[Retracted] MicroRNA­485 plays tumour­suppressive roles in colorectal cancer by directly targeting GAB2.

Following the publication of this paper, the authors contacted the Editorial Office to request that the article be retracted on account of an inability to obtain consistent results from repeated experiments. Independently, it was drawn to the Editor's attention that certain of the flow cytometric data shown in Figs. 2D, 5D and 6D were strikingly similar to data appearing in different form in another article by different authors. Owing to the fact that the contentious data in the above article were already under consideration for publication prior to its submission to Oncology Reports, the Editor has agreed to the authors' request that this article should be retracted from the Journal. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Oncology Reports 40: 554­564, 2018; DOI: 10.3892/or.2018.6449].

Retracted: Long Noncoding RNA Plasmacytoma Variant Translocation 1 (PVT1) Promotes Colon Cancer Progression via Endogenous Sponging miR-26b.

Retracted on authors' request due to detected data flaws. Reference: Rui Zhang, Jibin Li, Xiaofei Yan, Keer Jin, Wenya Li, Xin Liu, Jianfeng Zhao, Wen Shang, Yefu Liu. Long Noncoding RNA Plasmacytoma Variant Translocation 1 (PVT1) Promotes Colon Cancer Progression via Endogenous Sponging miR-26b. Med Sci Monit. 2018; 24: LBR8685-8692. 10.12659/MSM.910955.

Low-density lipoprotein-decorated and Adriamycin-loaded silica nanoparticles for tumor-targeted chemotherapy of colorectal cancer.

BACKGROUND: Chemotherapy for colorectal cancer remains an unsatisfactory method of treatment and requires the development of more advanced drug delivery systems (DDSs). Among inorganic materials, silica nanoparticles (SLNs) have been considered a suitable candidate to be developed as versatile carriers for drug delivery and imaging applications. Low-density lipoprotein (LDL) is a widespread material that is responsible for cholesterol transport in plasma. The concept of employing LDL-modified nanoparticles for tumor-targeted drug delivery has been widely adopted. OBJECTIVES: The objective of this study was to develop and test a new DDS for effective chemotherapy of colorectal cancer. MATERIAL AND METHODS: We successfully developed an Adriamycin (Adr)-loaded DDS based on LDL-modified SLNs (LDL/SLN/Adr). The tumor-homing property of LDL and the drug-loading capability of SLNs were combined to prepare LDL/SLN/Adr that can specifically deliver Adr to the cancer site to achieve effective chemotherapy of HT-29 colorectal cancer. RESULTS: In vitro analysis showed that LDL/SLN/Adr consisted of nano-sized particles and was capable of targeting the low-density lipoprotein receptors (LDLR) which were overexpressed in many cancer cell lines. As a result, LDL/SLN/Adr exerted better cytotoxicity than unmodified SLNs and free drugs. In vivo imaging and anticancer assays also confirmed the preferable tumor-homing and enhanced anticancer effect of LDL/SLN/Adr. CONCLUSIONS: LDL/SLN/Adr might be a promising DDS for effective chemotherapy of colorectal cancer.

Long non­coding RNA MLK7­AS1 promotes proliferation in human colorectal cancer via downregulation of p21 expression.

Current studies have highlighted long non­coding RNAs (lncRNAs) as critical regulators in various cancers, including colorectal cancer (CRC). By utilizing publicly available data from The Cancer Genome Atlas dataset, MLK7 antisense RNA 1 (MLK7­AS1) was identified as a novel lncRNA that correlated with CRC progression. The results of reverse transcription­quantitative polymerase chain reaction (RT­qPCR) revealed a significant upregulation of MLK7­AS1 in both CRC tissue samples and cell lines. In addition, a positive correlation was observed between increased MLK7­AS1 expression and several clinicopathological factors in patients with CRC. Importantly, MLK7­AS1 knockdown suppressed CRC cell proliferation and promoted G1/G0 phase arrest and apoptosis in vitro, whereas MLK7­AS1 overexpression exhibited opposite effects. Consistently, decreased MLK7­AS1 expression inhibited tumor growth in vivo. Furthermore, RT­qPCR and western blot assays revealed that p21 may be a potential downstream target of MLK7­AS1. To the best of the authors' knowledge, this is the first study to report that MLK7­AS1 has potential as a biomarker and may promote proliferation in CRC partially through downregulating p21 expression.

