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Introduction: Type 2 diabetes mellitus (T2DM) was associated with digestive system tumors. We analyzed publicly available data from GWAS studies using Mendelian randomization methods to clarify its causal relationship and mechanisms. Five common digestive system tumors and four diabetes-related phenotypes were included. Methods: Inverse variance weighted method was the main analytical method. Meta-analysis was used to summarize results of multiple data sources. Horizontal pleiotropy was tested using Egger-intercept method and validated by MRPRESSO method. Heterogeneity and sensitivity analysis were conducted by Cochran's Q test and leave-one-out method, respectively. Results: T2DM is associated with a reduced risk of esophageal (OR: 0.77, 95% CI: 0.71 to 0.83, P< 0.001), gastric (OR: 0.87, 95% CI: 0.84 to 0.90, P< 0.001) and colorectal cancer (OR: 0.88, 95% CI: 0.85 to 0.91, P< 0.001) and hepatocellular carcinoma (OR: 0.92, 95% CI: 0.86 to 0.97, P = 0.005) and an increased risk of pancreatic cancer (OR: 1.92, 95% CI: 1.47 to 2.50, P< 0.001) in East Asian population. T2DM causes decreased fasting insulin levels (OR = 0.966, 95% CI: 0.95 to 0.98, P< 0.001) and increased glycated hemoglobin levels (OR=1.41, 95% CI: 1.39 to 1.44, P<0.001). Elevated fasting insulin levels increase the risk of esophageal cancer (OR = 10.35, 95% CI: 1.10 to 97.25, P = 0.041), while increased glycated hemoglobin levels increase pancreatic cancer risk (OR=2.33, 95% CI: 1.37 to 3.97, P=0.002) but decrease gastric cancer risk (OR=0.801, 95% CI: 0.65 to 0.99, P=0.044). Conclusion: T2DM is associated with a reduced risk of esophageal, gastric and colorectal cancer and hepatocellular carcinoma in East Asian populations. The causal relationships between T2DM with esophageal and gastric cancer are partially mediated by decreased fasting insulin and increased glycated hemoglobin levels, respectively. T2DM indirectly increases the risk of pancreatic cancer by increasing glycated hemoglobin levels.
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Background: Colorectal cancer (CRC) is one of the deadliest causes of death by cancer worldwide. Liver metastasis (LM) is the main cause of death in patients with CRC. Therefore, identification of patients with the greatest risk of liver metastasis is critical for early treatment and reduces the mortality of patients with colorectal cancer liver metastases. Methods: Initially, we characterized cell composition through single-cell transcriptome analysis. Subsequently, we employed copy number variation (CNV) and pseudotime analysis to delineate the cellular origins of LM and identify LM-related epithelial cells (LMECs). The LM-index was constructed using machine learning algorithms to forecast the relative abundance of LMECs, reflecting the risk of LM. Furthermore, we analyzed drug sensitivity and drug targeted gene expression in LMECs and patients with a high risk of LM. Finally, functional experiments were conducted to determine the biological roles of metastasis-related gene in vitro. Results: Single-cell RNA sequencing analysis revealed different immune landscapes between primary CRC and LM tumor. LM originated from chromosomal variants with copy number loss of chr1 and chr6p and copy number gain of chr7 and chr20q. We identified the LMECs cluster and found LM-associated pathways such as Wnt/beta-catenin signaling and KRAS signaling. Subsequently, we identified ten metastasis-associated genes, including SOX4, and established the LM-index, which correlates with poorer prognosis, higher stage, and advanced age. Furthermore, we screened two drugs as potential candidates for treating LM, including Linsitinib_1510, Lapatinib_1558. Immunohistochemistry results demonstrated significantly elevated SOX4 expression in tumor samples compared to normal samples. Finally, in vitro experiments verified that silencing SOX4 significantly inhibited tumor cell migration and invasion. Conclusion: This study reveals the possible cellular origin and driving factors of LM in CRC at the single cell level, and provides a reference for early detection of CRC patients with a high risk of LM.
