Mex-3 RNA binding family member A (MEX3A)/circMPP6 complex promotes colorectal cancer progression by inhibiting autophagy.

RNA-binding proteins (RBPs)-RNA networks have contributed to cancer development. Circular RNAs (circRNAs) are considered as protein recruiters; nevertheless, the patterns of circRNA-protein interactions in colorectal cancer (CRC) are still lacking. Processing bodies (PBs) formed through liquid-liquid phase separation (LLPS) are membrane-less organelles (MLOs) consisting of RBPs and RNA. Previous evidence suggests a connection between PBs dynamics and cancer progression. Despite the increasingly acknowledged crucial role of RBPs and RNA in the accumulation and maintenance of MLOs, there remains a lack of specific research on the interactions between PBs-related RBPs and circRNAs in CRC. Herein, we identify that MEX-3 RNA binding family member A (MEX3A), frequently upregulated in CRC tissues, predicts poorer patient survival. Elevated MEX3A accelerates malignance and inhibits autophagy of CRC cells. Importantly, MEX3A undergoes intrinsically disordered regions (IDRs)-dependent LLPS in the cytoplasm. Specifically, circMPP6 acts as a scaffold to facilitate the interaction between MEX3A and PBs proteins. The MEX3A/circMPP6 complex modulates PBs dynamic and promotes UPF-mediated phosphodiesterase 5A (PDE5A) mRNA degradation, consequently leading to the aggressive properties of CRC cells. Clinically, CRC patients exhibiting high MEX3A expression and low PDE5A expression have the poorest overall survival. Our findings reveal a collaboration between MEX3A and circMPP6 in the regulation of mRNA decay through triggering the PBs aggregation, which provides prognostic markers and/or therapeutic targets for CRC.

NEIL1 drives the initiation of colorectal cancer through transcriptional regulation of COL17A1.

Deficiency of DNA repair pathways drives the development of colorectal cancer. However, the role of the base excision repair (BER) pathway in colorectal cancer initiation remains unclear. This study shows that Nei-like DNA glycosylase 1 (NEIL1) is highly expressed in colorectal cancer (CRC) tissues and associated with poorer clinical outcomes. Knocking out neil1 in mice markedly suppresses tumorigenesis and enhances infiltration of CD8+ T cells in intestinal tumors. Furthermore, NEIL1 directly forms a complex with SATB2/c-Myc to enhance the transcription of COL17A1 and subsequently promotes the production of immunosuppressive cytokines in CRC cells. A NEIL1 peptide suppresses intestinal tumorigenesis in ApcMin/+ mice, and targeting NEIL1 demonstrates a synergistic suppressive effect on tumor growth when combined with a nuclear factor κB (NF-κB) inhibitor. These results suggest that combined targeting of NEIL1 and NF-κB may represent a promising strategy for CRC therapy.

CEP63 upregulates YAP1 to promote colorectal cancer progression through stabilizing RNA binding protein FXR1.

Abnormal regulation of centrosome components can induce chromosome instability and tumorigenesis. Centrosomal protein 63 (CEP63) is a vital member for assembling centrosome. Yet, the involvement of CEP63 in cancer pathogenesis remains unclear. Here we identify CEP63 as an important mediator for RNA-binding proteins (RBPs) to facilitate regulation on their RNA targets in colorectal cancer (CRC). We demonstrate that CEP63 protein is upregulated in a large cohort of colorectal cancer tissues and predicts poor prognosis, and USP36 is identified for stabilizing CEP63 by enhancing its K48-dependent deubiquitination. CEP63 overexpression promotes the proliferation and tumor growth of CRC cells in vitro and in vivo. Furthermore, we find that CEP63 can promote cancer stem-like cell properties by enhancing YAP1 expression through binding with and inhibiting the K63-ubiquitylation degradation of RBP FXR1 in CRC cells. Importantly, we further verify that the KH domain of FXR1 is necessary for the interaction between CEP63 and FXR1. Moreover, microtube motor proteins can form a complex with CEP63 and FXR1 to mediate the regulation of FXR1 on RNA targets. Additionally, we also confirm that CEP63 can bind and regulate multiple RBPs. In conclusion, our findings unveil an unrecognized CEP63/RBPs/RNA axis that CEP63 may perform as an adapter facilitating the formation of RBPs complex to regulate RNA progression and discover the role of CEP63 involved in signal transduction and RNA regulation, providing potential therapeutic target for CRC patients.

KLF16 enhances stress tolerance of colorectal carcinomas by modulating nucleolar homeostasis and translational reprogramming.

Translational reprogramming is part of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, which acts to the advantage of cancer growth and development in different stress conditions, but the mechanism of ER stress-related translational reprogramming in colorectal carcinoma (CRC) progression remains unclear. Here, we identified that Krüppel-like factor 16 (KLF16) can promote CRC progression and stress tolerance through translational reprogramming. The expression of KLF16 was upregulated in CRC tissues and associated with poor prognosis for CRC patients. We found that ER stress inducers can recruit KLF16 to the nucleolus and increase its interaction with two essential proteins for nucleolar homeostasis: nucleophosmin1 (NPM1) and fibrillarin (FBL). Moreover, knockdown of KLF16 can dysregulate nucleolar homeostasis in CRC cells. Translation-reporter system and polysome profiling assays further showed that KLF16 can effectively promote cap-independent translation of ATF4, which can enhance ER-phagy and the proliferation of CRC cells. Overall, our study unveils a previously unrecognized role for KLF16 as an ER stress regulator through mediating translational reprogramming to enhance the stress tolerance of CRC cells and provides a potential therapeutic vulnerability.

