Association of MTHFR gene polymorphisms with non-Hodgkin lymphoma risk: Evidence from 31 articles.

Background: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms, particularly C677T and A1298C, have been implicated in various cancers, including non-Hodgkin lymphoma (NHL); however, their association with NHL risk remains inconclusive. Methods: We conducted an updated meta-analysis to assess the relationship between MTHFR gene polymorphisms (C677T and A1298C) and NHL risk. Relevant studies were identified through systematic literature searches in multiple databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Results: The meta-analysis included 32 studies (8222 cases vs. 12956 controls) for MTHFR C677T and 26 studies (6930 cases vs. 11611 controls) for the A1298C polymorphism. Our meta-analysis revealed no significant associations between MTHFR gene polymorphisms (C677T and A1298C) and NHL risk. However, subgroup analysis stratified by ethnicity and NHL subtype yielded interesting findings for the C677T polymorphism. Specifically, in the subgroup analysis of Caucasians, the C677T polymorphism was significantly associated with NHL risk (heterozygous: OR=1.16, 95% CI=1.02-1.32; allele comparison: OR=1.07, 95% CI=1.01-1.13). Furthermore, in the analysis stratified by NHL subtype, the C677T polymorphism was significantly associated with increased follicular lymphoma (FL) risk (homozygous: OR=1.25, 95% CI=1.02-1.53; recessive: OR=1.28, 95% CI=1.06-1.56). False-positive result possibility (FPRP) analysis verified that the association of the MTHFR C677T polymorphism with NHL risk for Caucasians and FL subtypes was a true positive and deserves attention. We also determined that the C677T polymorphism is an expression quantitative trait locus (eQTL) since it is associated with MTHFR gene expression. Conclusion: There was no overall association between MTHFR gene polymorphisms (C677T and A1298C) and NHL risk, but stratified analyses revealed significant associations in specific subgroups. While meta-analyses inherently build upon existing studies, our work distinguishes itself by incorporating recent data, applying rigorous analytical techniques, and providing more evidence of the MTHFR C677T polymorphism as an eQTL.

NCAPD3 enhances Warburg effect through c-myc and E2F1 and promotes the occurrence and progression of colorectal cancer.

BACKGROUND: NCAPD3 is one of the three non-SMC subunits of condensin II complex, which plays an important role in the chromosome condensation and segregation during mitosis. Notably, elevated levels of NCAPD3 are found in many somatic cancers. However, the clinical role, biological functions of NCAPD3 in cancers especially in colorectal cancer (CRC) and the underlying molecular mechanisms remain poorly elucidated. METHODS: Clinical CRC and adjacent normal tissues were used to confirm the expression of NCAPD3. The association of NCAPD3 expression with clinicopathological characteristics and patient outcomes were analyzed by using online database. In vivo subcutaneous tumor xenograft model, NCAPD3 gene knockout following azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced tumor mouse model, Co-IP, western blot, qRT-PCR, IHC, ChIP assays and cell functional assays were used to investigate the biological functions of NCAPD3 in CRC and the underlying molecular mechanisms. RESULTS: NCAPD3 was overexpressed in CRC tissues and positively correlated with poor prognosis of CRC patients. NCAPD3 knockout suppressed CRC development in AOM/DSS induced and xenograft mice models. Moreover, we found that NCAPD3 promoted aerobic glycolysis in CRC. Mechanistically, NCAPD3 up-regulated the level of c-Myc and interacted with c-Myc to recruit more c-Myc to the gene promoter of its downstream glycolytic regulators GLUT1, HK2, ENO1, PKM2 and LDHA, and finally enhanced cellular aerobic glycolysis. Also, NCAPD3 increased the level of E2F1 and interacted with E2F1 to recruit more E2F1 to the promoter regions of PDK1 and PDK3 genes, which resulted in the inhibition of PDH activity and TCA cycle. CONCLUSIONS: Our data demonstrated that NCAPD3 promoted glucose metabolism reprogramming and enhanced Warburg effect in colorectal tumorigenesis and CRC progression. These findings reveal a novel mechanism underlying NCAPD3 mediated CRC cell growth and provide new targets for CRC treatment.

NCAPD3 promotes prostate cancer progression by up-regulating EZH2 and MALAT1 through STAT3 and E2F1.

NCAPD3 is one of the non-SMC regulatory subunits of Condensin II, which is mainly responsible for the condensation and segregation of chromosomes during mitosis. However, its role in cancer especially in prostate cancer (PCa) and the molecular mechanism have not been clearly elucidated. Here, we find that NCAPD3 is high-expression and up-regulates the levels of EZH2 and MALAT1 in PCa. In detail, high expression of NCAPD3 increases the levels of transcription factor STAT3 and E2F1 and recruits more STAT3 and E2F1 to the promoter of EZH2 gene and more STAT3 to the promoter of MALAT1 gene, and then results in the increasing expression of both EZH2 and MALAT1 in PCa cells. In vitro and in vivo functional characterization reveals that overexpression of NCAPD3 enhances the growth of PCa cells, while knockdown of NCAPD3 impairs the growth of PCa cells. Together, our data demonstrate that NCAPD3 is a tumor-promoting factor which enhances the progression of PCa by up-regulating EZH2 and MALAT1.