Long Noncoding RNA Plasmacytoma Variant Translocation 1 (PVT1) Promotes Colon Cancer Progression via Endogenous Sponging miR-26b.

BACKGROUND Recently, long noncoding RNAs (lncRNAs) have received wide attention in the area of tumor progression. Dysregulation of lncRNAs has been shown to participated in colon cancer, a known malignant tumor. This study aimed to identify the way lncRNA PVT1 affects the progression of colon cancer. MATERIAL AND METHODS Both human colon cancer tissues and 30 paired adjacent normal tissue samples, as well as the colon cancer cells, were collected. Then quantitative real-time (qRT-PCR) was performed to detect the expression of lncRNA PVT1 and miR-26b. Furthermore, the role of PVT1 was determined by function assays such as cell proliferation assay, invasion assay, and wound healing assay. The mechanism was studied using western blot assay and luciferase assay. RESULTS We demonstrate that the expression of PVT1 was significantly higher in tumor tissue compared with the adjacent normal tissue with a lower expression of miR-26b. Moreover, PVT1 promoted tumor growth, migration, and invasion in vitro. In addition, further experiments revealed that miR-26b was a direct target of PVT1 and could inhibit cell migration, invasion, and proliferation in colon cancer. CONCLUSIONS Our results suggest that PVT1 could promote metastasis and proliferation of colon cancer via endogenous sponging and inhibiting the expression of miR-26b, which may highlight the significance of lncRNA PVT1 in colon cancer tumorigenesis.

Knockdown of Long Non-Coding RNA XIST Inhibited Doxorubicin Resistance in Colorectal Cancer by Upregulation of miR-124 and Downregulation of SGK1.

BACKGROUND/AIMS: Doxorubicin (DOX) is a widely used chemotherapeutic agent for colorectal cancer (CRC). However, the acquirement of DOX resistance limits its clinical application for cancer therapy. Mounting evidence has suggested that aberrantly expressed lncRNAs contribute to drug resistance of various tumors. Our study aimed to explore the role and molecular mechanisms of lncRNA X-inactive specific transcript (XIST) in chemoresistance of CRC to DOX. METHODS: The expressions of XIST, miR-124, serum and glucocorticoid-inducible kinase 1 (SGK1) mRNA in DOX-resistant CRC tissues and cells were detected by qRT-PCR or western blot analysis. DOX sensitivity was assessed by detecting IC50 value of DOX, the protein levels of P-glycoprotein (P-gp) and glutathione S-transferase-π (GST-π) and apoptosis. The interactions between XIST, miR-124 and SGK1 were confirmed by luciferase reporter assay, qRT-PCR and western blot. Xenograft tumor assay was used to verify the role of XIST in DOX resistance in CRC in vivo. RESULTS: XIST expression was upregulated and miR-124 expression was downregulated in DOX-resistant CRC tissues and cells. Knockdown of XIST inhibited DOX resistance of CRC cells, as evidenced by the reduced IC50 value of DOX, decreased P-gp and GST-π levels and enhanced apoptosis in XIST-silenced DOX-resistant CRC cells. Additionally, XIST positively regulated SGK1 expression by interacting with miR-124 in DOX-resistant CRC cells. miR-124 suppression strikingly reversed XIST-knockdown-mediated repression on DOX resistance in DOX-resistant CRC cells. Moreover, SGK1-depletion-elicited decrease of DOX resistance was greatly restored by XIST overexpression or miR-124 inhibition in DOX-resistant CRC cells. Furthermore, XIST knockdown enhanced the anti-tumor effect of DOX in CRC in vivo. CONCLUSION: XIST exerted regulatory function in resistance of DOX possibly through miR-124/SGK1 axis, shedding new light on developing promising therapeutic strategy to overcome chemoresistance in CRC patients.

miR-128 Targets the SIRT1/ROS/DR5 Pathway to Sensitize Colorectal Cancer to TRAIL-Induced Apoptosis.

