Cigarette smoke (CS) affects the expression of microRNAs (miRNAs), which are important regulators of gene expression by inducing DNA methylation. However, the effects of smoking on miRNA expression have not been fully elucidated in smoking-related lung carcinogenesis. Therefore, in this study, to investigate the change of miRNA expression pattern and to identify tumor suppressor miRNAs by smoking in lung carcinogenesis, we used lung carcinogenesis model cell lines that, derived from a murine xenograft model with human bronchial epithelial cells (BEAS-2B), exposed CS or not. The microarray analysis revealed that miR-584-5p expression was downregulated with cancer progression in lung carcinogenesis model cell lines. We confirmed by pyrosequencing that the methylation level of the miR-584-5p promoter increased with cancer progression. In vitro and in vivo experiments showed that miR-584-5p suppressed migration and invasion in non-small cell lung cancer (NSCLC) cells by targeting YKT6. Furthermore, we showed that high level of YKT6 was associated with a poor survival rate in NSCLC patients with a history of smoking. These results suggest that miR-584-5p acts as a tumor suppressor and is a potential molecular biomarker for smoking-related NSCLC.

Background & Aims: The application of circulating tumor DNA (ctDNA) has been studied for predicting recurrent disease after surgery and treatment response during systemic treatment. Metastasectomy can be curative for well-selected patients with metastatic colorectal cancer (mCRC). This prospective study investigated the ctDNA level before and after metastasectomy in patients with mCRC to explore its potential as a predictive biomarker. Methods: We collected data on 98 metastasectomies for mCRC performed from March 2017 to February 2020. Somatic mutations in the primary and metastatic tumors were identified and tumor-informed ctDNAs were selected by ultra-deep targeted sequencing. Plasma samples were mandatorily collected before and 3–4 weeks after metastasectomy and serially, if patients agreed. Results: Data on 67 of 98 metastasectomies (58 patients) meeting the criteria were collected. ctDNA was detected in 9 (29%) of 31 cases treated with upfront metastasectomy and in 7 (19.4%) of 36 cases treated with metastasectomy after upfront chemotherapy. The detection rate of ctDNA was higher in liver metastasis (p = 0.0045) and tumors measuring ≥1 cm (p = 0.0183). ctDNA was less likely to be detected if the response to chemotherapy was good. After metastasectomy, ctDNA was found in 4 (6%) cases with rapid progressive disease. Conclusion: The biological factors affecting the ctDNA shedding from the tumor should be considered when applying ctDNA assays in a clinical setting. After metastasectomy for oligometastatic lesions in good responders of chemotherapy, most ctDNA was cleared or existed below the detection level. To assist clinical decision making after metastasectomy for mCRC using ctDNA, further studies for improving specific outcomes are needed.

Insulin-like growth factor-1 receptor (IGF-1R), an important factor in promoting cancer cell growth and survival, is commonly upregulated in cancer cells. However, amplification of the IGF1R gene is extremely rare in tumors. Here, we have provided insights into the mechanisms underlying the regulation of IGF-1R protein expression. We found that PKM2 serves as a non-metabolic protein that binds to and increases IGF-1R protein expression by promoting the interaction between IGF-1R and heat-shock protein 90 (HSP90). PKM2 depletion decreases HSP90 binding to IGF-1R precursor, thereby reducing IGF-1R precursor stability and the basal level of mature IGF-1R. Consequently, PKM2 knockdown inhibits the activation of AKT, the key downstream effector of IGF-1R signaling, and increases apoptotic cancer cell death during hypoxia. Notably, we clinically verified the PKM2-regulated expression of IGF-1R through immunohistochemical staining in a tissue microarray of 112 lung cancer patients, demonstrating a significant positive correlation (r = 0.5208, p < 0.0001) between PKM2 and IGF-1R expression. Together, the results of a previous report demonstrated that AKT mediates PKM2 phosphorylation at serine-202; these results suggest that IGF-1R signaling and PKM2 mutually regulate each other to facilitate cell growth and survival, particularly under hypoxic conditions, in solid tumors with dysregulated IGF-1R expression.

This study aimed to identify novel biomarkers for metastatic colorectal cancer progression using exosomal RNA expression profiling. The exosomal RNA expression profiles of 54 patients with mCRC were investigated. Exosomal RNA profiling was performed at the time of relapse immediately before metastasectomy and cancer recurrence or progression after metastasectomy. The up- and down-regulated RNA expression profiles were screened and analyzed using H-cluster, principle component analysis and gene ontology. The tissue expression profile of the liver metastases was compared with the GSE 41258 set using GSEA tools. We identified two distinctive biological process gene sets (IFNA and PCDB families) related to metastatic progression. The interferon-α response gene set was enriched, especially when the tumor volume was ≥1 cm³. CXCL10, CXCL11 and SAMD 9 mRNA were highly expressed in the plasma exosome samples of patients with mCRC to the liver. Furthermore, high expression of CXCL10 but not CXCL11 or SAMD9 was associated with a poor prognosis and shorter progression-free survival. Conclusions: Cancer-derived exosomal CXCL10 may be a novel biomarker for liver metastasis of mCRC and a potential target for the prevention and treatment of mCRC with liver metastasis.