Development of a risk scoring system for patients with papillary thyroid cancer

As the importance of personalized therapeutics in aggressive papillary thyroid cancer (PTC) increases, accurate risk stratification is required. To develop a novel prognostic scoring system for patients with PTC (n = 455), we used mRNA expression and clinical data from The Cancer Genome Atlas. We performed variable selection using Network‐Regularized high‐dimensional Cox‐regression with gene network from pathway databases. The risk score was calculated using a linear combination of regression coefficients and mRNA expressions. The risk score and clinical variables were assessed by several survival analyses. The risk score showed high discriminatory power for the prediction of event‐free survival as well as the presence of metastasis. In multivariate analysis, the risk score and presence of metastasis were significant risk factors among the clinical variables that were examined together. In the current study, we developed a risk scoring system that will help to identify suitable therapeutic options for PTC.     

Small non‐coding RNA and colorectal cancer

Colorectal cancer (CRC) is the third most common malignance. Although great efforts have been made to understand the pathogenesis of CRC, the underlying mechanisms are still unclear. It is now clear that more than 90% of the total genome is actively transcribed, but lack of protein‐coding potential. The massive amount of RNA can be classified as housekeeping RNAs (such as ribosomal RNAs, transfer RNAs) and regulatory RNAs (such as microRNAs [miRNAs], PIWI‐interacting RNA [piRNAs], tRNA‐derived stress‐induced RNA, tRNA‐derived small RNA [tRFs] and long non‐coding RNAs [lncRNAs]). Small non‐coding RNAs are a group of ncRNAs with the length no more than 200 nt and they have been found to exert important regulatory functions under many pathological conditions. In this review, we summarize the biogenesis and functions of regulatory sncRNAs, such as miRNAs, piRNA and tRFs, and highlight their involvements in cancers, particularly in CRC.     

Long non‐coding RNA ZEB2‐AS1 promotes the proliferation,metastasis and epithelial mesenchymal transition in triple‐negative breast cancer by epigenetically activating ZEB2

The triple‐negative breast cancer is the most malignant type of breast cancer. Its pathogenesis and prognosis remain poor despite the significant advances in breast cancer diagnosis and therapy. Meanwhile, long noncoding RNAs (LncRNAs) play a pivotal role in the progression of malignant tumors. In this study, we found that LncRNA‐ZEB2‐AS1 was dramatically up‐regulated in our breast cancer specimens and cells (MDA231), especially in metastatic tumor specimens and highly invasive cells, and high lncRNA‐ZEB2‐AS1 expression is associated with clinicopathologic features and short survival of breast cancer patients. LncRNA‐ZEB2‐AS1 promotes the proliferation and metastasis of MDA231 cells in SCID mice. Thus, it is regarded as an oncogene in triple‐negative breast cancer. It is mainly endo‐nuclear and situated near ZEB2, positively regulating ZEB2 expression and activating the epithelial mesenchymal transition via the PI3K/Akt/GSK3β/Zeb2 signaling pathway. Meanwhile, EGF‐induced F‐actin polymerization in MDA231 cells can be suppressed by reducing lncRNA‐ZEB2‐AS1 expression. The migration and invasion of triple‐negative breast cancer can be altered through cytoskeleton rearrangement. In summary, we demonstrated that lncRNA‐ZEB2‐AS1 is an important factor affecting the development of triple‐negative breast cancer and thus a potential oncogene target.     

