PLD1 promotes reactive oxygen species production in vascular smooth muscle cells and injury-induced neointima formation.

Phospholipase D (PLD) generates the signaling lipid phosphatidic acid (PA) and has been known to mediate proliferation signal in vascular smooth muscle cells (VSMCs). However, it remains unclear how PLD contributes to vascular diseases. VSMC proliferation directly contributes to the development and progression of cardiovascular disease, such as atherosclerosis and restenosis after angioplasty. Using the mouse carotid artery ligation model, we find that deletion of Pld1 gene inhibits neointima formation of the injuried blood vessels. PLD1 deficiency reduces the proliferation of VSMCs in both injured artery and primary cultures through the inhibition of ERK1/2 and AKT signals. Immunohistochemical staining of injured artery and flow cytometry analysis of VSMCs shows a reduction of the levels of reactive oxygen species (ROS) in Pld1-/- VSMCs. An increase of intracellular ROS by hydrogen peroxide stimulation restored the reduced activities of ERK and AKT in Pld1-/- VSMCs, whereas a reduction of ROS by N-acetyl-l-cysteine (NAC) scavenger lowered their activity in wild-type VSMCs. These results indicate that PLD1 plays a critical role in neointima, and that PLD1 mediates VSMC proliferation signal through promoting the production of ROS. Therefore, inhibition of PLD1 may be used as a therapeutic approach to suppress neointimal formation in atherosclerosis and restenosis after angioplasty.

Erratum: MicroRNA-373 promotes migration and invasion in human esophageal squamous cell carcinoma by inhibiting TIMP3 expression.

[This corrects the article on p. 1 in vol. 6, PMID: 27073718.].

Human papillomavirus infection increases the chemoradiation response of esophageal squamous cell carcinoma based on P53 mutation.

BACKGROUND AND PURPOSE: A retrospective study was carried out to analyze multiple prognostic predictors, including human papillomavirus (HPV) infection for chemoradiation treatment of esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: DNA extracted from a total of 192 patients treated with chemoradiation for locally advanced ESCC was examined to determine HPV status by polymerase chain reaction (PCR) and P53 gene mutation by genetic sequencing. The relationships between the chemoradiation response (CRR) and overall survival (OS) rate with HPV status and P53 gene mutation were analyzed. RESULTS: Thirty-two of the 108 patients with P53 mutated tumors were stained positive for HPV, while thirty-five of the 84 P53 wild-type tumors were HPV positive. P53 mutation and HPV infection were two independent events (p=0.083, Kappa=0.083). HPV infection increased the CRR (p=0.017) and 3-year OS (p=0.047) compared with the HPV negative group. This difference was more significant in the P53 mutation subgroup (CRR p=0.019; OS p=0.025). However, HPV infection led to no difference in the P53 wild-type subgroup (CRR p=0.802; OS p=0.468). The P53 mutation status was an independent prognostic factor (CRR p=0.034; OS p<0.001). Age was another significant prognostic factor for OS (p=0.001). CONCLUSIONS: Depending on P53 mutation status, HPV infection can contribute to a higher tumor response and better prognosis of ESCC treated with chemoradiation therapy.

Erratum: MicroRNA-373 promotes migration and invasion in human esophageal squamous cell carcinoma by inhibiting TIMP3 expression.

[This corrects the article on p. 1 in vol. 6, PMID: 27073718.].

MicroRNA-373 promotes migration and invasion in human esophageal squamous cell carcinoma by inhibiting TIMP3 expression.

Esophageal squamous cell carcinoma (ESCC) is the predominant pathological type of esophageal carcinoma in Asia. MicroRNAs (miRNAs) are a class of 19-22-nucleotide non-coding RNAs acting on target mRNAs that function as either oncogenes or anti-oncogenes. It has been confirmed that miR-373 expression varies among different tumor types. However, its mechanism is still unclear in ESCC. In our current study, we found that miR-373 expression was upregulated in ESCC tissues compared with matched adjacent normal tissues, as well as in the plasma of ESCC patients compared with that of healthy volunteers. Overexpression of miR-373 in ECA109 cells enhanced proliferation, G1-phase cell proportion, migration, and invasion. On the other hand, suppression of miR-373 in KYSE410 cells decreased proliferation, G1-phase cell proportion, migration, and invasion and also improved cell apoptosis. Moreover, we found that TIMP3, which was reported to suppress invasion and metastasis of ESCC, was a direct target of miR-373. Overexpression of miR-373 in ECA109 caused a reduction of TIMP3 mRNA and protein, whereas suppression of miR-373 in KYSE410 led to an increase of TIMP3 mRNA and protein. Introducing TIMP3 in miR-373 over-expressed cells or knocking down TIMP3 in miR-373 suppressed cells could partially abrogate the effect of miR-373 on migration and invasion. Therefore, these results prove that as an oncogene, miRNA-373 would be an important and reliable biomarker for ESCC diagnosis and treatment by targeting TIMP3.

miR-143 inhibits tumor progression by targeting FAM83F in esophageal squamous cell carcinoma.

