Decreased level of miR-1301 promotes colorectal cancer progression via activation of STAT3 pathway

Abstract The molecular pathogenesis of colorectal cancer (CRC) has been widely investigated in recent years. Accumulating evidence has indicated that microRNA (miRNA) dysregulation participates in the processes of driving CRC initiation and progression. Aberrant expression of miR-1301 has been found in various tumor types. However, its role in CRC remains to be elucidated. In the present study, we identified miR-1301 was enriched in normal colorectal tissues and significantly down-regulated in CRC. Decreased level of miR-1301 strongly correlated with aggressive pathological characteristics, including advanced stage and metastasis. Bioinformatics and dual luciferase assay demonstrated that STAT3 is a direct target of miR-1301. Gain and loss-of-function assays showed that miR-1301 had no effect on cell proliferation. Overexpression of miR-1301 suppressed cell migration and invasion capacity of pSTA3-positive LoVo cells, but not pSTAT3-negative SW480 cells, while inhibition of miR-1301 consistently promoted cell migration and invasion in both cell lines. Additionally, miR-1301 inhibition restored the suppressed migration and invasion of STAT3- knockdown LoVo cells. MiR-1301 functioned as a tumor suppressor to modulate the IL6/STAT3 signaling pathway. In summary, this study highlights the significant role of miR- 1301/STAT3 axis in CRC metastasis.

Download Full-text

Comprehensively Analyzed Macrophage-Regulated Genes Indicate That PSMA2 Promotes Colorectal Cancer Progression

Frontiers in Oncology ◽

10.3389/fonc.2020.618902 ◽

2021 ◽

Vol 10 ◽

Author(s):

Jingbo Qi ◽

Zhiqiu Hu ◽

Shaoqun Liu ◽

Fan Li ◽

Sheng Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Death ◽

Cancer Progression ◽

Bioinformatic Analysis ◽

Luciferase Assay ◽

Migration And Invasion ◽

Loss Of Function ◽

Survival Times ◽

Promising Target ◽

Colorectal Cancer Progression

Colorectal cancer (CRC) is the third most common cancer worldwide. Here, we identified tumor-associated macrophages (TAMs) as regulators of genes in CRC. In total, the expressions of 457 genes were dysregulated after TAM coculture; specifically, 344 genes were up-regulated, and 113 genes were down-regulated. Bioinformatic analysis implied that these TAM-related genes were associated with regulation of the processes of macromolecule metabolism, apoptosis, cell death, programmed cell death, and the response to stress. To further uncover the interplay among these proteins, we constructed a PPI network; 15 key regulators were identified in CRC, including VEGFA, FN1, JUN, CDH1, MAPK8, and FOS. Among the identified genes, we focused on PSMA2 and conducted loss-of-function experiments to validate the functions of PSMA2 in CRC. To further determine the mechanism by which PSMA2 affected CRC, we conducted multiple assays in CRC cell lines and tissues. PSMA2 enhanced the proliferation, migration and invasion of CRC cells. Moreover, our data indicated that PSMA2 expression was dramatically increased in stage 1, stage 2, stage 3, and stage 4 CRC samples. Our data indicated that PSMA2 was one target of miR-132. A miR-132 mimic greatly hindered CRC cell proliferation. In addition, the luciferase assay results revealed that miR-132 directly regulated PSMA2. Moreover, our data indicated that miR-132 expression was greatly decreased in CRC samples, which was associated with longer survival times of CRC patients, implying that miR-132 was a probable biomarker for CRC. Collectively, these data indicate that PSMA2 is a promising target for the therapy of CRC.