BACKGROUND/AIMS: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an ideal anti-tumor drug because it exhibits selective cytotoxicity against cancer cells. However, certain cancer cells are resistant to TRAIL, and the potential mechanisms are still unclear. The aim of this study was to reduce the resistance of colorectal cancer (CRC) cells to TRAIL. METHODS: Quantitative real-time PCR analysis was performed to detect the expression of microRNA-128 (miR-128) in tissues from patients with CRC and CRC cell lines. MTT assays were used to evaluate the effect of miR-128 on TRAIL-induced cytotoxicity against CRC cell lines. The distribution of death receptor 5 (DR5) and the production of reactive oxygen species (ROS) were detected by flow cytometry analysis. Western blot, flow cytometry, and luciferase reporter assays were performed to evaluate the potential mechanism and pathway of miR-128-promoted apoptosis in TRAIL-treated CRC cells. RESULTS: MiR-128 expression was downregulated in tumor tissues from patients with CRC as well as in CRC cell lines in vitro. The enforced expression of miR-128 sensitized CRC cells to TRAIL-induced cytotoxicity by inducing apoptosis. Mechanistically, bioinformatics, western blot analysis, and luciferase reporter assays showed that miR-128 directly targeted sirtuin 1 (SIRT1) in CRC cells. miR-128 overexpression suppressed SIRT1 expression, which promoted the production of ROS in TRAIL-treated CRC cells. This increase of ROS subsequently induced DR5 expression, and thus increased TRAIL-induced apoptosis in CRC cells. CONCLUSION: The combination of miR-128 with TRAIL may represent a novel approach for the treatment of CRC.

Targeting Interleukin-6 (IL-6) Sensitizes Anti-PD-L1 Treatment in a Colorectal Cancer Preclinical Model.

BACKGROUND Limited efficacy of immune checkpoint blockades was observed in clinical trials in colorectal (CRC) patients, especially in the microsatellite-stable patients. Interleukin-6 (IL-6) is critical in modeling immune responses in cancers. However, the effects of targeting IL-6 in combination with immune checkpoint blockades is unknown in CRC. MATERIAL AND METHODS In the present study, we investigated the profile of IL-6 expression in tumor tissues of CRC patient and we established CRC mouse models with various IL-6 expression levels using CT26 cells and MC38 cells. Effects of anti-IL-6 and anti-PD-L1 combination treatment were tested in these models. RESULTS A total of 105 CRC patients were included in this study, with 41 (39%) females and 64 (61%) males. Sixty patients showed IL-6 high expression and 45 patients showed IL-6 low expression. The patients with IL-6 high expression tended to have shorter survival (median survival time of 25.5 months) than the patients with IL-6 low expression (median survival time of 46 months, P value=0.013). In the CRC mouse models, tumors with IL-6 overexpression tended to grow faster than the tumors with IL-6 knockout. The numbers of CD8+ T cells and CD4+ T cells were decreased in IL-6 overexpressed tumors. On the contrary, myeloid-derived suppressor cells and regulatory/suppressor T cells were more numerous in tumors with IL-6 overexpression. PD-L1 expression was upregulated in the tumors with IL-6 overexpression. Importantly, an IL-6 blockade reversed the anti-PD-L1 resistance and prolonged tumor-bearing mouse survival. CONCLUSIONS Our study indicates that IL-6 induces strong immunosuppression in the CRC microenvironment by recruiting immunosuppression cells and impairing T cell infiltration. Inhibition of IL-6 enhanced the efficacy of anti-PD-L1 in CRC, providing a novel strategy to overcome anti-PD-L1 resistance in CRC.

