Focal adhesion kinase regulates syndecan-2-mediated tumorigenic activity of HT1080 fibrosarcoma cells

박혜인 American Association Cancer Research 2005 Cancer Research Vol.65 No.21

Association between Alcohol Consumption and Survival in Colorectal Cancer: A Meta-analysis

Kim, Youngyo,Je, Youjin,Giovannucci, Edward L. American Association for Cancer Research 2019 Cancer Epidemiology, Biomarkers & Prevention Vol.28 No.11

<P><B>Background:</B></P><P>Although an association between alcohol consumption and risk of colorectal cancer is well established, little is known about the association between alcohol consumption and colorectal cancer survival. We conducted a meta-analysis of prospective cohort studies to quantitatively assess this association.</P><P><B>Methods:</B></P><P>Data searches were performed using PubMed and ISI Web of Science databases through December 2018. We estimated pooled RRs with 95% confidence intervals (CI) using random-effects models.</P><P><B>Results:</B></P><P>Twelve studies with 32,846 patients with colorectal cancer were included in the meta-analysis. Compared with no alcohol consumption, light (RR = 0.87; 95% CI, 0.81–0.94) and moderate (RR = 0.92; 95% CI, 0.85–1.00) prediagnostic alcohol consumption were associated with lower risk of all-cause mortality. Light prediagnostic alcohol consumption was associated with lower risk of colorectal cancer–specific mortality (RR = 0.87; 95% CI, 0.78–0.98). However, heavy prediagnostic alcohol consumption was not significantly associated with colorectal cancer survival. In a dose–response analysis, a nonlinear association between prediagnostic alcohol consumption and all-cause mortality was observed (<I>P</I><SUB>nonlinearity</SUB> = 0.0025), showing the reduction in RR at <30 g/day of alcohol consumption. By type of alcohol, wine consumption was associated with lower risk of mortality from all-causes and colorectal cancer, but a positive association was observed between moderate liquor consumption and all-cause mortality. There was no association between postdiagnostic alcohol consumption and colorectal cancer survival.</P><P><B>Conclusions:</B></P><P>Light and moderate prediagnostic alcohol consumption were associated with better survival in colorectal cancer.</P><P><B>Impact:</B></P><P>Our findings suggest that light and moderate alcohol consumption may be associated with better survival in colorectal cancer, but further studies are warranted.</P>

Isoflavones from phytoestrogens and gastric cancer risk: a nested case-control study within the Korean Multicenter Cancer Cohort.

Ko, Kwang-Pil,Park, Sue K,Park, Boyoung,Yang, Jae Jeong,Cho, Lisa Y,Kang, Chungwon,Kim, Cheong Sik,Gwack, Jin,Shin, Aesun,Kim, Yeonju,Kim, Jeongseon,Yang, Han-Kwang,Kang, Daehee,Chang, Soung-Hoon,Shin American Association for Cancer Research 2010 Cancer Epidemiology, Biomarkers & Prevention Vol.19 No.5

<P>BACKGROUND: The role of soybean products in gastric cancer risk is not clear in epidemiologic studies due to measurement error from dietary intake questionnaires and due to different degrees of bias according to study design. To examine the association between soybean products and gastric cancer risk, we measured phytoestrogen biological markers in a nested case-control study. METHODS: The study population was composed of 131 cases and 393 matched controls within the Korean Multicenter Cancer Cohort. The concentrations of the four biomarkers in the plasma samples were measured using time-resolved fluoroimmunoassay. Conditional and unconditional logistic regression models were used to compute the odds ratio (OR) and 95% confidence intervals (CI). RESULTS: Median plasma concentrations of genistein (229 nmol/L for controls, 181.8 nmol/L for cases; P=0.07) and daidzein (131.2 nmol/L for controls, 80.5 nmol/L for cases; P=0.04) in cases were lower than in controls, whereas equol concentrations were similar. Compared with the reference group, gastric cancer risk decreased in the highest groups for genistein (OR, 0.54; 95% CI, 0.31-0.93) and daidzein (OR, 0.21; 95% CI, 0.08-0.58). Higher equol concentrations were associated with a decreased risk for gastric cancer (OR, 0.50; 95% CI, 0.27-0.90). The combination of the highest concentrations for each isoflavone category was associated with a 0.09-fold decreased risk for gastric cancer compared with the combination of the lowest concentrations for each category. There was no association between plasma lignan concentrations and gastric cancer. CONCLUSIONS: High serum concentrations of isoflavones were associated with a decreased risk for gastric cancer. IMPACT: These results suggest a beneficial effect of high soybean product intake for gastric cancer risk.</P>

Serum high-density lipoprotein cholesterol and breast cancer risk by menopausal status, body mass index, and hormonal receptor in Korea.

