Heterogeneous nuclear ribonucleoprotein (hnRNP) Q1, an RNA-binding protein, has been implicated in many post-transcriptional processes, including RNA metabolism and mRNA splicing and translation. ...However, the role of hnRNP Q1 in tumorigenesis remains unclear. We previously performed RNA immunoprecipitation (RIP)-seq analysis to identify hnRNP Q1-interacting mRNAs and found that hnRNP Q1 targets a group of genes that are involved in mitotic regulation, including Aurora-A. Here, we demonstrate that altering the hnRNP Q1 level influences the expression of the Aurora-A protein, but not its mRNA. Stimulation with epidermal growth factor (EGF) enhances both binding between hnRNP Q1 and Aurora-A mRNA as well as the efficacy of the hnRNP Q1-induced translation of Aurora-A mRNA. The EGF/hnRNP Q1-induced translation of Aurora-A mRNA is mediated by the mTOR and ERK pathways. In addition, we show that hnRNP Q1 up-regulates the translation of a group of spindle assembly checkpoint (SAC) genes. hnRNP Q1 overexpression is positively correlated with the levels of Aurora-A and the SAC genes in human colorectal cancer tissues. In summary, our data suggest that hnRNP Q1 plays an important role in regulating the expression of a group of cell cycle-related genes. Therefore, it may contribute to tumorigenesis by up-regulating the translation of these genes in colorectal cancer.
The association between human epidermal growth factor receptor-2 (HER2) amplification and brain metastasis (BM) in patients having colorectal cancer (CRC) has been suggested but not yet established. ...This study investigated the expression patterns of HER2, its association with BM, and its prognostic value in patients having CRC.
We retrospectively identified 99 patients having metastatic CRC (mCRC) and BM (the BM cohort) and compared them with a cohort of 249 patients having mCRC and without BM (the stage IV cohort) by propensity score matching. Immunohistochemical studies of HER2 on all available paraffin-embedded tumour samples, either from the primary tumour, the metastasis (brain and/or extracranial sites) or both, were performed and analysed. HER2 fluorescent in situ hybridisation was applied when necessary. The expression of HER2 was compared and correlated with survival.
HER2 amplifications were detected in 16 (18.4%) of 87 and 9 (3.6%) of 249 patients who had specimens available in the BM and stage IV cohorts, respectively (P < .001). After propensity score matching, HER2 amplification was significantly associated with BM (odds ratio: 5.38, P = .003). HER2 heterogeneity was frequently observed not only at the single tumour level but also in paired tumour samples. A marginally significant longer survival since BM was found in patients having HER2-amplified mCRC than in those without (P = .07).
HER2 amplification was significantly associated with BM in patients having mCRC and might have prognostic value for survival since BM. Given the heterogeneity of HER2 expression, the testing of HER2 status on available tissues from both primary and metastatic tumours should be encouraged.
•Propensity score matching examined HER2 amplification and brain metastases.•High frequency of HER2 amplification in patients having metastatic colorectal cancer and brain metastasis was demonstrated.•Intra-patient heterogeneities of HER2 amplification were observed.
Abstract Obese patients have higher levels of free fatty acids (FFAs) in their plasma and a higher risk of cancer than their non-obese counterparts. However, the mechanisms involved in the regulation ...of cancer metastasis by FFAs remain unclear. In this study, we found that oleic acid (OA) induced angiopoietin-like 4 (ANGPTL4) protein expression and secretion and conferred anoikis resistance to head and neck squamous cell carcinomas (HNSCCs). The autocrine production of OA-induced ANGPTL4 further promoted HNSCC migration and invasion. In addition, the expression of peroxisome proliferator-activated receptor (PPAR) was essential for the OA-induced ANGPTL4 expression and invasion. The levels of OA-induced epithelial-mesenchymal transition markers, such as vimentin, MMP-9, and fibronectin and its downstream effectors Rac1/Cdc42, were significantly reduced in ANGPTL4-depleted cells. Knocking down fibronectin inhibited the expression of MMP-9 and repressed OA- and recombinant ANGPTL4-induced HNSCC invasion. On the other hand, ANGPTL4 siRNA inhibited OA-induced MMP-9 expression, which was reversed in fibronectin-overexpressing cells. Furthermore, the depletion of ANGPTL4 impeded the OA-primed metastatic seeding of tumor cells in the lungs. These results demonstrate that OA enhances HNSCC metastasis through the ANGPTL4/fibronectin/Rac1/Cdc42 and ANGPTL4/fibronectin/MMP-9 signaling axes.
