Publications by authors named "Mengdi Cai"

4 Publications

  • Page 1 of 1

Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitus.

BMC Endocr Disord 2021 Apr 17;21(1):73. Epub 2021 Apr 17.

Center for Molecular Medicine, Yanzhou People's Hospital, Jining Medical University, Jining, 272100, Shandong, China.

Background: Type 2 diabetes mellitus (T2D) is a common and complex disease. Dysfunction of pancreatic β cells, which cannot release sufficient insulin, plays a central role in T2D. Genetics plays a critical role in T2D etiology. Transcription factor GATA4 is required for the pancreatic development, and GATA4 gene mutations are implicated in neonatal or childhood-onset diabetes. In this study, we aimed to investigate whether regulatory variants in GATA4 gene may change GATA4 levels, conferring susceptibility to T2D development.

Methods: The promoter region of GATA4 gene was analyzed by targeted sequencing in T2D patients (n = 255) and ethnic-matched controls (n = 371). Dual luciferase activity assay was used for functional study, and EMSA (electrophoretic mobility shift assay) was performed for detecting transcription factor binding.

Results: Thirteen regulatory variants including 5 SNPs were identified. A novel heterozygous variant (32124C > T) and one SNP [31487C > G (rs1053351749)] were only identified in T2D. Both regulatory variants significantly affected GATA4 gene promoter activity in cultured HEK-293 and INS-1 cells. Furthermore, the variant (32124C > T) evidently enhanced the binding of unknown transcriptional activator.

Conclusions: Our data suggested that GATA4 gene regulatory variants may contribute to T2D development as a rare risk factor.
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April 2021

Competitive endogenous network of lncRNA, miRNA, and mRNA in the chemoresistance of gastrointestinal tract adenocarcinomas.

Biomed Pharmacother 2020 Oct 4;130:110570. Epub 2020 Aug 4.

Laboratory of Medical Genetics, Harbin Medical University, Harbin 150001, PR China; Key laboratory of preservation of human genetic resources and disease control in China, Harbin Medical University, Ministry of Education, PR China. Electronic address:

Chemotherapy is one of the main therapeutic strategies used for gastrointestinal tract adenocarcinomas (GTAs), but resistance to anticancer drugs is a substantial obstacle in successful chemotherapy. Accumulating evidence shows that non-coding RNAs, especially long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), can affect the drug resistance of tumor cells by forming a ceRNA regulatory network with mRNAs. The efficiency of the competing endogenous RNAs (ceRNAs) network can be affected by the number and integrality of miRNA recognition elements (MREs). Dynamic factors such as RNA editing, alternative splicing, single nucleotide polymorphism (SNP), RNA-binding proteins and RNA secondary structure can influence the MRE activity, which may in turn be involved in the regulation of chemoresistance-associated ceRNA network by prospective approaches. Besides activities in a single tumor cell, the components of the tumor micoenvironment (TME) also affect the ceRNA network by regulating the expression of non-coding RNA directly or indirectly. The alternation of the ceRNA network often has an impact on the malignant phenotype of tumor including chemoresistance. In this review, we focused on how MRE-associated dynamic factors and components of TME affected the ceRNA network and speculated the potential association of ceRNA network with chemoresistance. We also summarized the ceRNA network of lncRNAs, miRNAs, and mRNAs which efficiently triggers chemoresistance in the specific types of GTAs and analyzed the role of each RNA as a "promoter" or "suppressor" of chemoresistance.
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October 2020

Inhibiting homologous recombination decreases extrachromosomal amplification but has no effect on intrachromosomal amplification in methotrexate-resistant colon cancer cells.

Int J Cancer 2019 03 29;144(5):1037-1048. Epub 2018 Sep 29.

Laboratory of Medical Genetics, Harbin Medical University, Harbin, 150081, China.

Gene amplification, which involves the two major topographical structures double minutes (DMs) and homegeneously stained region (HSR), is a common mechanism of treatment resistance in cancer and is initiated by DNA double-strand breaks. NHEJ, one of DSB repair pathways, is involved in gene amplification as we demonstrated previously. However, the involvement of homologous recombination, another DSB repair pathway, in gene amplification remains to be explored. To better understand the association between HR and gene amplification, we detected HR activity in DM- and HSR-containing MTX-resistant HT-29 colon cancer cells. In DM-containing MTX-resistant cells, we found increased homologous recombination activity compared with that in MTX-sensitive cells. Therefore, we suppressed HR activity by silencing BRCA1, the key player in the HR pathway. The attenuation of HR activity decreased the numbers of DMs and DM-form amplified gene copies and increased the exclusion of micronuclei and nuclear buds that contained DM-form amplification; these changes were accompanied by cell cycle acceleration and increased MTX sensitivity. In contrast, BRCA1 silencing did not influence the number of amplified genes and MTX sensitivity in HSR-containing MTX-resistant cells. In conclusion, our results suggest that the HR pathway plays different roles in extrachromosomal and intrachromosomal gene amplification and may be a new target to improve chemotherapeutic outcome by decreasing extrachromosomal amplification in cancer.
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March 2019

Novel role for non-homologous end joining in the formation of double minutes in methotrexate-resistant colon cancer cells.

J Med Genet 2015 Feb 23;52(2):135-44. Epub 2014 Dec 23.

Laboratory of Medical Genetics, Harbin Medical University, Harbin, China Key Laboratory of Medical Genetics (Harbin Medical University), Heilongjiang Higher Education Institutions, Harbin, China.

Background: Gene amplification is a frequent manifestation of genomic instability that plays a role in tumour progression and development of drug resistance. It is manifested cytogenetically as extrachromosomal double minutes (DMs) or intrachromosomal homogeneously staining regions (HSRs). To better understand the molecular mechanism by which HSRs and DMs are formed and how they relate to the development of methotrexate (MTX) resistance, we used two model systems of MTX-resistant HT-29 colon cancer cell lines harbouring amplified DHFR primarily in (i) HSRs and (ii) DMs.

Results: In DM-containing cells, we found increased expression of non-homologous end joining (NHEJ) proteins. Depletion or inhibition of DNA-PKcs, a key NHEJ protein, caused decreased DHFR amplification, disappearance of DMs, increased formation of micronuclei or nuclear buds, which correlated with the elimination of DHFR, and increased sensitivity to MTX. These findings indicate for the first time that NHEJ plays a specific role in DM formation, and that increased MTX sensitivity of DM-containing cells depleted of DNA-PKcs results from DHFR elimination. Conversely, in HSR-containing cells, we found no significant change in the expression of NHEJ proteins. Depletion of DNA-PKcs had no effect on DHFR amplification and resulted in only a modest increase in sensitivity to MTX. Interestingly, both DM-containing and HSR-containing cells exhibited decreased proliferation upon DNA-PKcs depletion.

Conclusions: We demonstrate a novel specific role for NHEJ in the formation of DMs, but not HSRs, in MTX-resistant cells, and that NHEJ may be targeted for the treatment of MTX-resistant colon cancer.
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February 2015