Neoadjuvant chemoradiation alters biomarkers of anticancer immunotherapy responses in locally advanced rectal cancer.

BACKGROUND: Neoadjuvant chemoradiation therapy (CRT) is a widely used preoperative treatment strategy for locally advanced rectal cancer (LARC). However, a few studies have evaluated the molecular changes caused by neoadjuvant CRT in these cancer tissues. Here, we aimed to investigate changes in immunotherapy-related immunogenic effects in response to preoperative CRT in LARC. METHODS: We analyzed 60 pairs of human LARC tissues before and after irradiation from three independent LARC cohorts, including a LARC patient RNA sequencing (RNA-seq) dataset from our cohort and GSE15781 and GSE94104 datasets. RESULTS: Gene ontology analysis showed that preoperative CRT significantly enriched the immune response in LARC tissues. Moreover, gene set enrichment analysis revealed six significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways associated with downregulated genes, including mismatch repair (MMR) genes, in LARC tissues after CRT in all three cohorts. Radiation also induced apoptosis and downregulated various MMR system-related genes in three colorectal cancer cells. One patient with LARC showed a change in microsatellite instability (MSI) status after CRT, as demonstrated by the loss of MMR protein and PCR for MSI. Moreover, CRT significantly increased tumor mutational burden in LARC tissues. CIBERSORT analysis revealed that the proportions of M2 macrophages and CD8 T cells were significantly increased after CRT in both the RNA-seq dataset and GSE94104. Notably, preoperative CRT increased various immune biomarker scores, such as the interferon-γ signature, the cytolytic activity and the immune signature. CONCLUSIONS: Taken together, our findings demonstrated that neoadjuvant CRT modulated the immune-related characteristics of LARC, suggesting that neoadjuvant CRT may enhance the responsiveness of LARC to immunotherapy.

Dysregulation of the miRNA biogenesis components DICER1, DROSHA, DGCR8 and AGO2 in clear cell renal cell carcinoma in both a Korean cohort and the cancer genome atlas kidney clear cell carcinoma cohort.

Impairment of microRNA (miRNA) biogenesis may be involved in clear cell renal cell carcinoma (ccRCC). The objective of the present study was to investigate the mRNA levels of important miRNA machinery components, DICER1, DROSHA, DiGeroge syndrome critical region gene 8 (DGCR8), and Argonaute 2 (AGO2), and their correlations with clinicopathological characteristics of ccRCC using mRNA expression data from The Cancer Genome Atlas kidney clear cell carcinoma (TCGA KIRC) cohort and a Korean ccRCC cohort. mRNA levels of DICER1, DROSHA, and DGCR8 were significantly decreased in both cohorts. However, AGO2 was significantly downregulated only in the Korean ccRCC cohort. Additionally, positive correlations were observed between the altered mRNA levels of DICER1 and DROSHA as well as DROSHA and DGCR8 in both cohorts. In the TCGA KIRC cohort, alterations in the mRNA levels of DICER1 were significantly correlated with histological grade. Furthermore, the altered mRNA levels of DGCR8 showed significant associations with sex and histologic grades. However, in the Korean ccRCC cohort, no factors were significantly associated with any clinicopathological parameters, including sex, age, T stage, Fuhrman grade/The International Society of Urological Pathology grade, lymphovascular invasion, and peri-renal fat invasion. Taken together, these findings indicate that DICER1, DROSHA, DGCR8 and AGO2 are significantly dysregulated in ccRCC, suggesting that they are important in the pathophysiology of this malignancy.

Altered mRNA expression levels of the major components of sphingolipid metabolism, ceramide synthases and their clinical implication in colorectal cancer.

Ceramide synthases (CerSs) synthesize various ceramides of different acyl chain lengths and serve important roles in the proliferation and death of cancer cells by regulating sphingolipid metabolism­related signaling pathways. The present study investigated the mRNA expression levels of various CerS genes using mRNA expression data from six independent colorectal cancer (CRC) cohorts and a Korean CRC dataset. Expression levels of CERS2, CERS5 and CERS6 mRNA were significantly increased in the majority of the studied groups. However, CERS4 expression was only significantly altered in two groups. Additionally, a positive correlation was observed between altered CERS4 and CERS5 mRNA levels in The Cancer Genome Atlas Colon and Rectal Cancer dataset. Notably, CERS2 and CERS4, as well as CERS5 and CERS6 levels, were positively correlated with each other in Korean patients with CRC. However, the mRNA expression levels of these four CerS genes were not associated with any clinicopathological characteristics in Korean patients with CRC. Finally, overexpressing CERS2 or CERS6 inhibited the in vitro viability of various CRC cells. Taken together, these findings indicated that CERS2, CERS4, CERS5, and CERS6 are significantly dysregulated in CRC, suggesting they may serve important roles in the pathophysiology of this malignancy.

miRNA biogenesis-associated RNase III nucleases Drosha and Dicer are upregulated in colorectal adenocarcinoma.

Drosha and Dicer are important regulators of microRNA (miRNA) biogenesis, and it has been suggested that their aberrant regulation may cause colorectal cancer (CRC). The aim of the present study was to evaluate the mRNA expression levels of these two important RNase III nucleases and their association with clinical features in CRC specimens from South Korean patients. The expression levels of Drosha and Dicer mRNA were investigated in 77 CRC tissues and adjacent histologically non-neoplastic tissues using the quantitative polymerase chain reaction. The expression levels of Drosha and Dicer mRNA were identified to be upregulated in CRC. Neither the Drosha nor the Dicer mRNA expression level was associated with any clinical parameter, including sex, age, TNM stage, body mass index and carcinoembryonic antigen titer in patients with CRC. Furthermore, the expression levels of Drosha and Dicer mRNA were not associated with each other. The miRNA biogenesis-associated RNase III nucleases Drosha and Dicer are significantly upregulated in CRC, suggesting their importance in the pathobiology of colorectal carcinogenesis.