Various types of human cancer may develop aberrant trophoblastic differentiation, including histological changes and altered expression of β‑human chorionic gonadotropin (β‑hCG). Aberrant ...trophoblastic differentiation in epithelial cancer is usually associated with poor differentiation, tumor metastasis, unfavorable prognosis and treatment resistance. Since β‑hCG‑targeting vaccines have failed in an early phase II trial, it is crucial to obtain a better understanding of the molecular pathogenesis of trophoblastic differentiation in human cancer. The present review summarizes the clinical and translational research on this topic with the aim of accelerating the development of an effective targeted therapy. Ectopic expression of β‑hCG promotes proliferation, migration, invasion, vasculogenesis and epithelial‑mesenchymal transition (EMT)
, and enhances metastatic and tumorigenic capabilities
. Signaling cascades modulated by β‑hCG include the TGF‑β receptor pathway, EMT‑related pathways, the c‑MET receptor tyrosine kinase and mitogen‑activated protein kinase/ERK pathways, and the SMAD2/4 pathway. Taken together, these findings indicated that TGF‑β receptors, c‑MET and ERK1/2 are potential therapeutic targets. Nevertheless, further investigation on the molecular basis of aberrant trophoblastic differentiation is mandatory to improve the design of precision therapy for this aggressive type of human cancer.
The switch of cellular metabolism from mitochondrial respiration to glycolysis is the hallmark of cancer cells and is associated with tumor malignancy. Pyruvate dehydrogenase kinase-1 (PDK1) and PDK3 ...participate in the metabolic switch of cancer cells; however, the medical significance of PDK1 and PDK3 in cancer progression is not known. Here, we assessed the expression profiles of PDK1 and PDK3 in colorectal cancer. Western blot analysis ( n = 74) demonstrated that PDK3 was markedly increased in colon cancer compared to that in adjacent normal tissues, whereas PDK1 was decreased in cancer cells. In addition, PDK3 expression was positively correlated with that of hypoxia inducible factor-1α (HIF-1α) in cancer cells. Further analysis using immunohistochemical staining revealed that PDK3 levels were positively associated with severity of cancer and negatively associated with disease-free survival. In vitro studies using several colon cancer cell lines showed that PDK3 expression was controlled by HIF-1α and contributed to hypoxia-induced increased drug resistance, perhaps explaining why patients with PDK3 overexpression have a greater incidence of treatment failure. Taken together, our findings suggest that PDK3 plays an important role in the metabolic switch and drug resistance of colon cancer and is potentially a novel target for cancer therapy.
Gut mucosa-associated microbiota is more closely correlated with disease phenotypes than fecal microbiota; however sampling via tissue biopsy is more invasive and uncomfortable. Rectal swab may be a ...suitable substitute for tissue biopsy, but its effectiveness is controversial. This study aimed to evaluate differences in the microbiota at these sites in patients with inflammatory bowel disease (IBD).
Inflammatory bowel disease patients and a control group were enrolled when surveillance colonoscopy was scheduled. Samples of colon biopsy tissues, rectal swabs during colonoscopy, and feces before bowel preparation were collected to analyze microbial composition. To explore the short-term effects of bowel preparation on swab microbiota, prepreparation swab samples were also collected from 27 IBD patients.
A total of 33 Crohn's disease, 54 ulcerative colitis, and 21 non-IBD patients were enrolled. In beta diversity analysis, fecal microbiota clearly differed from swab and tissue microbiota in the 3 disease groups. The swab microbiota was closer to, but still different from, the tissue microbiota. Consistently, we identified that swab samples differed more in abundant genera from feces than from tissue. Beta diversity analysis did not reveal a difference in swab microbiota before and after bowel preparation, but the genus composition of most individuals varied markedly.
Swab microbiota more closely resembled tissue microbiota relative to fecal microbiota, but there were still differences. Bowel preparation did not alter the overall swab microbiota in the short term but markedly changed the microbial composition in most patients.
