Colorectal carcinoma (CRC) is one of the most frequently diagnosed carcinomas and one of the leading causes of cancer-related death worldwide. Metabolic reprogramming, a hallmark of cancer, is closely related to the initiation and progression of carcinomas, including CRC. Accumulating evidence shows that activation of oncogenic pathways and loss of tumor suppressor genes regulate the metabolic reprogramming that is mainly involved in glycolysis, glutaminolysis, one-carbon metabolism and lipid metabolism. The abnormal metabolic program provides tumor cells with abundant energy, nutrients and redox requirements to support their malignant growth and metastasis, which is accompanied by impaired metabolic flexibility in the tumor microenvironment (TME) and dysbiosis of the gut microbiota. The metabolic crosstalk between the tumor cells, the components of the TME and the intestinal microbiota further facilitates CRC cell proliferation, invasion and metastasis and leads to therapy resistance. Hence, to target the dysregulated tumor metabolism, the TME and the gut microbiota, novel preventive and therapeutic applications are required. In this review, the dysregulation of metabolic programs, molecular pathways, the TME and the intestinal microbiota in CRC is addressed. Possible therapeutic strategies, including metabolic inhibition and immune therapy in CRC, as well as modulation of the aberrant intestinal microbiota, are discussed.

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Epithelial membrane proteins (EMP1-3) are involved in epithelial differentiation and carcinogenesis. Dysregulated expression of EMP2 was observed in various cancers, but its role in human lung cancer is not yet clarified. In this study, we analyzed the expression of EMP1-3 and investigated the biological function of EMP2 in non-small cell lung cancer (NSCLC). The results showed that lower expression of EMP1 was significantly correlated with tumor size in primary lung tumors (p = 0.004). Overexpression of EMP2 suppressed tumor cell growth, migration, and invasion, resulting in a G1 cell cycle arrest, with knockdown of EMP2 leading to enhanced cell migration, related to MAPK pathway alterations and disruption of cell cycle regulatory genes. Exosomes isolated from transfected cells were taken up by tumor cells, carrying EMP2-downregulated microRNAs (miRNAs) which participated in regulation of the tumor microenvironment. Our data suggest that decreased EMP1 expression is significantly related to increased tumor size in NSCLC. EMP2 suppresses NSCLC cell growth mainly by inhibiting the MAPK pathway. EMP2 might further affect the tumor microenvironment by regulating tumor microenvironment-associated miRNAs.

Exploitation of autophagy might potentially improve therapeutic strategy. Here, we analyzed the protein expression of autophagy-associated genes including LC3A, LC3B, Beclin-1, p62, and Atg5 in 88–131 primary lung tumors by immunohistochemistry (IHC) on tissue-microarrays (TMAs). Additionally, the DNA methylation pattern of LC3A was investigated by bisulfite sequencing (BS) and methylation-specific-PCR (MSP). It turned out that the higher expression of LC3A protein was associated with adenocarcinoma compared to squamous cell carcinoma of lung (p = 0.008), positive staining of LC3B was significantly related to tumor grade (p = 0.006), and the protein expression of Beclin-1 was significantly correlated to pN stage (p = 0.041). The expression of p62 and Atg5 was however not significantly associated with any clinicopathological parameters. Downregulation of LC3A was related to DNA methylation in lung cancer cell lines, while in primary lung tumor samples, protein expression of LC3A was not significantly correlated with DNA methylation, and the methylation status of LC3A was not related to clinicopathological features. Taken together, our results suggest that autophagy-associated proteins such as LC3A, LC3B, and Beclin-1 might be potential biomarkers for subclassification, differentiation, and local metastasis in primary lung tumor, and epigenetic mechanism is partially responsible for gene silencing of LC3A in lung cancer cell lines.

Exosomes represent extracellular vesicles of endocytic origin ranging from 30 to 100 nm that are released by most of eukaryotic cells and can be found in body fluids. These vesicles in carrying DNA, RNA, microRNA (miRNA), Long noncoding RNA, proteins, and lipids serve as intercellular communicators. Due to their role in crosstalk between tumor cells and mesenchymal stroma cells, they are vital for tumor growth, progression, and anticancer drug resistance. Lung cancer is a global leading cause of cancer‐related deaths with 5‐year survival rates of about 7% in patients with distant metastasis. Although the implementation of targeted therapy has improved the clinical outcome of nonsmall cell lung cancer, drug resistance remains a major obstacle. Lung tumor‐derived exosomes (TDEs) conveying molecular information from tumor cells to their neighbor cells or cells at distant sites of the body activate the tumor microenvironment (TME) and facilitate tumor metastasis. Exosomal miRNAs are also considered as noninvasive biomarkers for early diagnosis of lung cancer. This review summarizes the influence of lung TDEs on the TME and metastasis. Their involvement in targeted therapy resistance and potential clinical applications are discussed. Additionally, challenges encountered in the development of exosome‐based therapeutic strategies are addressed.

