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Previously, we reported that non‐apoptotic cell death was induced in non‐malignant mammary epithelial cells (HMECs) upon loss of anchorage during 48 h incubation in suspension. In this study, we examined HMECs in suspension at an earlier time point and found that most of them lost attachment ability to substrata when replated, although >80% were alive. This suggested that HMECs lost reattachment ability (RA) prior to cell death upon detachment. Concomitant with the loss of RA, a decrease in the levels of β1 and β4 integrin was observed. In sharp contrast, breast cancer cells retained integrin levels, reattached to substrata, and formed colonies after exposure to anchorage loss as efficiently as those maintained under adherent conditions. Such RA of cancer cells is essential for the metastatic process, especially for establishing adhesion contact with ECM in the secondary organ after systemic circulation. Further analysis suggested that sustained levels of β4 integrin, which was mediated by Rac1, was critical for RA after anchorage loss and lung metastasis of breast cancer cells. In the cancer cells, persistent Rac1 activity enhanced escape of β4 integrin from lysosomal degradation depending on actin‐related protein 2/3 and TBC1D2, a GTPase‐activating protein of Rab7 GTPase. Notably, simultaneous high expression of ITGB4 and RAC1 was associated with poor prognosis in patients with breast cancer. Therefore, β4 integrin and Rac1 are attractive therapeutic targets to eliminate RA in cancer cells, thereby preventing the initial step of colonization at the secondary organ during metastasis. Anchorage‐independent reattachment ability (RA) of cells is as important as anchorage‐independent survival or growth for cancer metastasis. The Rac1/beta4 integrin axis has emerged as a critical mediator of RA of breast cancer cells in this study. Notably, simultaneous high expression of RAC1 and ITGB4 was associated with poor prognosis in patients with breast cancer.

Recent comprehensive analyses of mtDNA and orthogonal RNA‐sequencing data revealed that in numerous human cancers, mtDNA copy numbers and mtRNA amounts are significantly reduced, followed by low respiratory gene expression. Under such conditions (called mt‐Low), cells encounter severe cell proliferation defects; therefore, they must acquire countermeasures against this fatal disadvantage during malignant transformation. This study elucidated a countermeasure against the mt‐Low condition‐induced antiproliferative effects in hepatocellular carcinoma (HCC) cells. The mechanism relied on the architectural transcriptional regulator HMGA2, which was preferably expressed in HCC cells of the mt‐Low type in vitro and in vivo. Detailed in vitro analyses suggest that HMGA2 regulates insulin‐like growth factor binding protein 1 (IGFBP1) expression, leading to AKT activation, which then phosphorylates the cyclin‐dependent kinase inhibitor (CKI), P27KIP1, and facilitates its ubiquitin‐mediated degradation. Accordingly, intervention in the HMGA2 function by RNAi resulted in an increase in P27KIP1 levels and an induction of senescence‐like cell proliferation inhibition in mt‐Low‐type HCC cells. Conclusively, the HMGA2/IGFBP1/AKT axis has emerged as a countermeasure against P27KIP1 CKI upregulation under mt‐Low conditions, thereby circumventing cell proliferation inhibition and supporting the tumorigenic state. Notably, similar to in vitro cell lines, HMGA2 was likely to regulate IGFBP1 expression in HCC in vivo, thereby contributing to poor patient prognosis. Considering the significant number of cases under mt‐Low or the threat of CKI upregulation cancer‐wide, the axis is noteworthy as a vulnerability of cancer cells or target for tumor‐agnostic therapy inducing irreversible cell proliferation inhibition via CKI upregulation in a large population with cancer. mtDNA copy numbers and mtRNA amounts are reduced, followed by low respiratory gene expression in numerous cancer cells. High expression of HMGA2 activates the IGFBP1/AKT pathway, circumventing mitochondria deficiency‐caused cell proliferation defects. Intervention in the HMGA2 function results in an increase in P27KIP protein levels and an induction of senescence‐like cell cycle arrest in cancer cells.