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BACKGROUND AND AIMS: Reducing reactive oxygen species (ROS) production has proven an effective way for alleviating oxidative stress during ischemia-reperfusion injury (IRI). Moreover, inhibition of Rac1 could reduce ROS production and prevent oxidative stress injury. Previous studies have suggested a positive interactivation feedback loop between Rac1 and hypoxia-inducible factor (HIF)-1α, the latter being up-regulated early during ischemia. The positive inter-activation between Rac1 and HIF-1α would aggravate ROS production, thereby promoting IRI. This study was designed to verify the effects of Rac1 inhibition on hepatic IRI both at animal and cellular levels and to explore the interaction between Rac1 and HIF-1α during hepatic IRI. METHODS: C57B/6 mice and AML-12 cells were used for the construction of hepatic IRI animal and cell models. Rac1 inhibition was achieved by NSC23766 (a specific Rac1 inhibitor). Lentiviral vectors were used for Rac1 knockdown. At designated time points, serum and liver tissues were collected from the mice and treated cells were collected for further analysis. RESULTS: NSC23766 treatment significantly alleviated the hepatic IRI in mice, manifesting as lower vacuolation score and less apoptosis cells, lower ROS and serum/liver alanine aminotransferase/aspartate aminotransferase levels, and fewer activated inflammatory cells. IRI of AML-12 was also alleviated by 50 µM NSC23766 or Rac1-knockdown, manifesting as reduced cell apoptosis, less extensive interruption of mitochondrial membrane potential, down-regulation of apoptosis, and effects on DNA damage-related proteins. Interestingly, Rac1 knockdown also down-regulated the expression level of HIF-1α. CONCLUSIONS: Our study supports a protective effect of Rac1 inhibition on hepatic IRI. Aside from the classic topics of reducing ROS production and oxidative stress, our study showed an interaction between Rac1 and HIF-1α signaling during hepatic IRI.
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MicroRNAs (miRNAs) participate in tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, few miRNAs have been identified and entered clinical practice. Herein, we report that miR-29a is downregulated in tumor-initiating cells (T-ICs) and has an important function in liver T-ICs. Functional studies revealed that miR-29a knockdown promotes liver T-ICs self-renewal and tumorigenesis. Conversely, a forced miR-29a expression inhibits liver T-ICs self-renewal and tumorigenesis. Mechanistically, we find that miR-29a downregulates Bcl-2 via binding its mRNA 3'UTR in liver T-ICs. The correlation between miR-29a and Bcl-2 is validated in human HCC tissues. Furthermore, the miR-29a expression determines the responses of hepatoma cells to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-29a high patients are more sensitive to sorafenib treatment. In conclusion, our findings revealed the crucial role of the miR-29a in liver T-ICs expansion and sorafenib response, rendering miR-29a as an optimal target for the prevention and intervention of HCC.
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Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Transducción de Señal/genética , Regiones no Traducidas 3'/genética , Animales , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Autorrenovación de las Células/efectos de los fármacos , Autorrenovación de las Células/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Células Hep G2 , Xenoinjertos , Humanos , Hígado/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Ratones , Transducción de Señal/efectos de los fármacos , Sorafenib/farmacologíaRESUMEN
BACKGROUND/AIMS: The ionizing radiation (IR) has been applied in clinical treatment for many years and the radiosensitivity is crucial to the treatment. Radiosensitivity of cells is subjected to many environmental factors, such as hypoxia and temperature. Hyperosmolality as a common environmental factor has been demonstrated to be associated with survival and apoptosis of cells in many studies. Thus we investigated the influence of hyperosmolality on cells radiosensitivity. METHODS: We examined the viability and surviving fraction of L-O2 cells of irradiated L-O2 cells, and detected the effect on AHH-1 cells by flow cytometry, in order to investigate the effect of short-term hyperosmolality pretreatment on cells radiosensitivity. Comet assay was used to assess the DNA strand breaks. Then the detection of Akt1 by western blot and the process of regulatory volume increase by CYSY-TT were involved in the mechanism. RESULT: We demonstrated that a short-term hyperosmolality pretreatment on cells could reduce their radiosensitivity. Further research indicated that the short-term hypertonic condition could induce regulatory volume increase (RVI), which activated Akt1 and degenerated the IκB-α. This process was associated with reduced cells radiosensitivity. Finally, we used the flufenamic acid (FFA), a blocker to cation channels (HICCs) to inhabit RVI and consequently inhabit the protective effect of hyperosmolality on irradiated cells. CONCLUSION: a short-term hyperosmolality pretreatment could reduce the cells radiosensitivity by RVI and following activation of Akt1.