Nuclear matrix proteins as biomarkers in prostate cancer

The nuclear matrix (NM) is the structural framework of the nucleus that consists of the peripheral lamins and pore complexes, an internal ribonucleic protein network, and residual nucleoli. The NM contains proteins that contribute to the preservation of nuclear shape and its organization. These protein components better known as the NM proteins have been demonstrated to be tissue specific, and are altered in many cancers, including prostate cancer. Alterations in nuclear morphology are hallmarks of cancer and are believed to be associated with changes in NM protein composition. Prostate cancer is the most frequently diagnosed cancer in American men and many investigators have identified unique NM proteins that appear to be specific for this disease. These NM protein changes are associated with the development of prostate cancer, as well as in some cases being indicative of cancer stage. Identification of these NM proteins specific for prostate cancer provides an insight to understanding the molecular changes associated with this disease. This article reviews the role of NM proteins as tumor biomarkers in prostate cancer and the potential application of these proteins as therapeutic targets in the treatment of this disease.     

Colon cancer specific nuclear matrix protein alterations in human colonic adenomatous polyps

Most colon cancers arise within preexisting adenomatous polyps or adenomas. The slow evolution from the non-invasive premalignant lesion, the adenomatous polyp, to invasive cancer supports a strategy of early detection. Recently, we identified unique nuclear matrix proteins (NMPs) specific for colon cancer (CC2, CC3, CC4, CC5). Most of the NMPs identified are common to all cell types, but several identified NMPs are tissue and cell line specific. The objective of this study is to describe and characterize the NMP profile of premalignant adenomatous colon polyps. Specifically when in the adenoma-carcinoma sequence four specific colon cancer NMPs, previously described, appear. Using two-dimensional (2-D) gel analysis 20 colon polyps (one juvenile polyp, six tubular adenoma (TA), seven tubulovillous adenoma (TVA), six TVA with focal high-grade dysplasia (HGD), were analyzed for the presence of four (CC2, CC3, CC4, CC5) specific NMPs. CC2 was not seen in any of the premalignant polyps. CC5 was present in only two premalignant TVA with HGD and in one TA. CC3 and CC4 were present in most adenomas. None of the NMPs were seen in the juvenile polyp, which is not considered to be a precursor of colon cancer. CC2 and CC5 are NMPs expressed at the junction of an advanced adenoma and invasive colorectal cancer. CC3 and CC4 are expressed earlier in the evolution of adenomatous polyps. Development of an assay to these proteins may serve as a new method for early detection of colorectal cancer.     

The use of a colon cancer associated nuclear antigen CCSA-2 for the blood based detection of colon cancer

The early diagnosis of colorectal cancer (CRC) is central for effective treatment, as prognosis is directly related to the stage of the disease. Development of tumor markers found in the blood from patients, which can detect CRC at an early stage, should have a major impact in morbidity and mortality of this disease. The nuclear matrix is the structural scaffolding of the nucleus and specific nuclear matrix proteins (NMPs) have been identified as an "fingerprint" for various cancer types. Previous studies from our laboratory have identified four colon cancer associated NMPs termed colon cancer-specific antigen (CCSA)-2 to (CCSA)-5. The objective of the present study was to analyze the expression of one of these proteins, CCSA-2 in serum from various patient populations and to determine whether CCSA-2 antibodies could be used in a clinically applicable serum-based immunoassay specifically to detect colon cancer. Using an indirect ELISA, which detects CCSA-2, the protein was measured in the serum from 174 individuals, including healthy individuals, patients with colon cancer, patients with diverticulosis, colon polyps, inflammatory bowel disease (IBD) as well as other cancer types. With a predetermined cutoff absorbance of 0.6 OD we have successfully utilized this approach to develop an immunoassay that detected colon cancer. The immunoassay showed a sensitivity of 88.8% (24/27) and an overall specificity of 84.2% (106/127). This initial study showed the potential of CCSA-2 to serve as a highly specific blood based marker for colon cancer. Although potentially promising, the results of this study must be confirmed in larger independent validation studies.     

