Current Protein and Peptide Science - Volume 16, Issue 4, 2015

Tumor recurrence followed by chemoresistance is a major cause of the poor survival rates for ovarian cancer. Despite advances in ovarian cancer chemotherapies and increased knowledge of the characteristics of ovarian cancer, chemoresistance is still an enormous clinical challenge. Current research suggests that ovarian cancer stem cells (OCSCs) might be involved in the occurrence of chemoresistance in ovarian cancer. In this review, we focus on the relationship of ovarian cancer stem cells with drug-resistant ovarian cancer phenotypes. We also discuss the current knowledge regarding ovarian cancer stem cellbased therapeutic strategies as attempts to overcome chemoresistance, the largest obstacle for successful treatment. Finally, we discuss methods for improving the treatment outcomes of ovarian cancer patients with chemoresistance.

Ionizing radiation (IR) plays an important role in the treatment of epithelial tumors, such as lung and prostate cancer, by wounding and killing cancer cells. However, IR also activates sophisticated anti-apoptotic transcriptional factors such that cancer cells fail to repair DNA damage and obtain resistance to apoptosis under conditions of radiotherapy. Among these transcription factors, the transcription factor nuclear factor kappa B (NF-κB) is recognized as a key feature for protecting cells from apoptosis in most cell types. Moreover, the induction of radioresistance is mediated by several genes that are regulated by NF- κB. The primary purpose of this review is to introduce the studies of the signaling mechanisms of IR in NF-κB activation, such as ROS/NF-κB, ATM or DNA-PK/MAPKK/ p90rsk, PI3K/AKT/IKK and k-ras/c-raf/ MEKK/ NF-ΚB pathways. Moreover, we describe how the expression of the target genes (e.g., XIAP, A20, FLIP, Bcl-xL) are induced by NF-κB to regulate the activation of survival signaling pathways and to inhibit apoptotic signaling pathways. In addition, IR activates NF-κB to express cell cycle-specific genes, for example cyclin D1, which is associated with reinforcing radioresistance. We exhibit the signaling pathways that are induced by IR stimulation of NF-ΚB and illustrate the molecular mechanisms of radioresistance.

In this study, the culture supernatant of LPS-treated MSCs was collected and served as a conditioned medium (CM). It was found that the LPS-CM promoted the proliferation of tumor cells (SKBR3, MDA-MB-231, A549, 95D and HepG2). In addition, the colony formation ability was also enhanced by LPS-CM incubation. The inflammatory cytokines, IL-6 and IL-8, were demonstrated to be up-regulated in the LPS-CM, which we supposed to function in the tumor-growth promotion in vitro.

Colorectal cancer (CRC) is one of the most common tumor types worldwide. A frequent subtype of CRC is defined by a deficiency in the mismatch repair (MMR) pathway, constantly found in combination with microsatellite instability (MSI), which not only contributes to the pathogenesis of a large proportion of CRC, but also controls the response to multiple drugs used to treat CRCs. The most commonly used chemotherapeutic agent for CRC is 5-fluorouracil (5-FU). However, CRC with MSI frequently acquires 5-FU resistance, and the exact mechanism underlying how CRC cells acquire chemoresistance to 5-FU remains incompletely understood. Recently, emerging evidence has demonstrated that microRNAs (miRNAs) are key players in multidrug resistance. In this study, we aimed to characterize the expression profiles and functions of miRNAs in 5-FU-resistant CRC with MSI. We found that miR-23a was significantly elevated in MSI CRC cells and tissues compared to microsatellite stability (MSS) CRC cells and tissues. Ectopic expression of miR-23a increased the viability and survival of MSS CRC cells. Inversely, downregulation of miR-23a reduced viability in and promoted cell apoptosis in MSI CRC cells treated with 5-FU. Moreover, we demonstrated that ABCF1 is a direct target of miR-23a. Additionally, the expression of miR-23a was inversely correlated with the expression of ABCF1 in CRC tissues. Interestingly, repressing ABCF1 expression by either miR-23a overexpression or siABCF1 led to recovery of 5-FU sensitivity in MSI CRC cells. These data demonstrated that miR-23a enhances 5-FU resistance in MSI CRC cells through targeting ABCF1 and thus provided important implications for therapeutic approaches aiming to overcome MSI CRC resistance to 5-FU.

