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Gu, Mancang

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Mancang

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Gu, Mancang
Author's Publications: search.filters.isAuthorOfPublication.8697ddb1-c5aa-44ee-889f-4d2553391c71

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    Fusobacterium nucleatum in Colorectal Carcinoma Tissue According to Tumor Location
    (Nature Publishing Group, 2016) Mima, Kosuke; Cao, Yin; Chan, Andrew; Qian, Zhi Rong; Nowak, Jonathan; Masugi, Yohei; Shi, Yan; Song, Mingyang; da Silva, Annacarolina; Gu, Mancang; Li, Wanwan; Hamada, Tsuyoshi; Kosumi, Keisuke; Hanyuda, Akiko; Liu, Li; Kostic, Aleksandar; Giannakis, Marios; Bullman, Susan; Brennan, Caitlin; Milner, Danny; Baba, Hideo; Garraway, Levi; Meyerhardt, Jeffrey; Garrett, Wendy; Huttenhower, Curtis; Meyerson, Matthew; Giovannucci, Edward; Fuchs, Charles; Nakashima, Reiko; Ogino, Shuji
    Objectives: Evidence suggests a possible role of Fusobacterium nucleatum in colorectal carcinogenesis, especially in right-sided proximal colorectum. Considering a change in bowel contents and microbiome from proximal to distal colorectal segments, we hypothesized that the proportion of colorectal carcinoma enriched with F. nucleatum might gradually increase along the bowel subsites from rectum to cecum. Methods: A retrospective, cross-sectional analysis was conducted on 1,102 colon and rectal carcinomas in molecular pathological epidemiology databases of the Nurses’ Health Study and the Health Professionals Follow-up Study. We measured the amount of F. nucleatum DNA in colorectal tumor tissue using a quantitative PCR assay and equally dichotomized F. nucleatum-positive cases (high vs. low). We used multivariable logistic regression analysis to examine the relationship of a bowel subsite variable (rectum, rectosigmoid junction, sigmoid colon, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon, and cecum) with the amount of F. nucleatum. Results: The proportion of F. nucleatum-high colorectal cancers gradually increased from rectal cancers (2.5% 4/157) to cecal cancers (11% 19/178), with a statistically significant linear trend along all subsites (P<0.0001) and little evidence of non-linearity. The proportion of F. nucleatum-low cancers was higher in rectal, ascending colon, and cecal cancers than in cancers of middle segments. Conclusions: The proportion of F. nucleatum-high colorectal cancers gradually increases from rectum to cecum. Our data support the colorectal continuum model that reflects pathogenic influences of the gut microbiota on neoplastic and immune cells and challenges the prevailing two-colon (proximal vs. distal) dichotomy paradigm.
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    Tumor LINE-1 methylation level and colorectal cancer location in relation to patient survival
    (Impact Journals LLC, 2016) Mima, Kosuke; Nowak, Jonathan; Qian, Zhi Rong; Cao, Yin; Song, Mingyang; Masugi, Yohei; Shi, Yan; da Silva, Annacarolina; Gu, Mancang; Li, Wanwan; Hamada, Tsuyoshi; Zhang, Xuehong; Wu, Kana; Meyerhardt, Jeffrey; Baba, Hideo; Giovannucci, Edward; Chan, Andrew; Fuchs, Charles; Ogino, Shuji; Nakashima, Reiko
    Colorectal tumors arise with genomic and epigenomic alterations through interactions between neoplastic cells, immune cells, and microbiota that vary along the proximal to distal axis of colorectum. Long interspersed nucleotide element-1 (LINE-1) hypomethylation in colorectal cancer has been associated with worse clinical outcome. Utilizing 1,317 colon and rectal carcinoma cases in two U.S.-nationwide prospective cohort studies, we examined patient survival according to LINE-1 methylation level stratified by tumor location. Cox proportional hazards model was used to assess a statistical interaction between LINE-1 methylation level and tumor location in colorectal cancer-specific mortality analysis, controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, and KRAS, BRAF, and PIK3CA mutations. A statistically significant interaction was found between LINE-1 methylation level and tumor location in colorectal cancer-specific mortality analysis (Pinteraction = 0.011). The association of LINE-1 hypomethylation with higher colorectal cancer-specific mortality was stronger in proximal colon cancers (multivariable hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.21 to 2.28) than in distal colon cancers (multivariable HR, 1.18; 95% CI, 0.81 to 1.72) or rectal cancers (multivariable HR, 0.87; 95% CI, 0.57 to 1.34). Our data suggest the interactive effect of LINE-1 methylation level and colorectal cancer location on clinical outcome.
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    Aspirin exerts high anti-cancer activity in PIK3CA-mutant colon cancer cells
    (Impact Journals LLC, 2017) Gu, Mancang; Nakashima, Reiko; Chen, Yang; Li, Wanwan; Shi, Yan; Masugi, Yohei; Hamada, Tsuyoshi; Kosumi, Keisuke; Liu, Li; da Silva, Annacarolina; Nowak, Jonathan; Twombly, Tyler; Du, Chunxia; Koh, Hideo; Li, Wenbin; Meyerhardt, Jeffrey; Wolpin, Brian M.; Giannakis, Marios; Aguirre, Andrew; Bass, Adam; Drew, David; Chan, Andrew; Fuchs, Charles S.; Qian, Zhi Rong; Ogino, Shuji
    Evidence suggests that nonsteroidal anti-inflammatory drug aspirin (acetylsalicylic acid) may improve patient survival in PIK3CA-mutant colorectal carcinoma, but not in PIK3CA-wild-type carcinoma. However, whether aspirin directly influences the viability of PIK3CA-mutant colon cancer cells is poorly understood. We conducted in vitro experiments to test our hypothesis that the anti-proliferative activity of aspirin might be stronger for PIK3CA-mutant colon cancer cells than for PIK3CA-wild-type colon cancer cells. We measured the anti-proliferative effect of aspirin at physiologic concentrations in seven PIK3CA-mutant and six PIK3CA-wild-type human colon cancer cell lines. After exposure to aspirin, the apoptotic index and cell cycle phase of colon cancer cells were assessed. In addition, the effect of aspirin was examined in parental SW48 cells and SW48 cell clones with individual knock-in PIK3CA mutations of either c.3140A>G (p.H1047R) or c.1633G>A (p.E545K). Aspirin induced greater dose-dependent loss of cell viability in PIK3CA-mutant cells than in PIK3CA-wild-type cells after treatment for 48 and 72 hours. Aspirin treatment also led to higher proportions of apoptotic cells and G0/G1 phase arrest in PIK3CA-mutant cells than in PIK3CA-wild-type cells. Aspirin treatment of isogenic SW48 cells carrying a PIK3CA mutation, either c.3140A>G (p.H1047R) or c.1633G>A (p. E545K), resulted in a more significant loss of cell viability compared to wild-type controls. Our findings indicate that aspirin causes cell cycle arrest, induces apoptosis, and leads to loss of cell viability more profoundly in PIK3CA-mutated colon cancer cells than in PIK3CA-wild-type colon cancer cells. These findings support the use of aspirin to treat patients with PIK3CA-mutant colon cancer.