An TRIM59‐CDK6 axis regulates growth and metastasis of lung cancer

Lung cancer (LC) is a devastating malignancy with no effective treatments, due to its complex genomic profile. Using bioinformatics analysis and immunohistochemical of lung carcinoma tissues, we show that TRIM59 as a critical oncoprotein relating to LC proliferation and metastasis. In this study, high TRIM59 expression was significantly correlated with lymph node metastasis, distant metastasis, and tumour stage. Furthermore, up‐regulation of TRIM59 expression correlated with poorer outcomes in LC patients. Mechanistically, TRIM59 play a key role in promoting LC growth and metastasis through regulation of extracellular‐signal regulated protein kinase (ERK) signalling pathway and epithelial‐to‐mesenchymal transition (EMT)‐markers, as validated by loss‐of‐function studies. In‐depth bioinformatics analysis showed that there is preliminary evidence of co‐expression of TRIM59 and cyclin dependent kinase 6 (CDK6) in LC. Notably, CDK6 expression significantly decreased when TRIM59 was knocked down in the LC cells. In contrast, exogenous up‐regulation of TRIM59 expression also induced significant increases in the expression of CDK6. Moreover, the expression of CDK6 was also inhibited by the ERK signalling inhibitor, U0126. The results of both loss‐ and gain‐of‐function studies showed that TRIM59 could regulate the expression of CDK6. Collectively, these data provide evidence that TRIM59 is involved in lung carcinoma growth and progression possibly through the induction of CDK6 expression and EMT process by activation of ERK pathway.     

Berberine attenuates XRCC1‐mediated base excision repair and sensitizes breast cancer cells to the chemotherapeutic drugs

Berberine (BBR) is a natural isoquinoline alkaloid, which is used in traditional medicine for its anti‐microbial, anti‐protozoal, anti‐diarrhoeal activities. Berberine interacts with DNA and displays anti‐cancer activities, yet its effects on cellular DNA repair and on synthetic treatments with chemotherapeutic drugs remain unclear. In this study, we investigated the effects of BBR on DNA repair and on sensitization of breast cancer cells to different types of DNA damage anti‐tumoural drugs. We found BBR arrested cells in the cell cycle S phase and induced DNA breaks. Cell growth analysis showed BBR sensitized MDA‐MB‐231 cells to cisplatin, camptothecin and methyl methanesulfonate; however, BBR had no synergistic effects with hydroxurea and olaparib. These results suggest BBR only affects specific DNA repair pathways. Western blot showed BBR down‐regulated XRCC1 expressions, and the rescued XRCC1 recovered the resistance of cancer cells to BBR. Therefore, we conclude that BBR interferes with XRCC1‐mediated base excision repair to sensitize cancer cells to chemotherapeutic drugs. These finding can contribute to understanding the effects of BBR on cellular DNA repair and the clinical employment of BBR in treatment of breast cancer.     

Therapeutic efficacy of anti‐MMP9 antibody in combination with nab‐paclitaxel‐based chemotherapy in pre‐clinical models of pancreatic cancer

Matrix metalloproteinase 9 (MMP9) is involved in the proteolysis of extracellular proteins and plays a critical role in pancreatic ductal adenocarcinoma (PDAC) progression, invasion and metastasis. The therapeutic potential of an anti‐MMP9 antibody (αMMP9) was evaluated in combination with nab‐paclitaxel (NPT)‐based standard cytotoxic therapy in pre‐clinical models of PDAC. Tumour progression and survival studies were performed in NOD/SCID mice. The mechanistic evaluation involved RNA‐Seq, Luminex, IHC and Immunoblot analyses of tumour samples. Median animal survival compared to controls was significantly increased after 2‐week therapy with NPT (59%), Gem (29%) and NPT+Gem (76%). Addition of αMMP9 antibody exhibited further extension in survival: NPT+αMMP9 (76%), Gem+αMMP9 (47%) and NPT+Gem+αMMP9 (94%). Six‐week maintenance therapy revealed that median animal survival was significantly increased after NPT+Gem (186%) and further improved by the addition of αMMP9 antibody (218%). Qualitative assessment of mice exhibited that αMMP9 therapy led to a reduction in jaundice, bloody ascites and metastatic burden. Anti‐MMP9 antibody increased the levels of tumour‐associated IL‐28 (1.5‐fold) and decreased stromal markers (collagen I, αSMA) and the EMT marker vimentin. Subcutaneous tumours revealed low but detectable levels of MMP9 in all therapy groups but no difference in MMP9 expression. Anti‐MMP9 antibody monotherapy resulted in more gene expression changes in the mouse stroma compared to the human tumour compartment. These findings suggest that anti‐MMP9 antibody can exert specific stroma‐directed effects that could be exploited in combination with currently used cytotoxics to improve clinical PDAC therapy.     