PPIP5K2 promotes colorectal carcinoma pathogenesis through facilitating DNA homologous recombination repair.

Colorectal carcinoma (CRC) is the second most deadly cancer worldwide. Therapies that take advantage of DNA repair defects have been explored in various tumors but not yet systematically in CRC. Here, we found that Diphosphoinositol Pentakisphosphate Kinase 2 (PPIP5K2), an inositol pyrophosphate kinase, was highly expressed in CRC and associated with a poor prognosis of CRC patients. In vitro and in vivo functional studies demonstrated that PPIP5K2 could promote the proliferation and migration ability of CRC cells independent of its inositol pyrophosphate kinase activity. Mechanically, S1006 dephosphorylation of PPIP5K2 could accelerate its dissociation with 14-3-3 in the cytoplasm, resulting in more nuclear distribution. Moreover, DNA damage treatments such as doxorubicin (DOX) or irradiation (IR) could induce nuclear translocation of PPIP5K2, which subsequently promoted homologous recombination (HR) repair by binding and recruiting RPA70 to the DNA damage site as a novel scaffold protein. Importantly, we verified that S1006 dephosphorylation of PPIP5K2 could significantly enhance the DNA repair ability of CRC cells through a series of DNA repair phenotype assays. In conclusion, PPIP5K2 is critical for enhancing the survival of CRC cells via facilitating DNA HR repair. Our findings revealed an unrecognized biological function and mechanism model of PPIP5K2 dependent on S1006 phosphorylation and provided a potential therapeutic target for CRC patients.

[Effect of norcantharidin's derivative Nd3 on proliferation of human ovarian cancer cell line SKOV3 and its possible mechanisms].

BACKGROUND & OBJECTIVE: Norcantharidin (NCTD), the demethylated form of cantharidin, can inhibit the proliferation of many kinds of cancer cells, but its effect is milder than those of other drugs. This study was to explore the inhibitory effect of Nd3, a derivative of norcantharidin, on the proliferation of human ovarian cancer cell line SKOV3, compare its antitumor effect with that of norcantharidin, and investigate its possible molecular mechanisms. METHODS: SKOV3 cells were treated with Nd3 and norcantharidin, separately. Cell proliferation was evaluated by sulforhodamine B (SRB) assay. Cell cycle distribution and apoptosis were detected by flow cytometry. The expression of Cdc2, Cyclin B1, Bax, and Bcl-2 was detected by Western blot. RESULTS: When treated with 2.5, 5, 10, 20, 30, and 40 micromol/L Nd3 for 48 h, the inhibition rates of SKOV3 cells were 27.3%, 34.1%, 53.3%, 64.3%, 83.3%, and 96.7%, respectively, which were significantly higher than that of negative control cells (P<0.001). The 50% inhibition concentration of Nd3 was (25.1+/-2.3) micromol/L at 24 h, (21.8+/-2.8) micromol/L at 36 h, and (20.4+/-3.3) micromol/L at 48 h. When treated with 10, 20, 30, and 40 micromol/L Nd3 for 48 h, SKOV3 cells were arrested at G2/M phase at rates of 14.3%, 20.2%, 26.2%, and 27.9%; when treated with 30 micromol/L Nd3 for 12, 24, 36, and 48 h, the proportions of SKOV 3 cells at G2/M phase were 19.8%, 26.6%, 27.8%, and 32.0%. When treated with 40 micromol/L Nd3 for 48 h, the apoptosis rate of SKOV3 cells was significantly higher than that of control cells [(17.9+/-4.4)% vs. (2.5+/-2.8)%, P<0.01]. After treatment of Nd3, the expression of Cdc2, Cyclin B1, and Bcl-2 were down-regulated, and the expression of Bax was up-regulated. CONCLUSIONS: Nd3 inhibits SKOV3 cell proliferation more than norcantharidin does, blocks cell cycle at G2/M phase, and induces apoptosis. The antitumor mechanism of Nd3 is related to the changes of Cdc2, Cyclin B1, Bax, and Bcl-2 expression.

Volatilization behaviors of diesel oil from the soils.

The volatilization of diesel oil, Shengli crude oil and 90 # gasoline on glass surface of petri dishes were conducted at the ambient temperature of 25 degrees C. Diesel oil evaporates in a power manner, where the loss of mass is approximately power with time. 90 # gasoline evaporates in a logarithmic with time. Where as the volatilization of Shengli crude oil fit either the logarithmic or power equation after different time, and has similar R2. And the effects of soil type and diesel oil and water content on volatilization behavior in unsaturated soil were studied in this paper. Diesel oil and water content in the soils play a large role in volatilization from soils. Appropriate water helps the wicking action but too much water stops it. The wicking action behaves differently in four different types of soils in the same volatilization experiment of 18% diesel oil content and air-dry condition.