Colorectal cancer (CRC) is responsible for one of the major cancer incidence and mortality worldwide. It is well known that MicroRNAs (miRNAs) play vital roles in maintaining the cell development and other physiological processes, as well as, the aberrant expression of numerous miRNAs involved in CRC progression. MiRNAs are a class of small, endogenous, non-coding, single-stranded RNAs that bind to the 3’-untranslated region (3′-UTR) complementary sequences of their target mRNA, resulting in mRNA degradation or inhibition of its translation as a post-transcriptional regulators. Moreover, miRNAs also can target the long non-coding RNA (lncRNA) to regulate the expression of its target genes involved in proliferation and metastasis of CRC. The functions of these dysregulated miRNAs appear to be context specific, with evidence of having a dual role in both oncogenes and tumor suppression depending on the cellular environment in which they are expressed. Therefore, the unique expression profiles of miRNAs relate to the diagnosis, prognosis, and therapeutic outcome in CRC. In this review, we focused on several oncogenic and tumor-suppressive miRNAs specific to CRC, and assess their functions to uncover the molecular mechanisms of tumor initiation and progression in CRC. These data promised that miRNAs can be used as early detection biomarkers and potential therapeutic target in CRC patients.

Bcl-2 inhibits cell proliferation by delaying G/G to S phase entry. We tested the hypothesis that Bcl-2 regulates S phase entry through mitochondrial pathways. Existing evidence indicates mitochondrial adenosine tri-phosphate (ATP) and reactive oxygen species (ROS) are important signals in cell survival and cell death, however, the molecular details of how these 2 processes are linked remain unknown. In this study, 2 cell lines stably expressing Bcl-2, 3T3Bcl-2 and C3HBcl-2, and vector-alone PB controls were arrested in G/G phase by serum starvation and contact inhibition, and ATP and ROS were measured during re-stimulation of cell cycle entry. Both ATP and ROS levels were decreased in G/G arrested cells compared with normal growing cells. In addition, ROS levels were significant lower in synchronized Bcl-2 cells than those in PB controls. After re-stimulation, ATP levels increased with time, reaching peak value 1-3 hours ahead of S phase entry for both Bcl-2 cells and PB controls. Consistent with 2 hours of S phase delay, Bcl-2 cells reached ATP peaks 2 hours later than PB control, which suggests a rise in ATP levels is required for S phase entry. To examine the role of ATP and ROS in cell cycle regulation, ATP and ROS level were changed. We observed that elevation of ATP accelerated cell cycle progression in both PB and Bcl-2 cells, and decrease of ATP and ROS to the level equivalent to Bcl-2 cells delayed S phase entry in PB cells. Our results support the hypothesis that Bcl-2 protein regulates mitochondrial metabolism to produce less ATP and ROS, which contributes to S phase entry delay in Bcl-2 cells. These findings reveal a novel mechanistic basis for understanding the link between mitochondrial metabolism and tumor-suppressive function of Bcl-2.

The prognosis of patients with colorectal cancer (CRC) remains poor owing to diagnosis typically occurring at advanced stages of the disease. The understanding of the molecular regulatory signatures of CRC may lead to the identification of biomarkers for the early detection, prevention and clinical intervention of CRC. Epidemiological studies have indicated that cyclooxygenase-1 (COX-1) serves an active function in colon carcinogenesis. However, the molecular mechanism underlying COX-1 regulation in CRC remains unknown. In the present study, COX-1 was identified to be markedly upregulated in colorectal tissues of patients with CRC, and in the CRC cell lines HCT116 and HT29. To determine the function of COX-1 in cancer development, short hairpin RNA knockdown of COX-1 was employed in HCT116 and HT29 CRC cells in the present study. The results demonstrated that silencing of COX-1 depolarized the mitochondrial membrane potential, inhibited adenosine triphosphate production, induced the generation of intracellular reactive oxygen species and triggered caspase-dependent mitochondrial apoptosis. Furthermore, depletion of COX-1 suppressed anti-apoptotic B-cell lymphoma 2 and enhanced pro-apoptotic Bcl-2-associated X protein expression by inhibiting the p65 subunit phosphorylation of nuclear factor κB (NF-κB). Taken together, the results of the present study indicated that COX-1 inhibition significantly triggered cell death by destroying the mitochondrial function that is associated with deactivation of the NF-κB signaling pathway. These results suggest COX-1 as a potential anticancer target in CRC.

No abstract

No abstract