Identification of calreticulin as a nuclear matrix protein associated with human colon cancer

Colon cancer is one of the most common malignancies among populations in the United States and Western Europe, and one of the leading causes of worldwide morbidity and mortality due to cancer. The early detection of colon cancer is central to the effective treatment of this disease and early detection markers are needed. We have demonstrated that high-resolution two-dimensional gel analysis of nuclear matrix proteins (NMPs) demonstrated a specific oncological fingerprint of colon cancer. Utilizing this approach, four proteins specific for colon cancer was identified. Additionally, one protein was expressed much more strongly in colon cancer compared to adjacent and normal donor tissue. The amino acid composition of this protein revealed sequence similarity with calreticulin. The multi-functional protein, calreticulin, is normally found in the lumen of the endoplasmic reticulum although some reports have described a nuclear localization of the protein. The aim of this study was to confirm the identity of the protein as calreticulin as well as to evaluate the localization of calreticulin in the nuclear matrix of colon cancer tissue.     

Nuclear dreams: The malignant alteration of nuclear architecture

Cancer is diagnosed by examining the architectural alterations to cells and tissues. Changes in nuclear structure are among the most universal of these and include increases in nuclear size, deformities in nuclear shape, and changes in the internal organization of the nucleus. These may all reflect changes in the nuclear matrix, a non-chromatin nuclear scaffolding determining nuclear form, higher order chromatin folding, and the spatial organization of nucleic acid metabolism. Malignancy-induced changes in this structure may have profound effects on chromatin folding, on the fidelity of genome replication, and on gene expression. Elucidating the mechanisms and the biological consequences of nuclear changes will require the identification of the major structural molecules of the internal nuclear matrix and an understanding of their assembly into structural elements. If biochemical correlates to malignant alterations in nuclear structure can be identified then nuclear matrix proteins and, perhaps nuclear matrix-associated structural RNAs, may be an attractive set of diagnostic markers and therapeutic targets. J. Cell. Biochem. 70:172–180, 1998. © 1998 Wiley-Liss, Inc.     

MicroRNAs expression profiles as diagnostic biomarkers of gastric cancer: a systematic literature review

Objective: The early identification of gastric cancer (GC) represents a major clinical challenge. We conducted a systematic review of studies evaluating the miRNA expression profiling as a diagnostic tool in GC.

Methods: We performed a search of PubMed, ISI Web of Science and SCOPUS databases for studies on diagnostic miRNAs and GC, published in English up to October 2017. Eligibility criteria included case-control studies evaluating blood or tissue-based miRNA expression profiles, and incorporating at least two detection phases (screening and validation).

Results: We included 27 eligible studies, that reported on 97 deregulated miRNAs either in blood or tissue, out of which 30 were reported in at least two studies. Among 22 studies on tissue-diagnostic miRNAs, 13 consistently upregulated miRNAs (miR-214, miR-21, miR-103, miR-107, miR-196a, miR-196b, miR-7, miR-135b, miR-222, miR-23b, miR-25, miR-92 and miR-93), and six consistently downregulated miRNAs (miR-148a, miR-375, miR-133b, miR-30a, miR-193a and miR-204) were reported. Ten miRNAs with inconsistent direction of expression in tissues were identified. Among the five studies performed on blood samples, only one miRNA was consistently upregulated (miR-20a).

Conclusions: This review shows that some tissue or blood miRNAs may be considered as potential biomarkers for GC diagnosis, that urgently needs to be confirmed from large prospective studies.     

Oncogenic microRNAs (OncomiRs) as a new class of cancer biomarkers

Small non-coding RNAs (microRNAs or miRs) represent one of the most fertile areas of cancer research and recent advances in the field have prompted us to reconsider the traditional concept of cancer. Some miRs exert negative control over the expression of numerous oncoproteins in normal cells and consequently their deregulation is believed to be an important mechanism underlying cancer development and progression. Owing to their distinct patterns of expression associated with cancer type, remarkable stability and presence in blood and other body fluids, miRs are considered to be highly promising cancer biomarkers. The identification of "miR signatures" associating cancer cell phenotypes with disease outcome and specific risk factor exposures will undoubtedly open new avenues for early diagnosis and therapy of cancer, as well as for the development of novel strategies for cancer prevention.     