Long non‐coding RNA LINC01225 promotes proliferation,invasion and migration of gastric cancer via Wnt/β‐catenin signalling pathway

Emerging evidence has classified the aberrant expression of long non‐coding RNAs (lncRNAs) as a basic signature of various malignancies including gastric cancer (GC). LINC01225 has been shown to act as a hepatocellular carcinoma‐related gene, with its expression pattern and biological function not clarified in GC. Here, we verified that LINC01225 was up‐regulated in tumour tissues and plasma of GC. Analysis with clinicopathological information suggested that up‐regulation of LINC01225 was associated with advanced disease and poorer overall survival. Receiver operating characteristic (ROC) analysis showed that plasma LINC01225 had a moderate accuracy for diagnosis of GC. In addition, knockdown of LINC01225 led to retardation of cell proliferation, invasion and migration, and overexpression of LINC01225 showed the opposite effects. Mechanistic investigations showed that LINC01225 silencing inhibited epithelial‐mesenchymal transition (EMT) process and attenuated Wnt/β‐catenin signalling of GC. Furthermore, ectopic expression of Wnt1 or suppression of GSK‐3β abolished the si‐LINC01225‐mediated suppression against EMT, thereby promoting cell proliferation, invasion and migration of GC. In conclusion, LINC01225 promotes the progression of GC through Wnt/β‐catenin signalling pathway, and it may serve as a potential target or strategy for diagnosis or treatment of GC.     

LncRNA DUXAP9‐206 directly binds with Cbl‐b to augment EGFR signaling and promotes non‐small cell lung cancer progression

Long noncoding RNAs (lncRNAs) are involved in the pathology of various tumours, including non‐small cell lung cancer (NSCLC). However, the underlying molecular mechanisms of their specific association with NSCLC have not been fully elucidated. Here, we report that a cytoplasmic lncRNA, DUXAP9‐206 is overexpressed in NSCLC cells and closely related to NSCLC clinical features and poor patient survival. We reveal that DUXAP9‐206 induced NSCLC cell proliferation and metastasis by directly interacting with Cbl‐b, an E3 ubiquitin ligase, and reducing the degradation of epidermal growth factor receptor (EGFR) and thereby augmenting EGFR signaling in NSCLC. Notably, correlations between DUXAP9‐206 and activated EGFR signaling were also validated in NSCLC patient specimens. Collectively, our findings reveal the novel molecular mechanisms of DUXAP9‐206 in mediating the progression of NSCLC and DUXAP9‐206 may serve as a potential target for NSCLC therapy.     

An estrogen receptor (ER)‐related signature in predicting prognosis of ER‐positive breast cancer following endocrine treatment

Quite a few estrogen receptor (ER)‐positive breast cancer patients receiving endocrine therapy are at risk of disease recurrence and death. ER‐related genes are involved in the progression and chemoresistance of breast cancer. In this study, we identified an ER‐related gene signature that can predict the prognosis of ER‐positive breast cancer patient receiving endocrine therapy. We collected RNA expression profiling from Gene Expression Omnibus database. An ER‐related signature was developed to separate patients into high‐risk and low‐risk groups. Patients in the low‐risk group had significantly better survival than those in the high‐risk group. ROC analysis indicated that this signature exhibited good diagnostic efficiency for the 1‐, 3‐ and 5‐year disease‐relapse events. Moreover, multivariate Cox regression analysis demonstrated that the ER‐related signature was an independent risk factor when adjusting for several clinical signatures. The prognostic value of this signature was validated in the validation sets. In addition, a nomogram was built and the calibration plots analysis indicated the good performance of this nomogram. In conclusion, combining with ER status, our results demonstrated that the ER‐related prognostic signature is a promising method for predicting the prognosis of ER‐positive breast cancer patients receiving endocrine therapy.