCF-7 cells. We further discovered that miR-520b directly targets the 3-untranslated region (3UTR) of either hepatitis B X-interacting protein (HBXIP) or interleukin-8 (IL-8), which has been reported to contribute to cell migration. Surprisingly, tissue array assays showed that 75% (38:49) and 94% (36:38) of breast cancer tissues and metastatic lymph tissues, respectively, were positive for HBXIP expression. Moreover, overexpression of HBXIP was able to promote the migration of MCF-7 cells. Interestingly, HBXIP was able to regulate IL-8 transcription by NF-B, suggesting that the two target genes of miR-520b are functionally connected. In addition, we found that miR-520b could indirectly regulate IL-8 transcription by targeting HBXIP. Thus, we conclude that miR-520b is involved in regulating breast cancer cell migration by targeting HBXIP and IL-8 via a network in which HBXIP promotes migration by stimulating NF-B-mediated IL-8 expression. These studies point to HBXIP as a potential therapeutic target for breast cancer. MicroRNAs (miRNAs)3 are a class of small noncoding RNAs that act as post-transcriptional regulators of gene expression. It is currently estimated that the human genome may contain at least 700 miRNAs (1, 2). Emerging evidence has demonstrated that miRNAs can function as oncogenes or tumor suppressors involved in neoplasm development, progression, diagnosis, and prognostication (3, 4). It was recently reported that miRNAs are mutated or differentially expressed in breast cancer, with profound positive or negative effects on breast cancer cell migration. For instance, miR-10b is highly expressed in human and mouse metastatic breast cancer cell lines and positively regulates cell migration (5), and MiR-27b stimulates cell migration by targeting ST14 (6). Let-7g targets collagen type I ␣2 and inhibits cell migration in hepatocellular carcinoma (7). Although a large number of miRNAs have been identified to date, their roles in breast cancer cell migration and the underlying mechanisms of this regulation remain to be determined.Hepatitis B X-interacting protein (HBXIP) was originally identified by its interaction with the C terminus of the hepatitis B virus X protein (8). It forms a complex with survivin, leading to the suppression of apoptosis initiated through the mitochondrial cytochrome c pathway (9). HBXIP was shown to interact with the hSuv3 protein, which encodes an NTP-dependent DNA/RNA DEXH box helicase predominantly localized in mitochondria (10). Furthermore, HBXIP also plays a critical role in mitosis, serving ...

With the fast development of cell therapy, there has been a shift toward the development of injectable hydrogels as cell carriers that can overcome current limitations in cell therapy. However, the hydrogels are prone to damage during use, inducing cell apoptosis. Therefore, this study was carried out to develop an injectable and self-healing hydrogel based on chondroitin sulfate multiple aldehyde (CSMA) and N-succinyl-chitosan (SC). By varying the CSMA to SC ratio, the hydrogel stiffness, water content, and kinetics of gelation could be controlled. Gelation readily occurred at physiological conditions, predominantly due to a Schiff base reaction between the aldehyde groups on CSMA and amino groups on SC. Meanwhile, because of the dynamic equilibrium of Schiff base linkage, the hydrogel was found to be self-healing. Cells encapsulated in the hydrogel remained viable and metabolically active. In addition, the hydrogel produced minimal inflammatory response when injected subcutaneously in a rat model and showed biodegradability in vivo. This work establishes an injectable and self-healing hydrogel derived from carbohydrates with potential applications as a cell carrier and in tissue engineering.