Fatty acids are energy substrates and cell components which participate in regulating signal transduction, transcription factor activity and secretion of bioactive lipid mediators. The acyl-CoA synthetases (ACSs) family containing 26 family members exhibits tissue-specific distribution, distinct fatty acid substrate preferences and diverse biological functions. Increasing evidence indicates that dysregulation of fatty acid metabolism in the liver-gut axis , designated as the bidirectional relationship between the gut, microbiome and liver, is closely associated with a range of human diseases including metabolic disorders, inflammatory disease and carcinoma in the gastrointestinal tract and liver. In this review, we depict the role of ACSs in fatty acid metabolism, possible molecular mechanisms through which they exert functions, and their involvement in hepatocellular and colorectal carcinoma, with particular attention paid to long-chain fatty acids and small-chain fatty acids. Additionally, the liver-gut communication and the liver and gut intersection with the microbiome as well as diseases related to microbiota imbalance in the liver-gut axis are addressed. Moreover, the development of potentially therapeutic small molecules, proteins and compounds targeting ACSs in cancer treatment is summarized.

Fibulins (FBLNs), interacting with cell adhesion receptors and extracellular matrix (ECM) components, play multiple roles in ECM structures and tissue functions. Abnormal expression of FBLN2, one of the fibulin family members, contributes to tumor initiation and development. However, the function of FBLN2 in human non-small cell lung cancer (NSCLC) has not yet been elucidated. In this study, we found that FBLN2 was downregulated in 9 out of 11 lung cancer cell lines compared to normal bronchial epithelial cells, which was associated with DNA hypermethylation. Primary lung squamous cell carcinoma expressed significantly more FBLN2 protein compared to adenocarcinoma (p = 0.047). Ectopic expression of FBLN2 led to decreased cell proliferation, migration and invasion, accompanied by inactivated MAPK/ERK and AKT/mTOR pathways, while FBLN2 siRNA knockdown resulted in an opposite biological behaviour in NSCLC cells. Additionally, overexpression of FBLN2 led to dysregulation of cell adhesion molecules, ECM markers and a panel of lysate/exosome-derived-microRNAs, which are involved in cell adhesion and ECM remodelling. Taken together, our data indicate that FBLN2 is methylated and exerts a tumor suppressor function through modulation of MAPK/ERK and AKT pathways and regulation of cell adhesion and ECM genes. Moreover, FBLN2 might be a potential biomarker for the sub-classification of NSCLC.

Mutations of p53 occur in approximately 50% of advanced non-small cell lung cancer (NSCLC) cases, leading to loss of tumor suppressive function and/or gain of p53 oncogenic activity. Reactivation of mutant p53 and consequently induction of apoptosis in cancer cells is the goal of p53-targeted therapy. Recently, several p53 mutant reactivating compounds were discovered including SCH 529074. However, the role of SCH 529074 in NSCLC has not been fully explored. In the present study, the effects of this compound on cell survival, cell cycle progression, induction of apoptosis and modulation of cell signaling in p53 mutant NSCLC cells (H1975, H322 and H157) and p53 wild-type NSCLC cells (A549), was investigated. Cell-based functional assays, real-time RT-qPCR and western blot assays were used. HCT116 [p53 wild-type (WT)] and HCT116 p53 -/-(p53 null) were used as control cells. The results demonstrated that SCH 529074 treatment caused significant reduction in cell viability and colony formation activity in p53 mutant, p53 WT and p53-deficient cells. The treatment of NSCLC cells with SCH 529074 resulted in a dose-dependent induction of apoptosis and G0/G1 cell cycle arrest, which was associated with the activation of caspases (3 and 7), p53-independent upregulation of p21 and PUMA as well as increased LC3II, a biomarker of autophagy. The combination treatment with the autophagy inhibitor chloroquine (CQ) and SCH 529074 led to decreased cell viability, colony formation and increased induction of apoptosis. The data indicated that SCH 529074 may exert its growth inhibitory function in a p53-independent manner in NSCLC cells.