NCAPD2 inhibits autophagy by regulating Ca2+/CAMKK2/AMPK/mTORC1 pathway and PARP-1/SIRT1 axis to promote colorectal cancer.

Non-SMC condensin I complex subunit D2 (NCAPD2) is one of the three non-SMC subunits in condensin I. Previous studies have shown that NCAPD2 plays an important role in the chromosome condensation and segregation. However, its role in the development of colorectal cancer (CRC) and specific molecular mechanisms still need to be further studied. Here we show that NCAPD2 inhibits autophagy and blocks autophagic flux via Ca2+/CAMKK/AMPK/mTORC1 pathway and PARP-1/SIRT1 axis. NCAPD2 acts as a tumor promoter both in vitro and in vivo. NCAPD2 knockout suppresses colorectal cancer development in AOM/DSS induced mice model. Therefore, our findings support a role for NCAPD2 in autophagy to promote CRC development and highlight NCAPD2 as a potential target for CRC therapy.

Berberine activates caspase-9/cytochrome c-mediated apoptosis to suppress triple-negative breast cancer cells in vitro and in vivo.

Berberine (BBR) is an isoquinoline alkaloid isolated from Cotridis rhizoma and exhibits multiple biological roles including anti-microbe, anti-inflammation and anti-tumor activities. In this study, two triple-negative breast cancer cell (TNBC) lines, MDA-MB-231 and BT549, were used to investigate the effect of BBR on growth of TNBC in vitro and in vivo. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the viability of cells treated with BBR. After 48h treatments, a 50% inhibitory concentration (IC50) of BBR to BT549 and MDA-MB-231 cells are at 16.575±1.219µg/ml and 18.525±6.139µg/ml respectively. BBR reduced colony formation of BT549 and MDA-MB-231 cells. The wound-healing assay showed BBR decreased breast cancer cell migrations (P<0.01). AnnexinV-PI staining assay confirmed BBR induced cellular apoptosis. The expressions of caspase-3, caspase-9, Bcl-2 and Bax were detected by western blot, which showed BBR activated caspase-3, 9 and Bax, but down-regulated Bcl-2 expression. BBR promoted the release of cytochrome c through the immunofluorescent analysis (P<0.01). We also found BBR increased the level of cellular γH2AX and increased the expression of Ligase4, which suggests BBR induces the double-strand breaks (DSB). These results thus demonstrated that BBR induced DSB, subsequently increased the release of cytochrome c and eventually triggered the caspase9-dependent apoptosis. In addition, we used a MDA-MB-231 mouse-xenograftmodel to evaluate the effect of BBR on tumor growth. BBR suppressed tumor growth and increased caspase-9 levels in xenograft tumors through immunohistochemistry analysis (P<0.01). Taken together, these results demonstrate that BBR activates caspase-9/cytochrome c-mediated apoptosis to inhibit the growth of TNBC breast cancer cells in vitro and in vivo.

Berberine in combination with cisplatin suppresses breast cancer cell growth through induction of DNA breaks and caspase-3-dependent apoptosis.

Berberine (BBR) is an isoquinoline alkaloid extracted from medicinal plants such as Hydrastis canadensis, Berberis aristata and Coptis chinensis. BBR displays a number of beneficial roles in the treatment of various types of cancers, yet the precise mechanisms of its action remain unclear. Cisplatin is an effective cancer chemotherapeutic agent and functions by generating DNA damage, promoting DNA damage-induced cell cycle arrest and apoptosis; however, its efficacy is challenged by the resistance of tumor cells in clinical application. The aim of the present study was to investigate the effects of BBR in combination with cisplatin on human breast cancer cells. MTT assay showed that BBR inhibited breast cancer MCF-7 cell growth with a 50% inhibitory concentration (IC50) value of 52.178±1.593 µM and the IC50 value of cisplatin was 49.541±1.618 µM, while in combination with 26 µM BBR, the IC50 value of cisplatin was 5.759±0.76 µM. BBR sensitized the MCF-7 cells to cisplatin in a time- and dose-dependent manner. After treatment of BBR and cisplatin, the cellular pro-apoptotic capase-3 and cleaved capspase-3 and caspase-9 were upregulated and the anti-apoptotic Bcl-2 was downregulated. Importantly, BBR restrained the expression of cellular PCNA, and immunofluoresence analysis of γH2AX showed that BBR increased the DNA damages induced by cisplatin. Taken together, the results demonstrated that BBR sensitized MCF-7 cells to cisplatin through induction of DNA breaks and caspase-3-dependent apoptosis.