The neoadjuvant therapy has significantly improved the outcome of locally advanced resectable T3 rectal cancer patients. Actually, only a portion of patients show sensitivity to the preoperative chemoradiation and benefit markedly from this treatment. However, biomarkers for predicting neoadjuvant therapy sensitivity remain unclear. In this study, through screening of a series of microRNAs dysregulated in colorectal cancer patients, we observed that miRNA-497 expression was downregulated in tumor tissues of neoadjuvant chemotherapy responders as compared to that in non-responders. MiRNA-497 level was correlated with chemotherapeutic drug 5-fluorouracil (5-FU) sensitivity in colorectal cancer cells. Functional studies showed that restoration of miRNA-497 expression inhibited cell viability and enhanced 5-FU sensitivity in SW480 cells. By contrast, miRNA inhibitors-mediated silence of miRNA-497 promoted cell growth and reduced the sensitivity of LoVo cells to 5-FU. In addition, miRNA-497 targeted Smurf1 in CRC cells and the Smurf1 expression level was dramatically increased in neoadjuvant therapy-resistant patients compared with treatment-sensitive patients. These results indicate that down-regulation of miRNA-497 in colorectal cancer may contribute to the resistance of CRC cells to 5-FU treatment. Thus, miRNA-497 has the potential to be a novel biomarker for predicting the neoadjuvant chemotherapy sensitivity in CRC patients.

The incidence of thyroid cancer has been increased in the past few decades. GPX3 gene is located in 5q23, which is frequently deleted in prostate cancer. Methylation of GPX3 was found frequently in prostate, esophagus, gastric and breast cancers. To detect the expression and analyze the mechanism of GPX3 in human thyroid cancer, 94 cases of primary papillary thyroid cancer (PTC) which coupled with adjacent tissue samples, as well as 15 cases of normal thyroid epithelial tissue samples were collected. Methylation specific PCR (MSP), immunohistochemistry staining, transwell assay and siRNA knockdown technique were employed. GPX3 was methylated in 46.8% (44 of 94) of PTC and methylation of GPX3 was associated with tumor size (P<0.05) and regional lymph node metastasis (P<0.01) significantly. Consistent expression of GPX3 was observed in the adjacent tissue samples and absent/reduced expression of GPX3 was found frequently in primary PTC samples. In 44 cases of methylated cancer samples, loss of/ reduced expression was found in 36 cases and expression of GPX3 was found in 8 cases. In 50 cases of unmethylated PTC samples, loss of/ reduced expression was found in 31 cases and expression of GPX3 was found in 19 cases. Lost/ reduced expression of GPX3 is associated with promoter region hypermethylation (P<0.05). Wnt signaling was inhibited by GPX3 in TPC-1 and FTC133 cells. In conclusion, GPX3 is frequently methylated in human papillary thyroid cancer and the expression of GPX3 was regulated by promoter region methylation. Methylation of GPX3 is related to tumor size and lymph node metastasis. Metastasis of thyroid cancer was suppressed by GPX3 through inhibition Wnt/β-catenin signaling.

Loss of zinc-finger protein 331 (ZNF331) expression was reported in gastric cancer. To explore the regulation of expression and the function of ZNF331 in human esophageal cancer, 11 esophageal cancer cell lines, 7 cases of normal esophageal mucosa and 99 cases of primary esophageal squamous cancer were employed. Methylation specific PCR, semi-quantitive reverse transcriptase PCR, immunohistochemistry, western blot, flow cytometry, wound healing and transwell assay were used. The expression of ZNF331 was silenced by promoter region hypermethylation in 8 of 11 esophageal cancer cell lines. 56.5% (56/99) of primary human esophageal cancer was methylated, but no methylation was found in 7 cases of normal esophageal mucosa. The expression of ZNF331 was reduced in human primary esophageal cancer and reduced expression was associated with promoter region methylation. No significant change was found in cell viability (P>0.05) and cell phase distribution (P>0.05) before and after re-expression in KYSE150 and KYSE410 cells. The migration was suppressed by ZNF331 apparently under wound healing experiment. Re-expression of ZNF331 expression significantly suppressed cell migration and invasion (P<0.05). In conclusion, ZNF331 is frequently methylated in human esophageal cancer. The expression of ZNF331 is regulated by promoter region methylation. ZNF331 may suppress esophageal cancer metastasis.