Exosomal circRNAs as novel cancer biomarkers: Challenges and opportunities

Identifying high specificity and sensitivity biomarkers has always been the focus of research in the field of non-invasive cancer diagnosis. Exosomes are extracellular vesicles with a lipid bilayer membrane that can be released by all types of cells, which contain a variety of proteins, lipids, and a variety of non-coding RNAs. Increasing research has shown that the lipid bilayer can effectively protect the nucleic acid in exosomes. In cancers, tumor cell-derived exosomal circRNAs can act on target cells or organs through the transport of exosomes, and then participate in the regulation of tumor development and metastasis. Since exosomes exist in various body fluids and circRNAs in exosomes exhibit high stability, exosomal circRNAs have the potential as biomarkers for early and minimally invasive cancer diagnosis and prognosis judgment. In this review, we summarized circRNAs and their biological roles in cancers, with the emerging value biomarkers in cancer diagnosis, disease judgment, and prognosis observation. In addition, we briefly compared the advantages of exosomal circRNAs as biomarkers and the current obstacles in the exosome isolation technology, shed light to the future development of this technology.     

Matrix metalloproteases and TIMPs as prognostic biomarkers in breast cancer patients treated with radiotherapy: A pilot study

Breast cancer (BC) is the most common tumour in women and one of the most important causes of cancer death worldwide. Radiation therapy (RT) is widely used for BC treatment. Some proteins have been identified as prognostic factors for BC (Ki67, p53, E‐cadherin, HER2). In the last years, it has been shown that variations in the expression of MMPs and TIMPs may contribute to the development of BC. The aim of this pilot work was to study the effects of RT on different MMPs (‐1, ‐2, ‐3, ‐7, ‐8, ‐9, ‐10, ‐12 and ‐13) and TIMPs (‐1 to ‐4), as well as their relationship with other variables related to patient characteristics and tumour biology. A group of 20 BC patients treated with RT were recruited. MMP and TIMP serum levels were analysed by immunoassay before, during and after RT. Our pilot study showed a slight increase in the levels of most MMP and TIMP with RT. However, RT produced a significantly decrease in TIMP‐1 and TIMP‐3 levels. Significant correlations were found between MMP‐3 and TIMP‐4 levels, and some of the variables studied related to patient characteristics and tumour biology. Moreover, MMP‐9 and TIMP‐3 levels could be predictive of RT toxicity. For this reason, MMP‐3, MMP‐9, TIMP‐3 and TIMP‐4 could be used as potential prognostic and predictive biomarkers for BC patients treated with RT.     

Thoracic surface temperature rhythms as circadian biomarkers for cancer chronotherapy

