Dataset Information

MiR675 Accelerates Malignant Transformation of Mesenchymal Stem Cells by Blocking DNA Mismatch Repair.

ABSTRACT: miR675 is highly expressed in several human tumor tissues and positively regulates cell progression. Herein, we demonstrate that miR675 promotes malignant transformation of human mesenchymal stem cells. Mechanistically, we reveal that miR675 enhances the expression of the polyubiquitin-binding protein p62. Intriguingly, P62 competes with SETD2 to bind histone H3 and then significantly reduces SETD2-binding capacity to substrate histone H3, triggering drastically the reduction of three methylation on histone H3 36th lysine (H3K36me3). Thereby, the H3K36me3-hMSH6-SKP2 triplex complex is significantly decreased. Notably, the ternary complex's occupancy capacity on chromosome is absolutely reduced, preventing it from DNA damage repair. By virtue of the reductive degradation ability of SKP2 for aging histone H3.3 bound to mismatch DNA, the aging histone H3.3 repair is delayed. Therefore, the mismatch DNA escapes from repair, triggering the abnormal expression of several cell cycle-related genes and causing the malignant transformation of mesenchymal stem cells. These observations strongly suggest understanding the novel functions of miR675 will help in the development of novel therapeutic approaches in a broad range of cancer types.

SUBMITTER: Lu Y

PROVIDER: S-EPMC6307386 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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miR675 Accelerates Malignant Transformation of Mesenchymal Stem Cells by Blocking DNA Mismatch Repair.

Lu Yanan Y Song Shuting S Jiang Xiaoxue X Meng Qiuyu Q Wang Chen C Li Xiaonan X Yang Yuxin Y Xin Xiaoru X Zheng Qidi Q Wang Liyan L Pu Hu H Gui Xin X Li Tianming T Lu Dongdong D

Molecular therapy. Nucleic acids 20181124

miR675 is highly expressed in several human tumor tissues and positively regulates cell progression. Herein, we demonstrate that miR675 promotes malignant transformation of human mesenchymal stem cells. Mechanistically, we reveal that miR675 enhances the expression of the polyubiquitin-binding protein p62. Intriguingly, P62 competes with SETD2 to bind histone H3 and then significantly reduces SETD2-binding capacity to substrate histone H3, triggering drastically the reduction of three methylatio ...[more]

PMID: 30594073

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Project description:Background:Except for a few studies with contradictory observations, information is lacking on the possibility of association between DNA mismatch repair (MMR) status and the presence of cancer stem cells in colorectal carcinoma (CRC), two important aspects in colorectal carcinogenesis. Methods:Eighty (40 right-sided and 40 left-sided) formalin-fixed, paraffin-embedded primary CRC were immunohistochemically studied for CD133, a putative CRC stem cell marker, and MMR proteins MLH1, MSH2, MSH6 and PMS2. CD133 expression was semi-quantitated for proportion of tumor immunopositivity on a scale of 0-5 and staining intensity on a scale of 0-3 with a final score (units) being the product of proportion and intensity of tumor staining. The tumor was considered immunopositive only when the tumor demonstrated moderate to strong intensity of CD133 staining (a decision made after analysis of CD133 expression in normal colon). Deficient MMR (dMMR) was interpreted as unequivocal loss of tumor nuclear staining for any MMR protein despite immunoreactivity in the internal positive controls. Results:CD133 was expressed in 36 (90.0%) left-sided and 28 (70.0%) right-sided tumors (p < 0.05) and CD133 score was significantly higher in left- (mean ± SD = 9.6 ± 5.3 units) compared with right-sided tumors (mean ± SD = 6.8 ± 5.6 units) p < 0.05). dMMR was noted in 14 (35%) right-sided and no (0%) left-sided CRC. When stratified according to MMR status, dMMR cases showed a lower frequency of CD133 expression (42.9%) and CD133 score (mean ± SD = 2.5 ± 3.6 units) compared with pMMR tumors on the right (frequency = 84.6%; mean score ± SD = 9.2 ± 5.0 units) as well as pMMR tumors on the left (frequency = 90.0%; mean score ± SD = 9.6 ± 5.3 units) (p < 0.05). Interestingly, frequencies of CD133 immunoreactivity and CD133 scores did not differ between pMMR CRC on the right versus the left (p > 0.05). Conclusion:Proficient MMR correlated with high levels of CD133-marked putative cancer stem cells in both right- and left-sided tumors, whereas significantly lower levels of CD133-marked putative cancer stem cells were associated with deficient MMR status in colorectal carcinomas found on the right.

Project description:Background:Mesenchymal stem cells (MSCs) can be easily expanded without losing the ability of multilineage differentiation, including oesteogenic, chondrogenic and adipogenic differentiation. These characters make MSCs a promising cell resource for cartilage defect repair. MSCs could be recruited by inflammatory stimulation, then home to the injury tissues. However, its capacity of homing is extremely limited. Thus, it has become extremely necessary to develop an agent or a method, which can be used to enhance the efficiency of MSCs homing. This study investigates the effect of stearic acid methyl ester (SAME) on MSCs mobilisation and cartilage regeneration. Methods:MSCs were isolated from femurs of Sprague-Dawley (SD) rats. MTT assay was used to detect effect of SAME on viability of MSCs. Transwell assay and wound healing assay were used to detect effect of SAME on migration of MSCs. RNA-seq, quantitative real-time PCR and western blot were performed to analyze the expression of RNAs and proteins. Colony forming assay and flow cytometry were used to evaluate the effect of SAME on MSCs mobilisation in vivo. A rat cartilage defect model was created to evaluate the effect of SAME on cartilage regeneration. Results:We found that SAME could promote the migration of MSCs. Interestingly, we found SAME significantly increased the expression levels of Vav1 in MSCs. On the other hand, the enhanced migration ability of MSCs induced by SAME was retarded by Vav1 small interfering RNA (siRNA) and Rho-associated protein kinase 2 (ROCK2) inhibitor. In addition, we also checked the effect of SAME on mobilisation of MSCs in vivo. The results showed that SAME increased the number of MSCs in peripheral blood and enhanced the capacity of colony formation. Finally, using a cartilage defect model in rats, we found SAME could improve cartilage repair. Conclusion:Our study demonstrates that SAME can enhance MSCs migration ability mainly through the Vav1/ROCK2 signaling pathway, which could contribute to the accelerated cartilage regeneration. The translational potential of this article:These findings provide evidence that SAME could be used as a therapeutic reagent for MSCs mobilisation and cartilage regeneration.

Dataset Information

MiR675 Accelerates Malignant Transformation of Mesenchymal Stem Cells by Blocking DNA Mismatch Repair.

Publications

miR675 Accelerates Malignant Transformation of Mesenchymal Stem Cells by Blocking DNA Mismatch Repair.

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