MicroRNA-485 plays tumour-suppressive roles in colorectal cancer by directly targeting GAB2.

Colorectal cancer (CRC) is reported to be the third most common cancer and the fourth leading cause of cancer-related deaths around the world. MicroRNA-485 (miR-485) has been reported to be aberrantly expressed and play important roles in several types of human malignancy. However, the expression level, biological functions and underlying molecular mechanisms of miR-485 in CRC remain unclear. Therefore, the aim of the present study was to determine miR-485 expression levels and their clinical significance in CRC and to explore the functions and underlying mechanisms of miR-485 in this disease. In the present study, miR-485 was lowly expressed in CRC tissues and cell lines. Decreased miR-485 expression was associated with tumour size, lymph node metastasis, distant metastasis and TNM stage. Functional assays indicated that upregulation of miR-485 impaired CRC cell proliferation, invasion and induced cell apoptosis. Grb2-associated binding 2 (GAB2) was identified as a direct target of miR-485 in CRC. GAB2 was upregulated in CRC tissues and was negatively correlated with the miR-485 expression level. Furthermore, GAB2 knockdown simulated the tumour-suppressing roles of miR-485 overexpression in CRC cells. Moreover, restored GAB2 expression reversed the effects of miR-485 overexpression in CRC cells. In addition, miR-485 suppressed the AKT and ERK signalling pathways in CRC by directly targeting GAB2. Collectively, these findings demonstrate that miR-485 may play tumour suppressive roles in CRC by directly targeting GAB2 and indirectly regulating AKT and ERK signalling pathways, suggesting that miR-485 may be a potential therapeutic target for patients with this disease.

Suppression of Capn4 by microRNA-1271 impedes the proliferation and invasion of colorectal cancer cells.

Accumulating evidence has suggested that calpain small subunit 1 (Capn4) plays an important role in the development and progression of malignant tumors. However, little is known about the role of Capn4 in colorectal cancer (CRC). In this study, we aimed to investigate the potential role of Capn4 in CRC and the regulation of Capn4 by microRNAs (miRNAs). Here, we found that Capn4 expression was highly up-regulated in CRC cell lines. Knockdown of Capn4 by siRNA significantly inhibited the proliferation and invasion of CRC cell lines. Furthermore, knockdown of Capn4 suppressed Wnt signaling in CRC cells. Interestingly, Capn4 was found to be a target gene of miR-1271, a tumor suppressive miRNA. The results showed that miR-1271 negatively regulated Capn4 expression in CRC cells. An inverse correlation between miR-1271 and Capn4 was also shown in CRC clinical tissues. Moreover, the overexpression of miR-1271 suppressed the proliferation, invasion and Wnt signaling of CRC cells. Importantly, we found that the restoration of Capn4 expression significantly reversed the antitumor effects of miR-1271 in CRC cells. Overall, these results suggest that miR-1271 inhibits the proliferation and invasion of CRC cells by down-regulating Capn4. Our study suggests that Capn4 and miR-1271 may serve as potential therapeutic targets for the treatment of CRC.

SODD promotes glucose uptake of colorectal cancer cells via AKT pathway.

Altered glucose metabolism has been found in a variety of malignant diseases and recognized as one of the hallmarks of cancer. However, the molecular mechanism behind it is far from well understood. In current study, we found silencer of death domains (SODD) regulates glucose uptake of colorectal cancer cells. When cultured under low level of glucose, SODD overexpressing RKO and SW1417 cells generated more colonies, compared with control cells, in clonogenic assay. SODD upregulation enhanced RKO and SW1417 cells viability. Furthermore, SODD induced more GLUT1 (Glucose transporter 1) expression and enhanced glucose uptake. AKT phosphorylation was upregulated in SODD overexpression cells. Moreover, inhibition of GLUT1 or AKT could reverse SODD induced glucose uptake enhancement. In conclusion, our findings indicate that SODD positively regulates glucose uptake and may be a potential therapeutic target of colorectal cancer.