No abstract

To provide a detailed record of a relatively rare thrust surface rupture and examine its active tectonic implications, we have conducted field mapping of the surface rupture associated with the 2005 M w 7.6 Kashmir earthquake. Despite the difficulty arising from massive earthquake-induced landslides along the surface rupture, we found that typical pressure ridges and warps extend northwestward for a distance of ∼70 km, with a northeast-side-up vertical separation of up to ∼7 m. Neither the main frontal thrust nor the main boundary thrust is responsible for the earthquake, but three active faults or fault segments within the Sub-Himalaya, collectively called the Balakot-Bagh fault, compose the causative fault. Although the fault exhibits substantial geomorphic expression of repeated similar surface ruptures, only a part of it had been mapped as active before the earthquake. The location of the hypocenter suggests that the rupture was initiated at a deep portion of the northern-central segment boundary and propagated bilaterally to eventually break all three segments. Our obtained surface rupture traces and the along-strike-slip distribution are both in good agreement with results of prompt analyses of satellite images, indicating that space geodesy can greatly aid in time-consuming field mapping of surface ruptures. Assuming that the extensive fill terrace in the meizoseismal area was abandoned during 10-30 ka, we tentatively estimate the earthquake recurrence interval and shortening rate on the Balakot-Bagh fault to be 1000-3300 yr and 1:4-4:1 mm=yr, respectively. These estimates indicate that the Balakot-Bagh fault is not a main player of Himalayan contraction accommodation. Ⓔ Selected field photographs and ArcGIS files of the mapped surface rupture traces and measured vertical separations are available in the electronic edition of BSSA.Online Material: Field photographs and ArcGIS files of surface rupture traces and vertical separations.

Macrophages are polarized into functional classically activated and alternatively activated (M2) phenotypes depending on their microenvironment, and these cells play an important role in the immune system. M2-like polarization of tumor-associated macrophages (TAMs) is activated by various secretions from cancer cells; however, the interaction between cancer cells and TAMs is not well understood. Recent studies showed that cancer cell-derived extracellular vesicles (EVs) contribute to tumor development and modulation of the tumor microenvironment. In the current study, we investigated colorectal cancer-derived EVs containing miR-145 with respect to the polarization of TAMs. Colorectal cancer cells positively secreted miR-145 via EVs, which were taken up by macrophage-like cells. Interestingly, colorectal cancer-derived EVs polarized macrophage-like cells into the M2-like phenotype through the downregulation of An in vivo study showed that EV-treated macrophages caused significant enlargement of the tumor volumes. These findings suggest that colorectal cancer cells use miR-145 within EVs to efficiently modulate M2-like macrophage polarization and tumor progression.

It is known that pyruvate kinase in muscle (PKM), which is a rate-limiting glycolytic enzyme, has essential roles in the Warburg effect and that expression of cancer-dominant PKM2 is increased by polypyrimidine tract-binding protein 1 (PTBP1), which is a splicer of the PKM gene. In other words, PKM2 acts as a promoter of the Warburg effect. Previously, we demonstrated that the Warburg effect was partially established by down-regulation of several microRNAs (miRs) that bind to PTBP1 and that ectopic expression of these miRs suppressed the Warburg effect. In this study, we investigated the functions of miR-1 and -133b, which are well known as muscle-specific miRs, from the viewpoint of the Warburg effect in colorectal tumors. The expression levels of miR-1 and -133b were relatively high in colon tissue except muscle and very frequently down-regulated in 75 clinical colorectal tumors samples, even in adenomas, compared with those of the adjacent normal tissue samples. The ectopic expression of these miRs induced growth suppression and autophagic cell death through the switching of PKM isoform expression from PKM2 to PKM1 by silencing PTBP1 expression both in vitro and in vivo. Also, we showed that the resultant increase in the intracellular level of reactive oxygen species (ROS) was involved in this mechanism. Furthermore, PTBP1 was highly expressed in most of the 30 clinical colorectal tumor samples examined, even in adenomas. Our results suggested that PTBP1 and PTBP1-associated miR-1 and -133b are crucial molecules for the maintenance of the Warburg effect in colorectal tumors.

