CD44 as one of the most putative stem cell markers plays a key role in many cellular processes, including cancer cell growth and migration. Functional single nucleotide polymorphisms (SNPs) of CD44 may modulate its gene functions and thus cancer risk. In the current study, we investigated if polymorphisms in the 3’-untranslated region (UTR) of CD44 are associated with increased susceptibility to colorectal cancer (CRC) by conducting a case-control study of 946 CRC patients and 989 cancer-free controls. Three polymorphisms (rs13347C/T, rs10836347C/T, rs11821102G/A) in the 3’-UTR of CD44 were genotyped. We found that the variant genotypes (CT and TT) of rs13347 (adjusted odds ratio (OR)=1.79, 95% confidence interval (CI)=1.50-2.17) increased an individual’s susceptibility to CRC, compared with rs13347CC homozygous genotypes. We also found that CRC patients with the CT/TT genotype had a 1.6-fold increased risk for developing advanced (stage III + IV) CRC. Furthermore, functional assays showed that the C to T base change at rs13347C/T disrupts the binding site for the microRNA hsa-mir-509-3p, thereby increasing CD44 transcriptional activity and expression level. These findings suggest that the rs13347C/T in microRNA binding site may be potential biomarkers for genetic susceptibility to CRC.

Purpose To explore the clinical feasibility of predicting the efficacy of neoadjuvant chemoradiotherapy (nCRT) for rectal cancer on the basis of texture analysis (TA) of T2-weighted imaging (T2WI). Methods The cohort for this prospective study comprised 136 patients with rectal cancer to be treated with nCRT, all of whom underwent three MR scans (pre-, early, and post-nCRT). Treatment efficacy was assessed on the basis of the outcomes of pathologic complete response (pCR) and non-pCR as determined by postoperative pathological examination. Extraction and analysis of texture features in T2WI of defined tumor regions were performed by AK software. Pre-and early-nCRT texture features were selected as potential predictors of outcomes by logistic regression analysis, and a prediction model for pCR was developed. A receiver operating characteristic (ROC) curve was used to assess the predictive power of texture features in pre-and early-nCRT images.Results Univariate logistic regression analysis demonstrated that the pre-nCRT features of energy, entropy, and skewness, and early-nCRT features of variance, kurtosis, energy, and entropy were independent predictors of pCR. A prediction model incorporating these predictors was constructed by multivariate logistic regression, The AUCs of pre-nCRT, early, and combined models were 0.751, 0.831, and 0.873, respectively; the sensitivities 66, 71, and 75%, respectively; and the specificities 87.22, 86.11, and 91.67%, respectively. Conclusions TA of T2WI images can predict the efficacy of nCRT for rectal cancer, possibly providing a new marker of tumor biological response in clinical practice.

Colorectal cancer (CRC) is highly prevalent worldwide, but there has been limited development of efficient and affordable treatment. Induced autophagy has recently been recognized as a novel therapeutic strategy in cancer treatment, and disulfiram (DSF), a well-known antialcohol drug, is also found to inhibit tumor growth in various malignancies. Recently, DSF has been reported to induce excessive autophagy in oral squamous cells; however, little is known about whether it can induce autophagy and suppress proliferation in CRC. In this study, we investigate the effect of DSF with copper (DSF/Cu) on CRC both in vitro and in vivo and find that the combination significantly inhibits CRC cell viability and mainly induces autophagy instead of apoptosis. Furthermore, we use whole genome CRISPR library screening and identify a new mechanism by which DSF triggers autophagy by ULK1. Overall, these findings provide a potential CRC treatment.

Novel nitro oxide (NO)-donating N-hydroxycinnamamide derivatives 12a-j were designed and synthesized by coupling the carboxyl group of N-hydroxycinnamamides with phenylsulfonylfuroxan through various diols or alkylol amines, and their in vitro biological activities were evaluated. It was discovered that most of target compounds showed good histone deacetylases (HDACs) inhibition and anti-tumor activities, particularly for 12j, which had great HDACs inhibitory activities (IC 50 s 0.15-0.26 µM) and antiproliferative effects (IC 50 s 3.21-7.12 µM) comparable to suberoylanilide hydroxamic acid (SAHA) (IC 50 s 0.16-1.41 µM for HDACs, IC 50 s 3.15-7.45 µM for cancer cell inhibition). Furthermore, compound 12j with strong antitumor activities produced high levels of NO (up to 8.0 µM of nitrites/nitrates) in colon cancer cells, and its antiproliferative activity was nearly half-diminished by hemoglobin (10 µM), an NO scavenger. These results suggest that the strong antiproliferative activity of 12j could be attributed to the additive effects of high levels of NO production and inhibition of HDAC in the cancer cells.Key words nitro oxide; histone deacetylase inhibitor; furoxan; N-hydroxycinnamamide; anti-tumor agent Pharmacological targeting of proteins that regulate epigenetics has emerged as a promising therapeutic area of study.1,2) Epigenetic or chromatin modification is recognized by nonhistone proteins and is a code of gene expression. Among the various histone modifiers, Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are two reversible enzymes regulating histone acetylation status and executing the acetylation and deacetylation of the lysine residues at the amino terminal of histones.3) However, abnormal HDAC overexpression has been found to be involved in the development of several kinds of human cancers, including myeloid neoplasia and solid tumors. 4) Recent studies have shown that acetylation of non-histone proteins is also relevant for tumorigenesis, cancer cell proliferation, and immune functions.5) Consequently, histone deacetylases are considered to be important targets in the development of anticancer agents, and in recent years considerable attention has been paid to HDAC inhibitors (HDACI) as anticancer agents. [6][7][8] There has been a high level of interest in developing smallmolecule HDACI, and numerous structurally diverse HDACI have been developed as potential anticancer agents, which are grouped chemically into four classes: hydroxamic acids, benzamides, cyclic tetrapeptides, and short-chain fatty acids.9) The common pharmacophore of these HDACI consists of three domains: a zinc-binding group (ZBG), such as hydroxamic acid; a cap group, generally a hydrophobic and aromatic group; a saturated or unsaturated linker domain, composed of linear or cyclic structures that connect the ZBG and the cap group. Up to now, two of these HDACI, suberoylanilide hydroxamic acid (SAHA, Fig. 1) and cyclic peptide Romidepsin (FK228), have been approved by the U.S. Food and Drug Administration (FDA) f...