Androgen receptor (AR) is a ligand-activated transcription factor and a key driver of prostate cancer (PCa) growth and progression. Understanding the factors influencing AR-mediated gene expression provides new opportunities for therapeutic intervention. Poly(ADP-ribose) Polymerase (PARP) is a family of enzymes, which posttranslationally modify a range of proteins and regulate many different cellular processes. PARP-1 and PARP-2 are two well-characterized PARP members, whose catalytic activity is induced by DNA-strand breaks and responsible for multiple DNA damage repair pathways. PARP inhibitors are promising therapeutic agents that show synthetic lethality against many types of cancer (including PCa) with homologous recombination (HR) DNA-repair deficiency. Here, we show that, beyond DNA damage repair function, PARP-2, but not PARP-1, is a critical component in AR transcriptional machinery through interacting with the pioneer factor FOXA1 and facilitating AR recruitment to genome-wide prostate-specific enhancer regions. Analyses of PARP-2 expression at both mRNA and protein levels show significantly higher expression of PARP-2 in primary PCa tumors than in benign prostate tissues, and even more so in castration-resistant prostate cancer (CRPC) tumors. Selective targeting of PARP-2 by genetic or pharmacological means blocks interaction between PARP-2 and FOXA1, which in turn attenuates AR-mediated gene expression and inhibits AR-positive PCa growth. Next-generation antiandrogens act through inhibiting androgen synthesis (abiraterone) or blocking ligand binding (enzalutamide). Selective targeting of PARP-2, however, may provide an alternative therapeutic approach for AR inhibition by disruption of FOXA1 function, which may be beneficial to patients, irrespective of their DNA-repair deficiency status.

Hepatitis B X-interacting protein (HBXIP) is a novel oncoprotein and plays a key role in the development of breast cancer. However, its mechanisms of action are poorly understood. Lin28B functions as an oncogene in a variety of human cancers. In our study, we report that HBXIP acts with its partner Lin28B to contribute to carcinogenesis. Our data showed that the expression levels of HBXIP were significantly positively correlated with those of Lin28B in clinical breast cancer tissues. Then, we found that HBXIP was able to upregulate Lin28B in breast cancer MCF-7 cells. Chromatin immunoprecipitation assay (ChIP) and electrophoretic mobility shift assay (EMSA) revealed that HBXIP occupied the promoter region (21199/-1073 nt) of Lin28B. Importantly, co-immunoprecipitation (Co-IP) and GST pull-down assay validated that HBXIP directly bound to the TATA-binding protein (TBP), a basal subunit of transcription factor TF II D complex. In addition, we discovered that Lin28B could block the downregulation of HBXIP via suppressing miR-520b which directly targeted HBXIP mRNA in the cells. In function, we demonstrated that HBXIP enhanced the proliferation of breast cancer cells through Lin28B in vitro and in vivo. Thus, we conclude that the oncoprotein HBXIP as a co-activator of TF II D transactivates Lin28B promoter via directly binding to TBP to upregulate the expression of Lin28B in promotion of proliferation of breast cancer cells, in which Lin28B maintains the high level of HBXIP through suppressing miR-520b in a feedback manner. Therapeutically, HBXIP may serve as a target of breast cancer.Hepatitis B X-interacting protein (HBXIP), a conserved 18KDa protein, is originally identified by its interaction with the hepatitis B virus X protein (HBx) and negatively regulates the activity of HBx and alters the replicative life cycle of the virus. 1 Expression of HBXIP mRNA occurs in nearly all tissues not limited to liver and is also in mice and other rodents. 2 The sequences of the HBXIP gene, containing a putative leucine zipper motif and two consensus phosphorylation sites for protein kinase C and casein kinase II, are well conserved among mammalian species. 1 HBXIP can regulate the duplication of centrosome and HBXIP-deficient Hela cells succumb eventually to apoptosis. In addition, a mouse model of liver regeneration experiment shows HBXIP is a critical regulator of hepatocyte cell growth in vivo. 3 Studies also report that HBXIP functions as a cofactor with survivin through forming a complex to suppress apoptosis. 2 Importantly, our group shows that HBXIP plays crucial roles in the development of breast cancer, serving as a key oncoprotein in cancer. [4][5][6][7] Recently, we show that HBXIP promotes the breast cancer cell growth by upregulating S100A4. 7 However, the mechanism by which HBXIP enhances the proliferation of breast cancer cells remains poorly understood.Lin28B, a homolog of Lin28, originally identified in hepatocellular carcinoma conserves a cold shock domain and a pair of CCHC zinc finger domains. 8 Lin28B i...