The Warburg effect is a well-known feature of cancer cells. However, its' functional significance hasn't been elucidated yet. Pyruvate kinase muscle (PKM), which is a rate-limiting glycolytic enzyme, has 2 isoforms, PKM1 and PKM2. It has been reported that PKM2 is a tumor-specific isoform and promotes the Warburg effect. Also, it has been thought that tumor cells switch their PKM isoform from PKM1 to PKM2 during tumor development. Here, we showed that this switching machinery was induced only in limited cases, based on PKM expression in normal tissues, and that brain-specific microRNA (miR)-124 and muscle-specific miR-133b regulated this machinery by controlling PKM expression through targeting polypyrimidine tract-binding protein 1 (PTB1), which is a splicer of the PKM gene. Also, we confirmed that the PKM2/PKM1 ratio was further elevated in other PKM2-dominant organs such as colon through the down-regulation of these PTB1-associated microRNAs during tumor development.

Serine and arginine rich splicing factor 3 (SRSF3), an SR-rich family protein, has an oncogenic function in various kinds of cancer. However, the detailed mechanism of the function had not been previously clarified. Here, we showed that the SRSF3 splicer regulated the expression profile of the pyruvate kinase, which is one of the rate-limiting enzymes in glycolysis. Most cancer cells express pyruvate kinase muscle 2 (PKM2) dominantly to maintain a glycolysis-dominant energy metabolism. Overexpression of SRSF3, as well as that of another splicer, polypyrimidine tract binding protein 1 (PTBP1) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), in clinical cancer samples supported the notion that these proteins decreased the Pyruvate kinase muscle 1 (PKM1)/PKM2 ratio, which positively contributed to a glycolysis-dominant metabolism. The silencing of SRSF3 in human colon cancer cells induced a marked growth inhibition in both in vitro and in vivo experiments and caused an increase in the PKM1/PKM2 ratio, thus resulting in a metabolic shift from glycolysis to oxidative phosphorylation. At the same time, the silenced cells were induced to undergo autophagy. SRSF3 contributed to PKM mRNA splicing by co-operating with PTBP1 and hnRNPA1, which was validated by the results of RNP immunoprecipitation (RIP) and immunoprecipitation (IP) experiments. These findings altogether indicated that SRSF3 as a PKM splicer played a positive role in cancer-specific energy metabolism.

No abstract

Despite considerable research on K‐Ras inhibitors, none had been established until now. We synthesized nuclease‐resistant synthetic miR‐143 (miR‐143#12), which strongly silenced K‐Ras, its effector signal molecules AKT and ERK, and the K‐Ras activator Sos1. We examined the anti‐proliferative effect of miR‐143#12 and the mechanism in human colon cancer DLD‐1 cell (G13D) and other cell types harboring K‐Ras mutations. Cell growth was markedly suppressed in a concentration‐dependent manner by miR‐143#12 (IC50: 1.32 nmol L−1) with a decrease in the K‐Ras mRNA level. Interestingly, this mRNA level was also downregulated by either a PI3K/AKT or MEK inhibitor, which indicates a positive circuit of K‐Ras mRNA expression. MiR‐143#12 silenced cytoplasmic K‐Ras mRNA expression and impaired the positive circuit by directly targeting AKT and ERK mRNA. Combination treatment with miR‐143#12 and a low‐dose EGFR inhibitor induced a synergistic inhibition of growth with a marked inactivation of both PI3K/AKT and MAPK/ERK signaling pathways. However, silencing K‐Ras by siR‐KRas instead of miR‐143#12 did not induce this synergism through the combined treatment with the EGFR inhibitor. Thus, miR‐143#12 perturbed the K‐Ras expression system and K‐Ras activation by silencing Sos1 and, resultantly, restored the efficacy of the EGFR inhibitors. The in vivo results also supported those of the in vitro experiments. The extremely potent miR‐143#12 enabled us to understand K‐Ras signaling networks and shut them down by combination treatment with this miRNA and EGFR inhibitor in K‐Ras‐driven colon cancer cell lines.