Download Full-text

Cooperation of SRPK2, Numb and p53 in the malignant biology and chemosensitivity of colorectal cancer

Bioscience Reports ◽

10.1042/bsr20191488 ◽

2020 ◽

Vol 40 (1) ◽

Author(s):

Guosen Wang ◽

Weiwei Sheng ◽

Jingtong Tang ◽

Xin Li ◽

Jianping Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Migration ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Migration And Invasion ◽

Chemical Agent ◽

Cell Migration And Invasion ◽

Agent Treatment ◽

Hct116 Cells

Abstract Serine-arginine protein kinase 2 (SRPK2) is aberrantly expressed in human malignancies including colorectal cancer (CRC). However, little is known about the molecular mechanisms, and the role of SRPK2 in chemosensitivity remains unexplored in CRC. We recently showed that SRPK2 promotes pancreatic cancer progression by down-regulating Numb and p53. Therefore, we investigated the cooperation between SRPK2, Numb and p53 in the cell migration, invasion and chemosensitivity of CRC in vitro. Here, we showed that SRPK2 expression was higher in CRC tumors than in nontumor tissues. SRPK2 expression was positively associated with clinicopathological characteristics of CRC patients, including tumor differentiation, T stage, N stage and UICC stage. Additionally, SRPK2 had no association with mutant p53 (mtp53) in SW480 and SW620 cells, but negatively regulated Numb and wild-type p53 (wtp53) in response to 5-fluorouracil or cisplatin treatment in HCT116 cells. Moreover, SRPK2, Numb and p53 coimmunoprecipitated into a triple complex with or without the treatment of 5-fluorouracil in HCT116 cells, and p53 knockdown reversed the up-regulation of wtp53 induced by SRPK2 silencing with chemical agent treatment. Furthermore, overexpression of SRPK2 increased cell migration and invasion and decreased chemosensitivity to 5-fluorouracil or cisplatin in HCT116 cells. Conversely, SRPK2 silencing decreased cell migration and invasion and increased chemosensitivity to 5-fluorouracil or cisplatin, yet these effects could be reversed by p53 knockdown under chemical agent treatment. These results thus reveal a novel role of SRPK2-Numb-p53 signaling in the progression of CRC and demonstrate that SRPK2 is a potential therapeutic target for CRC clinical therapy.

Download Full-text

miR-224 targets BTRC and promotes cell migration and invasion in colorectal cancer

3 Biotech ◽

10.1007/s13205-020-02477-x ◽

2020 ◽

Vol 10 (11) ◽

Author(s):

Qi Zheng ◽

Jane J. Yu ◽

Chenggang Li ◽

Jiali Li ◽

Jiping Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Migration ◽

Protein Expression ◽

Molecular Mechanisms ◽

Early Stage ◽

Luciferase Assay ◽

Migration And Invasion ◽

Cell Migration And Invasion ◽

Normal Tissues ◽

The Impact

AbstractOur study aims to investigate the impact of miR-224 on cell migration and invasion in colorectal cancer (CRC) as well as its molecular mechanisms. The results showed that miR-224 was significantly upregulated in CRC compared to normal tissues via the TCGA database. Overexpression of miR-224 promoted CRC cell migration and invasion, while inhibition of miR-224 demonstrated the opposite result via transwell assays. In addition, we found that BTRC was a target gene of miR-224 through the miRecords database and dual-luciferase assay, while western blot together with RT-qPCR showed that inhibition of miR-224 led to elevated BTRC expression in protein level but not in mRNA level, and also decreased the expression of β-catenin. In reference to the Human Protein Atlas, BTRC protein expression was higher in normal tissues than in CRC tissues. In conclusion, miR-224 regulates its target BTRC protein expression and its related Wnt/β-catenin pathway. Its impact on cell migration and invasion in CRC cells suggested that miR-224 could be a prospective therapeutic target for early-stage non-metastatic CRC.