The role of the electron transport chain (ETC) in cell proliferation control beyond its crucial function in supporting ATP generation has recently emerged. In this study, we found that, among the four ETC complexes, the complex I (CI)‐mediated NAD+ regeneration is important for cancer cell proliferation. In cancer cells, a decrease in CI activity by RNA interference (RNAi) against NADH:ubiquinone oxidoreductase core subunit V1 (NDUFV1) arrested the cell cycle at the G1/S phase, accompanying upregulation of p21Cip1 cyclin‐dependent kinase inhibitor expression. Mechanistically, a decrease in the NAD+/NADH ratio downregulated SIRT3 and SIRT7 function, which suppressed p21Cip1 expression at the translational and transcriptional levels, respectively, resulting in the upregulation of the antiproliferative molecule. Importantly, high expression levels of the core subunits of CI correlated with poor prognosis in patients with the hormone receptor(+)/human epidermal growth factor receptor 2(−) (HR+/HER2−) subtype of breast cancer. Therefore, NDUFV1 and SIRT3/7 have emerged as promising therapeutic targets against this breast cancer subtype. NAD+ regeneration by mitochondrial complex I NADH dehydrogenase is important for cancer cell proliferation. Specifically, NAD+ is necessary for the activities of NAD+‐dependent deacetylases SIRT3 and SIRT7, which suppress the expression of p21Cip1 cyclin‐dependent kinase inhibitor, an antiproliferative molecule, at the translational and transcriptional levels, respectively. Thus, the NAD+–SIRT3/7–p21Cip1 pathway couples cellular metabolism and proliferation, supporting cancer cell proliferation.

Mitochondria are multifunctional organelles; they have been implicated in various aspects of tumorigenesis. In this study, we investigated a novel role of the basal electron transport chain (ETC) activity in cell proliferation by inhibiting mitochondrial replication and transcription (mtR/T) using pharmacological and genetic interventions, which depleted mitochondrial DNA/RNA, thereby inducing ETC deficiency. Interestingly, mtR/T inhibition did not decrease ATP levels despite deficiency in ETC activity in different cell types, including MDA‐MB‐231 breast cancer cells, but it severely impeded cell cycle progression, specifically progression during G2 and/or M phases in the cancer cells. Under these conditions, the expression of a group of cell cycle regulators was downregulated without affecting the growth signaling pathway. Further analysis suggested that the transcriptional network organized by E2F1 was significantly affected because of the downregulation of E2F1 in response to ETC deficiency, which eventually resulted in the suppression of cell proliferation. Thus, in this study, the E2F1‐mediated ETC‐dependent mechanism has emerged as the regulatory mechanism of cell cycle progression. In addition to E2F1, FOXM1 and BMYB were also downregulated, which contributed specifically to the defects in G2 and/or M phase progression. Thus, ETC‐deficient cancer cells lost their growing ability, including their tumorigenic potential in vivo. ETC deficiency abolished the production of reactive oxygen species (ROS) from the mitochondria and a mitochondria‐targeted antioxidant mimicked the deficiency, thereby suggesting that ETC activity signaled through ROS production. In conclusion, this novel coupling between ETC activity and cell cycle progression may be an important mechanism for coordinating cell proliferation and metabolism. A novel coupling between ETC activity and the core regulatory machinery for cell cycle progression.

The role of the electron transport chain (ETC) in cell proliferation control beyond its crucial function in supporting ATP generation has recently emerged. In this study, we found that, among the four ETC complexes, the complex I (CI)‐mediated NAD + regeneration is important for cancer cell proliferation. In cancer cells, a decrease in CI activity by RNA interference (RNAi) against NADH:ubiquinone oxidoreductase core subunit V1 ( NDUFV1 ) arrested the cell cycle at the G 1 /S phase, accompanying upregulation of p21 Cip1 cyclin‐dependent kinase inhibitor expression. Mechanistically, a decrease in the NAD + /NADH ratio downregulated SIRT3 and SIRT7 function, which suppressed p21 Cip1 expression at the translational and transcriptional levels, respectively, resulting in the upregulation of the antiproliferative molecule. Importantly, high expression levels of the core subunits of CI correlated with poor prognosis in patients with the hormone receptor(+)/human epidermal growth factor receptor 2(−) (HR+/HER2−) subtype of breast cancer. Therefore, NDUFV1 and SIRT3/7 have emerged as promising therapeutic targets against this breast cancer subtype.

BackgroundNonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction associated fatty liver disease (MAFLD) have important associations with cardiovascular disease (CVD). The main objective of this study was to compare the frequency of incidence rate of CVD in the NAFLD or MAFLD patients utilizing a large claims database.MethodsUsing the JMDC database from April 2013 to March 2019, we retrospectively analyzed data for 1,542,688 and 2,452,949 people to estimate the relationship between CVD and NAFLD, MAFLD, respectively.ResultsThe incidence rates of CVD were 0.97 (95% CI 0.94–1.01) and 2.82 (95% CI 2.64–3.01) per 1000 person-years in the non-NAFLD and NAFLD groups, respectively, and 1.01 (95% CI 0.98–1.03) and 2.69 (95% CI 2.55–2.83) per 1000 person-years in the non-MAFLD and MAFLD groups, respectively. The overall prevalence of hypertriglyceridemia and diabetes mellitus (DM) was 13.1, and 4.2%, respectively, in the non-NAFLD group and 63.6, and 20.2%, respectively, in the NAFLD group. The overall prevalenceof hypertriglyceridemia and DM was 13.6 and 4.3%, respectively, in the non-MAFLD group and 64.1, and 20.6%, respectively, in the MAFLD group. HRs for CVD increased with hypertriglyceridemia and DM.ConclusionsResults indicated that incident rate of CVD increased with NAFLD/MAFLD; the complication rate of DM and hypertriglyceridemia among NAFLD/MAFLD patients is high and may affect the development of CVD.

Periodontal disease is associated with nonalcoholic fatty liver disease (NAFLD). We evaluated periodontal treatment efficacy in patients with NAFLD and periodontal disease. This multicenter, 2-arm, randomized study recruited adult patients with NAFLD and periodontitis, alanine aminotransferase levels ≥40 U/L, and equivalent steatosis grade ≥1. Forty eligible patients (18 men and 22 women) were randomly assigned to 2 groups (scaling and root planning [SRP; n = 20] and tooth brushing [n = 20] groups) stratified by age and sex. The primary and secondary endpoints were changes in alanine aminotransferase levels and serum Porphyromonas gingivalis IgG antibody titers from baseline to 12 weeks, respectively. Efficacy analysis was performed using an intention-to-treat approach ( t test). This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000022079). We observed a significantly higher decrease in absolute alanine aminotransferase levels and P. gingivalis IgG antibody titers in the SRP group than in the tooth brushing group (-12 vs 1 U/L; mean difference [δ], -12; 95% confidence interval [CI], -20 to -5; P = 0.002). The decrease in P. gingivalis IgG antibody titer was significantly higher in the SRP group than in the tooth brushing group (FDC381, -1.6 [2.5]; δ, -1.6; 95% CI, -2.7 to -0.4; P = 0.0092; SU63, -1.7 [2.0]; δ, -1.7; 95% CI, -2.7 to -0.7). No life-threatening events or treatment-related deaths occurred. Periodontal treatment induced significant short-term and mid-term reductions in liver enzyme levels and antibody titers. Further research is warranted to clearly define SRP efficacy and tolerability in patients with NAFLD and periodontitis.

Background Few studies have investigated measures to prevent small bowel injuries induced by aspirin. Our aim was to evaluate the effect of probiotic treatment on the small bowel injuries induced by chronic low-dose aspirin use. Methods Thirty-five patients who took low-dose enteric-coated aspirin 100 mg daily (for more than 3 months) plus omeprazole 20 mg daily and were diagnosed as having unexplained iron deficiency anemia participated in this prospective randomized controlled trial. We assigned the patients to receive probiotic treatment with Lactobacillus casei for 3 months ( L. casei group) or not receive the probiotic (control group). Patients underwent capsule endoscopy (CE) before and after treatment. Results Twenty-five patients, including 13 in the L. casei group and 12 in the control group, underwent the full analysis. Significant decreases in the number of mucosal breaks and the CE score were observed at the 3-month evaluation in the L. casei group as compared with the results in the control group ( P  = 0.039). The change from the baseline in the median number of mucosal breaks in the L. casei group was −2, as compared with 0.5 in the control group. The change from the baseline in the median CE score in the L. casei group was −228 compared with −4 in the control group ( P  = 0.026). Conclusions Co-administration of L. casei is effective for the treatment of aspirin-associated small bowel injury.

