LIN28A enhances regenerative capacity of human somatic tissue stem cells via metabolic and mitochondrial reprogramming.

Developing methods to improve the regenerative capacity of somatic stem cells (SSCs) is a major challenge in regenerative medicine. Here, we propose the forced expression of LIN28A as a method to modulate cellular metabolism, which in turn enhances self-renewal, differentiation capacities, and engraftment after transplantation of various human SSCs. Mechanistically, in undifferentiated/proliferating SSCs, LIN28A induced metabolic reprogramming from oxidative phosphorylation (OxPhos) to glycolysis by activating PDK1-mediated glycolysis-TCA/OxPhos uncoupling. Mitochondria were also reprogrammed into healthy/fused mitochondria with improved functional capacity. The reprogramming allows SSCs to undergo cell proliferation more extensively with low levels of oxidative and mitochondrial stress. When the PDK1-mediated uncoupling was untethered upon differentiation, LIN28A-SSCs differentiated more efficiently with an increase of OxPhos by utilizing the reprogrammed mitochondria. This study provides mechanistic and practical approaches of utilizing LIN28A and metabolic reprogramming in order to improve SSCs utility in regenerative medicine.

Relevance of Colonic Gas Analysis and Transit Study in Patients With Chronic Constipation.

BACKGROUND/AIMS: Colon transit time (CTT) is a useful diagnostic tool in chronic constipation, but requires good patient compliance. We analyzed the correlation between the gas volume score (GVS) and CTT in patients with chronic constipation. METHODS: The study included 145 consecutive patients (65 men) with chronic constipation. The primary outcome was the correlation be-tween the colon GVS and CTT. Secondary outcomes were the differences in colon GVS according to CTT and subtypes of chronic constipation. RESULTS: There were 81 patients with "CTT < 45 hours" and 64 patients with "CTT ≥ 45 hours." In addition, 88 patients were classi-fied as having functional constipation and 57 were classified as having constipation predominant irritable bowel syndrome (IBS-C). There was no significant correlation between CTT and colon GVS. However, the right colon GVS showed a positive cor-relation with right CTT (r = 0.255, P = 0.007). The median total colon GVS was significantly higher in patients with "CTT ≥ 45 hours" than in those with "CTT < 45 hours" (5.65% vs 4.15%, P = 0.010). There were no significant differences in colon GVS between the functional constipation and IBS-C. CONCLUSIONS: We were unable to detect a correlation between GVS and CTT in patients with chronic constipation. However, total colon GVS may be a method of predicting slow transit in patients with chronic constipation.

Expression of early growth response-1 in human gastric cancer and its relationship with tumor cell behaviors and prognosis.

The early growth response-1 (Egr-1) is crucial in many cell regulatory processes related to the progression of human cancers. Its overexpression has been demonstrated in variable human cancers and may have prognostic significance. The aims of this current study were to evaluate whether Egr-1 affects invasive and oncogenic phenotypes of human gastric cancer cells, and to examine the relationships between its expression and various clinicopathological parameters, including survival in human gastric cancer patients. We investigated the biologic role of Egr-1 in tumor cell behavior by using a small interfering RNA in human gastric cancer cell lines, AGS and TMK1. The expression of Egr-1 by reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry was investigated in human gastric cancer tissues. The knockdown of Egr-1 suppressed tumor cell migration and invasion in AGS and TMK1 cells. Egr-1 expression was significantly increased in human gastric cancer and metastatic lymph node tissues compared to the normal gastric mucosa and non-metastatic lymph node tissues. Positive expression of Egr-1 was significantly associated with tumor size, depth of invasion, lymph node metastasis, tumor stage and poor survival. These results indicate that Egr-1 is associated with human gastric cancer progression through the alteration of tumor cell behavior, such as migration and invasion. Egr-1 expression may help in predicting the clinical outcomes of human gastric cancer patients.

Expression and prognostic significance of Livin in gastric cancer.

Livin is one of the most important members of the inhibitor of apoptosis protein family. It is overexpressed in several types of tumors and may have prognostic significance. The present study investigated the biological role of Livin in the oncogenic behavior of gastric cancer cells, the expression of Livin in gastric cancer tissue and the relationship of its expression with various clinicopathological parameters and patient survival. Small interfering RNA blocked Livin gene expression in AGS and SNU638 human gastric cancer cell lines. The expression of Livin was investigated in gastric cancer tissues by RT-PCR, western blotting and immunohistochemistry. The associations with various clinicopathological parameters and survival were analyzed. Livin knockdown inhibited tumor cell migration, invasion and proliferation in AGS and SNU638 cells. Livin knockdown induced apoptosis by activating caspase-3, caspase-7 and PARP. Livin knockdown induced cell cycle arrest by a decrease in cyclin D1, cyclin-dependent kinase 4 and 6 and an increase in expression of p21 and p27. The ERK1/2 and JNK signaling pathways were inhibited by Livin knockdown. Livin expression was upregulated in gastric cancer tissues at the mRNA and protein levels. However, no significant correlation was found between Livin expression and various clinicopathological parameters including survival. In conclusion, Livin expression may be important in the alteration of invasive and oncogenic phenotypes of gastric cancer cells. The prognostic relevance of Livin remains unclear.