Family with sequence similarity 83 (FAM83) members play important roles in carcinogenesis and tumor progression in several tumor types. However, the mechanism by which cancer cells regulate FAM83F still remains unclear. In this study, we found that the FAM84F protein and messenger RNA (mRNA) levels were consistently upregulated in esophageal squamous cell carcinoma (ESCC) tissues, which suggests that a post-transcriptional mechanism may be involved in the regulation of FAM83F. Since microRNAs (miRNAs) are powerful post-transcriptional regulators of gene expression, we performed bioinformatic analyses to search for miRNAs that could potentially target FAM83F. We identified the specific targeting site of miR-143 in the 3'-untranslated region (3'-UTR) of FAM83F and confirmed the inverse correlation between the levels of miR-143 and FAM83F protein and mRNA in ESCC tissue samples. By overexpressing or silencing miR-143 in ESCC cells, we experimentally validated that miR-143 directly binds to the 3'-UTR of the FAM83F transcript and degrades the FAM83F mRNA to regulate FAM83F expression. Furthermore, the biological consequences that miR-143 mediated by targeting FAM83F were examined using in vitro cell proliferation, apoptosis, migration, and invasion assays. We demonstrate that miR-143 exerted a tumor-suppressing effect by inhibiting the proliferation, migration, and invasion and inducing G1/G0 phase arrest of ESCC cells via the negative regulation of FAM83F expression. Taken together, our findings provide important evidence which supports the role of miR-143 as a tumor suppressor in ESCC via the inhibition of FAM83F expression.

RETRACTED: MiR-143 inhibits tumor cell proliferation and invasion by targeting STAT3 in esophageal squamous cell carcinoma.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor in Chief. The term miR-143 has been used instead of the term miR-143* in the introduction and discussion which is misleading. With the misuse of this term subsequent errors and misleading statements appear throughout the paper. The authors apologize for this mistake.

Use of texture analysis based on contrast-enhanced MRI to predict treatment response to chemoradiotherapy in nasopharyngeal carcinoma.

PURPOSE: To explore the clinical potential of texture analysis using contrast-enhanced 3.0T magnetic resonance imaging (MRI) for predicting the therapeutic response of nasopharyngeal carcinoma (NPC) to chemoradiotherapy. MATERIALS AND METHODS: The dataset comprised pretreatment T1 -, T2 -, and diffusion-weighted MR images from 53 eligible patients with newly diagnosed NPC. The patients were divided into two sets: the training set including 31 responders and 11 nonresponders and the testing set including eight responders and three nonresponders. The region of interest (ROI) was delineated by two radiologists for each sequence. Quantitative image parameters were extracted and statistically filtered to identify a subset of reproducible and nonredundant parameters that were used to construct the predictive model. The internal validation was performed using stratified 10-fold cross-validation in the training set and the external validation was performed in the testing set. McNemar's test was used to test the statistical difference between the performances of the extracted parameters in predicting the treatment response. RESULTS: All three parameter sets showed potential in predicting treatment response with high accuracy (T1 : 0.952/0.939, T2 : 0.904/0.905, diffusion-weighted [DWI]: 0.881/0.929). Supervised learning models based on parameters extracted from the T1 sequence showed better classification performance than those extracted from the T2 -weighted (T2 W) (artificial neural network [ANN]: P = 0.043, k-nearest neighbors [kNN]: P = 0.033) and DWI (ANN: P = 0.032. kNN: P = 0.014). No statistical difference was observed in the performance of the two classifiers (P = 0.083). CONCLUSION: Texture analysis based on T1 W, T2 W, and DWI could act as imaging biomarkers of tumor response to chemoradiotherapy in NPC patients and serve as a new radiological analysis tool for treatment prediction. J. Magn. Reson. Imaging 2016;44:445-455.

MiR-1290 promotes cancer progression by targeting nuclear factor I/X(NFIX) in esophageal squamous cell carcinoma (ESCC).

The nuclear factor I/X (NFIX) plays important roles in cell differentiation, but its function in cancer is still unclear. Besides, accumulating studies reported the important role of microRNAs (miRNAs) in the regulation of gene expression, among of which, the miR-1290 has been widely reported in various cancers. In this study, we investigated the mechanism through which NFIX was regulated by miRNAs. Firstly, we found that the NFIX protein and mRNA levels were consistently down-regulated in ESCC tissues suggesting that a post-transcriptional mechanism maybe involved in the regulation of NFIX. Since microRNAs (miRNAs) are powerful post-transcriptional regulators of gene expression, we performed bioinformatic analyses to search for miRNAs that potentially target NFIX. We identified the specific targeting site of miR-1290 in the 3'-UTR of NFIX and the inverse correlation between the levels of miR-1290 and NFIX protein and mRNA in ESCC tissue samples was then confirmed. By overexpressing or silencing miR-1290 in ESCC cells, we experimentally validated that miR-1290 directly binds to the 3'-UTR of the NFIX transcript and degrade the NFIX mRNA to regulate NFIX expression. Furthermore, the biological consequences that miR-1290 mediated by targeting NFIX were examined in vitro. We demonstrated that miR-1290 could promote proliferation, migration and invasion via the negative regulation of NFIX expression. Taken together, our findings suggested that miR-1290 functions as a tumor oncogene in the progression of ESCC by targeting NFIX.

Intratumoral Heterogeneity of Subcutaneous Nodules in a Never-Smoker Woman of Lung Squamous Cell Carcinoma Detected on 18F-Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography: A Case Report.

Subcutaneous tissue is a rare site of metastasis, accounting for only 1-2% of all lung neoplasms. Positron emission tomography (PET) using ¹8F-fluorodeoxyglucose (FDG) has been reported to increase the diagnostic accuracy of subcutaneous metastasis. A 58-year-old woman presented with complaints of dry coughing, in which three positive subcutaneous nodules were found on ¹8F-FDG positron emission tomography and computed tomography (PET/CT). Pathologic examination confirmed that each of the nodules contained 1) necrotic fat, 2) small amounts of blood cells and glandular epithelium, and 3) subcutaneous metastasis of moderately differentiated lung squamous cell carcinoma, respectively. Although PET/CT is useful for the detection of subcutaneous metastasis of primary lung cancer, we noted heterogeneous accumulation of ¹8F-FDG in subcutaneous tumors. This case highlights the importance of obtaining histological confirmation of malignant diseases whenever possible.