The risk factors for non-alcoholic fatty liver disease (NAFLD) progression are not completely known. Porphyromonas gingivalis infection is a risk factor for systemic diseases. We investigated the association of P. gingivalis infection with the risk of non-alcoholic steatohepatitis progression. Here, hematological tests, periodontal examination, and saliva collection were performed for 164 patients with NAFLD. P. gingivalis was identified in saliva using polymerase chain reaction. Hepatic steatosis and stiffness were evaluated using vibration-controlled transient elastography (VCTE) and magnetic resonance imaging. In patients with NAFLD, P. gingivalis positivity ( P. gingivalis ratio ≥ 0.01%) in saliva correlated with liver stiffness determined using magnetic resonance elastography (MRE; p < 0.0001). A P. gingivalis ratio of 0.01% corresponds to 100,000 cells/mL and indicates the proportion of P. gingivalis in the total number of bacteria in the oral cavity. Patients with NAFLD and advanced fibrosis on MRE showed significantly elevated endotoxin activity; those who had > 10 periodontal pockets with depths ≥ 4 mm had significantly increased hepatic stiffness on both VCTE and MRE.

Importance The COVID-19 pandemic has delayed medical consultations, possibly leading to the diagnosis of gastrointestinal cancer at advanced stages. Objective To evaluate stage at diagnosis among patients with gastrointestinal cancer in Japan before and during the COVID-19 pandemic. Design, Setting, and Participants This retrospective cohort study included patients in a hospital-based cancer registry who were diagnosed with gastrointestinal cancer (ie, esophageal, gastric, colorectal, pancreatic, liver, and biliary tract cancers) between January 2016 and December 2020 at 2 tertiary Japanese hospitals. Exposures The pre–COVID-19 period was defined as January 2017 to February 2020, and the COVID-19 period was defined as March 2020 to December 2020. Main Outcome and Measure Monthly numbers of patients with newly diagnosed cancer were aggregated, classified by stage, and compared. Results The study evaluated 5167 patients, including 4218 patients (2825 [67.0%] men; mean [SD] age, 71.3 [10.9] years) in the pre–COVID-19 period and 949 patients (607 [64.0%] men; mean [SD] age, 71.8 [10.7] years) in the COVID-19 period. Comparing the pre–COVID-19 period with the COVID-19 period, significant decreases were observed in the mean (SD) number of patients with newly diagnosed gastric cancer (30.63 [6.62] patients/month vs 22.40 [5.85] patients/month; –26.87% change;P < .001) and colorectal cancer (41.61 [6.81] patients/month vs 36.00 [6.72] patients/month; –13.47% change;P = .03). Significant decreases were also observed in the mean (SD) number of cases of stage I gastric cancer (21.55 [5.66] cases/month vs 13.90 [5.99] cases/month; –35.51% change;P < .001), stage 0 colorectal cancer (10.58 [3.36] cases/month vs 7.10 [4.10] cases/month; –32.89% change;P = .008), and stage I colorectal cancer (10.16 [3.14] cases/month vs 6.70 [2.91] cases/month; –34.04% change;P = .003). No significant increases were observed for esophageal, gastric, pancreatic, liver, or biliary tract cancers. A significant decrease was observed in the mean (SD) number of cases per month of stage II colorectal cancer (7.42 [3.06] cases/month vs 4.80 [1.75] cases/month; –35.32% change;P = .01); a significant increase was observed for the mean (SD) number of cases per month of stage III colorectal cancer (7.18 [2.85] cases/month vs 12.10 [2.42] cases/month; 68.42% change;P < .001). Conclusions and Relevance In this cohort study of patients in a hospital-based cancer registry form Japan, significantly fewer patients were diagnosed with stage I gastric and colorectal cancers during the COVID-19 pandemic. Thus, the number of screening-detected cancers might have decreased, and colorectal cancer may have been diagnosed at more advanced stages.