Purpose: Previous research has proposed that the hypomethylating agent decitabine can sensitize ovarian cancer cells to chemical agents. In this open-label, phase I/II clinical study, we analyzed the toxicity and efficacy of low dose decitabine combined with taxol and platinum chemotherapy in treatment of refractory and recurrent ovarian cancer. Methods: Decitabine was administered intravenously at 7 mg/m2 for 30 minutes over five consecutive days and followed by reduced dose taxol and platinum chemotherapy treatment (TC) every 28 days for at least four cycles. Adverse events (AEs) were graded according to the Common Terminology Criteria for AEs (NCI-CTCAE), and efficacy was assessed using the Response Evaluation Criteria in Solid Tumors assessment (RECIST). Results: Twenty-one patients diagnosed with relapsed/refractory ovarian cancer were initially enrolled in this study, and 17 patients were able to be evaluated. The combination of low dose decitabine and TC was well-tolerated. The most common adverse effects were nausea (77.8%) and neutropenia (66.7%), and adverse events greater than Grade 4 were not observed. The clinical benefit rate (CBR) was 70.6% (12/17), and the partial response (PR) and stable disease (SD) rates were 17.6% (3/17) and 52.9% (9/17), respectively. A significant decrease in serum CA125 levels was observed in many of the responsive cases even after completing the first treatment cycle. Conclusion: Low dose decitabine combined with taxol and platinum was well-tolerated and suitable for treating refractory/refractory ovarian cancer. The change in CA125 levels might be a potential predictor for patient clinical response. The efficacy of low dose decitabine for treatment of ovarian cancer requires more volunteers for further investigation.

Lectins have been reported from various tissues of a diversity of fish species including Japanese eel, conger eel, electric eel, bighead carp, gibel carp, grass carp, Arabian Gulf catfish, channel catfish, blue catfish, catfish, pike perch, perch, powan, zebrafish, toxic moray, cobia fish, steelhead trout, Japanese trout, Atlantic salmon, chinook salmon, olive rainbow smelt, rainbow smelt, whitespotted charr, tilapia, blue gourami, ayu, Potca fish, Spanish mackerel, gilt head bream, tench, roach, rudd, common skate, and sea lamprey. The tissues from which the lectins were isolated comprise gills, eggs, electric organ, stomach, intestine, and liver. Lectins have also been isolated from skin, mucus serum, and plasma. The lectins differ in molecular weight, number of subunits, glycosylation, sugar binding specificity and amino acid sequence. Their activities include antimicrobial, antitumor, immunoregulatory and a role in development.

This article continues a series of reviews on the abundance and roles of intrinsic disorder in milk proteins. Besides caseins, which are the major proteinaceous constituents of any milk that can be isolated by isoelectric precipitation, milk contains a set of soluble whey proteins, such as β-lactoglobulin, α-lactalbumin, serum albumin, immunoglobulins, lactoferrin, lactoperoxidase, glycomacropeptide, and proteose peptone (the last two are soluble casein derivatives). Lactoferrin and lactoperoxidase (LPO) are known to possess prominent biocidal activity, serving as efficient antibiotics and antiviral agents against a wide spectrum of bacteria, fungi, and viruses. LPO is a heme-containing peroxidase expressed as preproprotein. The mature protein has a single catalytic domain, structure of which is known for a protein isolated from several species. Functionally, LPO is a crucial component of the LPO system that includes LPO, hydrogen peroxide (H2O2), and thiocyanate (SCN−), being a well-studied, naturally occurring antimicrobial system in milk that is effective against many microorganisms and some viruses. Although various aspects of LPO structure and function are rather well studied and were subjects of several recent reviews, the abundance and potential functional roles of intrinsically disordered regions in this protein have never being addressed as of yet. The major goal of this article is to fill this gap and to show how intrinsic disorder is encoded in the amino acid sequence of LPO, and how intrinsic disorder is related to functions of this important milk protein.