Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that anti-diabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic alpha-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor-E2-related factor 2 (NRF2)-mediated antioxidant response via inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated naturally-occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis.

Long non‐coding RNAs (LncRNAs) have been recently found to be pervasively transcribed in the genome and critical regulators of the epigenome. HOTAIR, as a well‐known LncRNA, has been found to play important roles in several tumors. Herein, the clinical application value and biological functions of HOTAIR were focused and explored in esophageal squamous cell carcinoma (ESCC). It was found that there was a great upregulation of HOTAIR in ESCC compared to their adjacent normal esophageal tissues. Meanwhile, patients with high HOTAIR expression have a significantly poorer prognosis than those with low expression. Moreover, HOTAIR was further validated to promote migration and invasion of ESCC cells in vitro. Then some specific molecules with great significance were investigated after HOTAIR overexpression using microarray and quantitative real time‐polymerase chain reaction (qPCR). WIF‐1 playing an important role in Wnt/β‐catenin signaling pathway was selected and further tested by immunehistochemistry. Generally, inverse correlation between HOTAIR and WIF‐1 expression was demonstrated both in ESCC cells and tissues. Mechanistically, HOTAIR directly decreased WIF‐1 expression by promoting its histone H3K27 methylation in the promoter region and then activated the Wnt/β‐catenin signaling pathway. This newly identified HOTAIR/WIF‐1 axis clarified the molecular mechanism of ESCC cell metastasis and represented a novel therapeutic target in patients with ESCC.

Long noncoding RNAs (lncRNA) are emerging as key molecules in human cancer. Prostate cancer-associated ncRNA transcripts 1 (PCAT-1), a lncRNA, has been recently revealed involving in human prostate cancer progression. However, whether PCAT-1 could serve as novel biomarker to predict prognosis in colorectal cancer (CRC) or not is unknown. We therefore carried out the present study to explore the correlation between PCAT-1 expression and the progression of CRC. In this study, the expression of PCAT-1 in 108 cases of CRC tissues and matched 81 adjacent normal tissues were determined by quantitative real-time PCR. Furthermore, the copy number variation of PCAT-1 was also measured in 17 tumor tissues and matched normal tissues. Our results showed that PCAT-1 expression in CRC tissues was significantly upregulated compared with the matched normal tissues (p < 0.001) and the overexpression of PCAT-1(upregulated by more than 50 %) was found in 64 % (62/81) of CRC. Moreover, PCAT-1 gene copy number variation explains only a few percent of observed overexpression. In addition, there was a significant association between PCAT-1 expression and distant metastasis (p = 0.04), but not other clinical characteristics. More important, CRC patients with PCAT-1 higher expression have shown significantly poorer overall survival than those with lower PCAT-1 expression (p < 0.001). Also, multivariable Cox regression analysis identified PCAT-1 overexpression as an independent prognostic factor for CRC (p = 0.007, HR = 3.12 95 %CI = 1.355-7.185). In conclusion, our results suggest that high expression of PCAT-1 is involved in CRC progression and could be a novel biomarker of poor prognosis in patient with colorectal cancer.

The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets.

Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism and DNA synthesis. A number of studies have examined the association of MTHFR C677T and A1298C polymorphisms with non-Hodgkin lymphoma (NHL) susceptibility; however, the conclusions were contradictory. We searched available publications assessing the polymorphisms of MTHFR and NHL susceptibility from MEDLINE, EMBASE and CBM. Genotype-based mRNA expression analysis was performed using data from 270 individuals with three different ethnicities. Ultimately, a total of 7448 cases and 11146 controls from 25 studies were included for the C677T polymorphism, 6173 cases and 9725 controls from 19 studies for the A1298C polymorphism. Pooled results indicated that neither C677T nor A1298C polymorphism was associated with NHL susceptibility. However, C677T polymorphism showed a statistically significantly increased risk for Caucasians, but a decreased risk for Asians in the subgroup analysis by ethnicity. The same variants may confer increased susceptibility to develop follicular lymphoma (FL). Moreover, A1298C polymorphism was associated with increased NHL risk for Asians. This meta-analysis indicated that C677T polymorphism was associated with altered NHL susceptibility for Caucasians, Asians and FL. Increased NHL risk was also shown for A1298C among Asians. These findings warrant validation in large and well-designed prospective studies.