The disruption of the temperature circadian rhythm has been associated with cancer progression, while its amplification resulted in cancer inhibition in experimental tumor models. The current study investigated the relevance of skin surface temperature rhythms as biomarkers of the Circadian Timing System (CTS) in order to optimize chronotherapy timing in individual cancer patients. Baseline skin surface temperature at four sites and wrist accelerations were measured every minute for 4?days in 16 patients with metastatic gastro-intestinal cancer before chronotherapy administration. Temperature and rest-activity were recorded, respectively, with wireless skin surface temperature patches (Respironics, Phillips) and an actigraph (Ambulatory Monitoring). Both variables were further monitored in 10 of these patients during and after a 4-day course of a fixed chronotherapy protocol. Collected at baseline, during and after therapy longitudinal data sets were processed using Fast Fourier Transform Cosinor and Linear Discriminant Analyses methods. A circadian rhythm was statistically validated with a period of 24?h (p?<?0.05) for 49/61 temperature time series (80.3%), and 15/16 rest-activity patterns (93.7%) at baseline. However, individual circadian amplitudes varied from 0.04?°C to 2.86?°C for skin surface temperature (median, 0.72?°C), and from 16.6 to 146.1?acc/min for rest-activity (median, 88.9?acc/min). Thirty-nine pairs of baseline temperature and rest-activity time series (75%) were correlated (r?>?|0.7|; p?<?0.05). Individual circadian acrophases at baseline were scattered from 15:18 to 6:05 for skin surface temperature, and from 12:19 to 15:18 for rest-activity, with respective median values of 01:10 (25–75% quartiles, 22:35–3:07) and 14:12 (13:14–14:31). The circadian patterns in skin surface temperature and rest-activity persisted or were amplified during and after fixed chronotherapy delivery for 5/10 patients. In contrast, transient or sustained disruption of these biomarkers was found for the five other patients, as indicated by the lack of any statistically significant dominant period in the circadian range. No consistent correlation (r?<?|0.7|, p?≥?0.05) was found between paired rest-activity and temperature time series during fixed chronotherapy delivery. In conclusion, large inter-patient differences in circadian amplitudes and acrophases of skin surface temperature were demonstrated for the first time in cancer patients, despite rather similar rest-activity acrophases. The patient-dependent coupling between both CTS biomarkers, and its possible alteration on a fixed chronotherapy protocol, support the concept of personalized cancer chronotherapy.     

Nuclear and chromatin structure in rat spermatozoa

The nuclei of mature mammalian spermatozoa contain a highly ordered, lamellar substructure, presumably constituting the nucleoprotein of the haploid chromosomal complement. With a view toward constructing a plausible model of chromatin packing in sperm, we have determined some of the quantitative parameters associated with these “nuclear lamellae” in rat spermatozoa. Epididymal sperm from white, Sprague-Dawley rats were examined by conventional sectioning methods, freeze fracture of fixed and unfixed specimens, and by whole mount replica techniques. Fixation and glycerolation did not significantly alter nuclear structure as seen by freeze fracture. Numerical data obtained from cross fractures of sperm heads indicate that the number of lamellae are quite constant at 10.4 ± 1.8 and that the linear measure of the lamellae is 7.2 ± 2.3 μm per cross fracture. The total area of cross fracture, assuming an elliptical profile is 2.3 k 0.7 μm² and the thickness of the lamellae is 18.2 ± 3.5 nm with a range of 13.5 to 25.5 nm. An estimate of the total surface area of the nuclear lamellae could be made from measurements of projected nuclear area (from replicas and sections) as 173 ± 15 μm². From these data and the known amount of DNA in the rat sperm nucleus, a model can be proposed for the organization of the nucleoprotein in these lamellar sheets. It is suggested that the chromatin is arranged in a coiled-coil configuration closely associated together in a side-by-side fashion and continuous in extent. Approximate calculations based on this simple model are within a factor of 2 or 3 of predicting the correct amount of DNA in the sperm nucleus.     

Pathway mapping and development of disease‐specific biomarkers: protein‐based network biomarkers

It is known that a disease is rarely a consequence of an abnormality of a single gene, but reflects the interactions of various processes in a complex network. Annotated molecular networks offer new opportunities to understand diseases within a systems biology framework and provide an excellent substrate for network‐based identification of biomarkers. The network biomarkers and dynamic network biomarkers (DNBs) represent new types of biomarkers with protein–protein or gene–gene interactions that can be monitored and evaluated at different stages and time‐points during development of disease. Clinical bioinformatics as a new way to combine clinical measurements and signs with human tissue‐generated bioinformatics is crucial to translate biomarkers into clinical application, validate the disease specificity, and understand the role of biomarkers in clinical settings. In this article, the recent advances and developments on network biomarkers and DNBs are comprehensively reviewed. How network biomarkers help a better understanding of molecular mechanism of diseases, the advantages and constraints of network biomarkers for clinical application, clinical bioinformatics as a bridge to the development of diseases‐specific, stage‐specific, severity‐specific and therapy predictive biomarkers, and the potentials of network biomarkers are also discussed.     