Damage associated molecular patterns (DAMPs), including calreticulin (CRT) exposure, high-mobility group box 1 protein (HMGB1) elevation, and ATP release, characterize immunogenic cell death (ICD) ...and may play a role in cancer immunotherapy. Triple negative breast cancer (TNBC) is an immunogenic subtype of breast cancer with higher lymphocyte infiltration. Here, we found that regorafenib, a multi-target angiokinase inhibitor previously known to suppress STAT3 signaling, induced DAMPs and cell death in TNBC cells. Regorafenib induced the expression of HMGB1 and CRT, and the release of ATP. Regorafenib-induced HMGB1 and CRT were attenuated following STAT3 overexpression. In a 4T1 syngeneic murine model, regorafenib treatment increased HMGB1 and CRT expression in xenografts, and effectively suppressed 4T1 tumor growth. Immunohistochemical staining revealed increased CD4+ and CD8+ tumor-infiltrating T cells in 4T1 xenografts following regorafenib treatment. Regorafenib treatment or programmed death-1 (PD-1) blockade using anti-PD-1 monoclonal antibody reduced lung metastasis of 4T1 cells in immunocompetent mice. While regorafenib increases the proportion of MHC II high expression on dendritic cells in mice with smaller tumors, the combination of regorafenib and PD-1 blockade did not show a synergistic effect on anti-tumor activity. These results suggest that regorafenib induces ICD and suppresses tumor progression in TNBC. It should be carefully evaluated when developing a combination therapy with an anti-PD-1 antibody and a STAT3 inhibitor.
Colorectal cancer (CRC) is one of the most prevalent malignant diseases worldwide. Risk prediction for tumor recurrence is important for making effective treatment decisions and for the survival ...outcomes of patients with CRC after surgery. Herein, we aimed to explore a prediction algorithm and the risk factors for postoperative tumor recurrence using a machine learning (ML) approach with standardized pathology reports for patients with stage II and III CRC.
Pertinent clinicopathological features were compiled from medical records and standardized pathology reports of patients with stage II and III CRC. Four ML models based on logistic regression (LR), random forest (RF), classification and regression decision trees (CARTs), and support vector machine (SVM) were applied for the development of the prediction algorithm. The area under the curve (AUC) of the ML models was determined in order to compare the prediction accuracy. Genomic studies were performed using a panel-targeted next-generation sequencing approach.
A total of 1073 patients who received curative intent surgery at the National Cheng Kung University Hospital between January 2004 and January 2019 were included. Based on conventional statistical methods, chemotherapy (
= 0.003), endophytic tumor configuration (
= 0.008), TNM stage III disease (
< 0.001), pT4 (
< 0.001), pN2 (
< 0.001), increased numbers of lymph node metastases (
< 0.001), higher lymph node ratios (LNR) (
< 0.001), lymphovascular invasion (
< 0.001), perineural invasion (
< 0.001), tumor budding (
= 0.004), and neoadjuvant chemoradiotherapy (
= 0.025) were found to be correlated with the tumor recurrence of patients with stage II-III CRC. While comparing the performance of different ML models for predicting cancer recurrence, the AUCs for LR, RF, CART, and SVM were found to be 0.678, 0.639, 0.593, and 0.581, respectively. The LR model had a better accuracy value of 0.87 and a specificity value of 1 in the testing set. Two prognostic factors, age and LNR, were selected by multivariable analysis and the four ML models. In terms of age, older patients received fewer cycles of chemotherapy and radiotherapy (
< 0.001). Right-sided colon tumors (
= 0.002), larger tumor sizes (
= 0.008) and tumor volumes (
= 0.049), TNM stage II disease (
< 0.001), and advanced pT3-4 stage diseases (
= 0.04) were found to be correlated with the older age of patients. However, pN2 diseases (
= 0.005), lymph node metastasis number (
= 0.001), LNR (
= 0.004), perineural invasion (
= 0.018), and overall survival rate (
< 0.001) were found to be decreased in older patients. Furthermore,
and
mutations (
= 0.032 and 0.039, respectively) were more frequently found in older patients with stage II-III CRC compared to their younger counterparts.
This study demonstrated that ML models have a comparable predictive power for determining cancer recurrence in patients with stage II-III CRC after surgery. Advanced age and high LNR were significant risk factors for cancer recurrence, as determined by ML algorithms and multivariable analyses. Distinctive genomic profiles may contribute to discrete clinical behaviors and survival outcomes between patients of different age groups. Studies incorporating complete molecular and genomic profiles in cancer prediction models are beneficial for patients with stage II-III CRC.
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