Background Increasing evidence indicates that the gut microbiota contributes to the occurrence and development of metabolic diseases. However, little is known about the effects of commonly used antidiabetic agents on the gut microbiota. In this study, we investigated the roles of dipeptidyl peptidase-4 inhibitors (DPP-4i) and α-glucosidase inhibitor in modulating the gut microbiota. Methods 16S-rDNA sequencing was performed to analyse the effects of DPP-4i and acarbose on the gut microbiota in mice fed a high-fat diet (HFD). Fecal microbiota transplantation (FMT) from type 2 diabetes patients to germ-free mice was performed to investigate the contribution of the altered microbiome to antidiabetic effects of the drugs. Fecal metabolomics was also analysed by untargeted and targeted GC–MS systems. Findings Although DPP-4i and α-glucosidase inhibitor both altered the gut microbial composition, only the microbiome modulation of DPP-4i contributed to its hypoglycemic effect. Specifically, the changes of 68.6% genera induced by HFD were rescued by DPP-4i. FMT showed that the DPP-4i-altered microbiome improved glucose tolerance in colonized mice, while acarbose did not. Moreover, DPP-4i increased the abundance of Bacteroidetes, and also promoted a functional shift in the gut microbiome, especially increasing the production of succinate. Interpretation Our findings demonstrate an important effect of DPP-4i on the gut microbiota, revealing a new hypoglycemic mechanism and an additional benefit of it. Furthermore, modulating the microbial composition, and the functional shift arising from changes in the microbiome, might be a potential strategy for improving glucose homeostasis. Fund This work was supported by grants from the National Natural Science Foundation of China (No. 81700757, No. 81471039, No. 81700714 and No. 81770434), the National Key R&D Program of China (No. 2017YFC1309602, No. 2016YFC1101100, No. 2017YFD0500503 and No. 2017YFD0501001), and the Natural Science Foundation of Chongqing (No. cstc2014jcyjjq10006, No. cstc2016jcyjA0093 and No. cstc2016jcyjA0518).

Due to its fast and high resolution characteristics, dual-comb spectroscopy has attracted an increasing amount of interest since its first demonstration. In the terahertz frequency range where abundant absorption lines (finger prints) of molecules are located, multiheterodyne spectroscopy that employs the dual-comb technique shows an advantage in real-time spectral detection over the traditional Fourier transform infrared or time domain spectroscopies. Here, we demonstrate compact terahertz dual-comb spectroscopy based on quantum cascade lasers (QCLs). In our experiment, two free-running QCLs generate approximately 120 GHz wide combs centered at 4.2 THz, with slightly different repetition frequencies. We observe that ∼490 nW terahertz power coupling of one laser into the other suffices for laser-self-detecting the dual-comb spectrum that is registered by a microwave spectrum analyzer. Furthermore, we demonstrate practical terahertz transmission dual-comb spectroscopy with our device, by implementing a short air path at room temperature. Spectra are shown of semiconductor samples and of moist air, the latter allowing rapid monitoring of the relative humidity. Our devices should be readily extendable to perform imaging, microscopy and near-field microscopy in the terahertz regime. arXiv:1904.03330v5 [physics.optics]

Aberrant expression of receptor interacting protein kinase 4 (RIPK4), a crucial regulatory protein of Wnt/β-catenin signaling, has recently been reported to be involved in several cancers. Here, we report the potential clinical implication and biological functions of RIPK4 in cervical squamous cell carcinoma (CSCC). One hundred and ninety-eight CSCC cases, 109 low-grade squamous intraepithelial lesions (LSILs), 141 high-grade squamous intraepithelial lesions (HSILs) and 63 chronic cervicitis were collected. The expression of RIPK4 was detected by immunohistochemistry (IHC), and its clinical value and oncogenic functions were further assessed. RIPK4 expression increased significantly with disease progression from 3.2% in chronic cervicitis, 19.3% in LSILs and 85.1% in HSILs to 94.4% in CSCCs (P < 0.001). Moreover, RIPK4 may serve as a useful biomarker to distinguish HSIL from chronic cervicitis/LSIL, which are two different clinical types for therapeutic procedures, with a high sensitivity and specificity (85.1% and 86.6%, respectively) and the performance improved when combined with p16INK4a. Further, RIPK4 overexpression was associated with overall (HR = 2.085, P = 0.038) and disease-free survival (HR = 1.742, P = 0.037). Knockdown of RIPK4 reduced cell migration and invasion via inhibition of Vimentin, MMP2 and Fibronectin expression in cervical cancer cells. RIPK4 might act as a potential diagnostic and independent prognostic biomarker for CSCC patients.