Standardizing cancer biomarkers criteria: data elements as a foundation for a database. Inflammatory mediator/M-CSF as model marker

The purpose of this position article was to design a set of criteria (data elements) for a wide range of cancer biomarkers (CBs) in an attempt to standardize biomarkers features through a common language as a foundation for a database. Data elements are described as a set of generic criteria, which should characterize nearly all biomarkers introduced in the literature. Data elements were extracted from the review of prominent features that biomarkers represent within various categories. The extracted characteristics of biomarkers produced a short list of shared and unique generic features such as biological nature and history; stage/phase of study; sensitivity and specificity; modes of action; risk assessment; validation status; technology, and recommendation status for diversified biomarkers. To tailor data elements on specific markers, a cytokine, such as macrophage-colony stimulating factor (M-CSF), which has been proposed as a ‹potentially suitable biomarker’ for diagnosis of ovarian, lung, breast, pancreatic, and colorectal cancers, was selected as a Model biomarker. Small scale clinical studies suggested the superior usefulness of M-CSF compared with traditional markers for cancer detection. A key criterion for selecting Model marker and tailoring data elements for detection of cancer was the comparison of data on its specificity and sensitivity with traditional markers. The design of data elements for standardizing CBs criteria is considered a Research Tool and a foundation for developing a comprehensive CBs database useful for oncology researchers for a wide range of biomarkers. Validation, integration and proper packaging, data visualization and recommendation of suitability of CBs, by a panel of experts, for technology development are important challenging next steps toward developing a reliable database, which would allow professionals to effectively retrieve and study integrated information on potentially useful markers; identify important knowledge gaps and limitations of data; and assess state of technologies and commercialization of markers at a point of need. Appropriate use of integrated information on biomarkers in clinical practices would eventually account for more cost-effective characteristics of an individual’s state of health.     

Six genes as potential diagnosis and prognosis biomarkers for hepatocellular carcinoma through data mining

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the third of cancer mortality worldwide. Although the study of HCC has made great progress, the molecular mechanism and signal pathways of HCC are not yet clear. Therefore, it is necessary to investigate the early diagnosis and prognosis biomarkers for HCC. The aim of this study is to screen the relevant genes and study the association of gene expression with the survival status of HCC patients using bioinformatics approaches, in the hope of establishing marker genes for diagnosis and prognosis of HCC. The gene expression data and corresponding clinical information of HCC samples were downloaded from the The Cancer Genome Atlas database. We performed to study the relationship between gene expression and prognosis of HCC and screen significantly relevant genes associated with prognosis of HCC by analyzing survival and function enrichment of genes. In this study, we collected 421 samples with gene expression data, including 371 tumor samples and 50 normal samples. By using single factor Cox regression analysis, we screened 1,197 genes significantly associated with survival time in the modeling data containing 117 samples and also searched six genes as the best markers to predict living status of HCC patients. Besides, we established score system of survival risk of HCC. Our study recognized six genes (PGBD3, PGM5P3-AS1, RNF5, UTP11, BAG6, and KCND2) to be significantly associated with diagnosis and prognosis of HCC, providing novel targets for studying potential mechanism about the progression of HCC.     

子宫颈癌细胞学新型生物标志、诊断标志物的筛选和开发现状

子宫颈癌至今仍是全球范围内一个重要的公共卫生问题,是妇女疾病死亡的主要原因之一。因此,子宫颈癌细胞学的筛查、早期诊断和治疗越来越受到重视,虽然新的技术不断推出使子宫颈癌的早期筛查及诊治水平有了很大提高,但仍缺乏新型的特异性生物学标志物。本文从新的子宫颈癌相关蛋白生物标志物和诊断靶标的发现,治疗子宫颈癌的药物作用、治疗靶标和作用机制的评估,子宫颈癌相关微小核糖核酸作为诊断和治疗靶标的筛选等方面对子宫颈脱落细胞筛查方法的开发和研究进展进行综述,为子宫颈癌的早期筛查和诊断寻找新的生物学标志物。