Download Full-text

LncRNA LBX2-AS1 promotes colorectal cancer progression and 5-fluorouracil resistance

Cancer Cell International ◽

10.1186/s12935-021-02209-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yu-Nan Ma ◽

Yong-Gang Hong ◽

Guan-Yu Yu ◽

Si-yuan Jiang ◽

Bo-lun Zhao ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Ex Vivo ◽

Prognostic Indicator ◽

Migration And Invasion ◽

Loss Of Function ◽

Clinical Benefits ◽

Colorectal Cancer Progression

Abstract Background Recent reports suggest that the long non-coding RNA LBX2 antisense RNA 1 (LBX2-AS1) acts as an important regulator in cancer progression, but its significance in colorectal cancer (CRC) remains undetermined. Methods LBX2-AS1 expression levels in CRC were determined from the GEPIA database and CRC tissues to investigate clinical relevance. meRIP-PCR assays investigated the molecular mechanisms underlying the function of m6A in LBX2-AS1. Loss of function experiments was used to define the role of LBX2-AS1 in the progression of CRC. The ceRNA function of LBX2-AS1 was evaluated by RNA immunoprecipitation. In vitro and PDX models were used to determine if LBX2-AS1 promotes 5-fluorouracil resistance. Results Data from the TCGA and our institutional patient cohorts established that LBX2-AS1 levels were significantly upregulated in most CRC tissues relative to normal adjacent colon tissues. Moreover, LBX2-AS1 levels were positively correlated with aggressive disease characteristics, constituting an independent prognostic indicator of overall patient survival. Mechanistic investigations suggested that the increased LBX2-AS1 in CRC was mediated by METTL3-dependent m6A methylation. In vitro experiments indicated that knockdown of LBX2-AS1 inhibited CRC proliferation, migration and invasion with this phenotype linked to LBX2-AS1-mediated regulation of AKT1, acting as a ceRNA to sponge miR-422a. Ex vivo analysis of patient-derived CRC xenografts showed that low LBX2-AS1 expression cases exhibited 5-FU responsiveness and clinical investigations confirmed that low LBX2-AS1 expression was associated with improved clinical benefits from 5-FU therapy. Conclusions Together these results suggest that LBX2-AS1 may serve as a therapeutic target and predictor of 5-FU benefit in CRC patients.

Download Full-text

MiR-375 Enriched in Bone Marrow Mesenchymal Stem Cells (BMSC) Exosomes Inhibits Prostate Cancer Cell Migration and Invasion by Down-Regulating Trefoil Factor 3 (TFF3)

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2021.2827 ◽

2021 ◽

Vol 11 (12) ◽

pp. 2407-2414

Author(s):

Qihong Liang ◽

Wei Zhong

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Cell Proliferation ◽

Cell Migration ◽

Luciferase Assay ◽

Migration And Invasion ◽

Clinical Samples ◽

Cell Migration And Invasion ◽

Marrow Mesenchymal Stem Cells ◽

Proliferation And Metastasis

To study the effect and mechanism of miR-375 enriched in BMSC exosomes on prostate cancer (PC) cells. Bioinformatics assessed the potential regulatory miRNA of TFF3 and miR-375 level in breast cancer cells and breast cancer clinical samples was detected by PCR. Dual luciferase assay validated the relationship between TFF3 and miR-375. miR-375 mimics or sh-TFF3 was transfected into PC cells, followed by measuring miR-375 and TFF3 by PCR and Western-blot. Cell proliferation, invasion, migration and apoptosis by Edu staining, transwell and flow cytometry. The BMSC exosomes were then isolated and co-cultured with PC cells to detect cell proliferation and invasion. PC cells and tissues showed the expression of miR-375 was decreased, indicated that miR-375 specifically inhibited TFF3 level. miR-375 was enriched in MSC-derived exosomes and could be transferred to PC cells. miR-375 mimics, exosome miR-375 or silenced TFF3 inhibited TFF3 level, up-regulated PCNA, MMP-2/9 expression, thereby inhibiting cell proliferation and metastasis, and promoting cell apoptosis. miR-375 is enriched in BMSC exosomes and inhibits PC cell migration and invasion by reducing TFF3.

Download Full-text