Kim, Yeonju,Park, Sue K,Han, Wonshik,Kim, Dong-Hyun,Hong, Yun-Chul,Ha, Eun Hee,Ahn, Sei-Hyun,Noh, Dong-Young,Kang, Daehee,Yoo, Keun-Young American Association for Cancer Research 2009 Cancer Epidemiology, Biomarkers & Prevention Vol.18 No.2

<P>High-density lipoprotein cholesterol (HDL-C) has been suggested to be associated with breast cancer. However, the roles of HDL-C and hypertriglyceridemia on breast cancer still have been controversial. The goal of this study was to investigate the association between HDL-C with breast cancer risk, stratifying by menopausal status, and body mass index. The hormonal receptor status of breast has been proposed to modify the effect of HDL-C on breast cancer. Multicenter hospital-based case-control study was conducted from November 2004 to December 2005 in Korea. After one to two individual matchings by age (+/-5 years) and menopausal status, 690 cases and 1,380 controls were included in the analysis. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by conditional, unconditional, and multinomial logistic regressions. Protective effect of HDL-C on breast cancer was only observed among premenopausal women with an OR (95% CI) of 0.49 (0.33-0.72) for HDL-C > or = 60 versus <50 mg/dL (P(trend) < 0.01). Only nonobese premenopausal women had a significant decreased risk (OR, 0.34; 95% CI, 0.22-0.53). OR (95% CI) of low HDL-C (<50 mg/dL) and high triglyceride (TG; > or = 150 mg/dL) category was 2.20 (1.32-3.67) on estrogen receptor-negative and progesterone receptor-negative breast cancer compared with high HDL-C (> or = 50 mg/dL) and low TG (<150 mg/dL) category. This study suggests that higher level of HDL-C may reduce breast cancer risk among premenopausal women. Estrogen receptor-negative and progesterone receptor-negative breast cancer was associated with dyslipidemia, which implicates that association among HDL-C, TG, and breast cancer may be modified by receptor status.</P>

An Antibody Designed to Improve Adoptive NK-Cell Therapy Inhibits Pancreatic Cancer Progression in a Murine Model

Lee, Jaemin,Kang, Tae Heung,Yoo, Wonbeak,Choi, Hyunji,Jo, Seongyea,Kong, Kyungsu,Lee, Sang-Rae,Kim, Sun-Uk,Kim, Ji-Su,Cho, Duck,Kim, Janghwan,Kim, Jeong-Yoon,Kwon, Eun-Soo,Kim, Seokho AMERICAN ASSOCIATION FOR CANCER RESEARCH 2019 CANCER IMMUNOLOGY RESEARCH Vol.7 No.2

<P>The homing of natural killer (NK) cells is often inhibited by pancreatic cancer tumors. A mesothelin-directed antibody conjugated to a cleavable NK cell—recruiting chemokine increased NK-cell infiltration of PDAC tumors, reduced tumor burden, and improved survival.</P><P>Natural killer (NK) cells are primary immune cells that target cancer cells and can be used as a therapeutic agent against pancreatic cancer. Despite the usefulness of NK cells, NK-cell therapy is limited by tumor cell inhibition of NK-cell homing to tumor sites, thereby preventing a sustained antitumor immune response. One approach to successful cancer immunotherapy is to increase trafficking of NK cells to tumor tissues. Here, we developed an antibody-based NK-cell–homing protein, named NK-cell–recruiting protein-conjugated antibody (NRP-body). The effect of NRP-body on infiltration of NK cells into primary and metastatic pancreatic cancer was evaluated <I>in vitro</I> and in murine pancreatic ductal adenocarcinoma models. The NRP-body increased NK-cell infiltration of tumors along a CXCL16 gradient (CXCL16 is cleaved from the NRP-body by furin expressed on the surface of pancreatic cancer cells). CXCL16 induced NK-cell infiltration by activating RhoA via the ERK signaling cascade. Administration of the NRP-body to pancreatic cancer model mice increased tumor tissue infiltration of transferred NK cells and reduced the tumor burden compared with that in controls. Overall survival of NRP-body–treated mice (even the metastasis models) was higher than that of mice receiving NK cells alone. In conclusion, increasing NK-cell infiltration into tumor tissues improved response to this cancer immunotherapy. The combination of an NRP-body with NK-cell therapy might be useful for treating pancreatic cancer.</P>

YAP/TAZ-Mediated Upregulation of GAB2 Leads to Increased Sensitivity to Growth Factor–Induced Activation of the PI3K Pathway

Wang, Chao,Gu, Chao,Jeong, Kang Jin,Zhang, Dong,Guo, Wei,Lu, Yiling,Ju, Zhenlin,Panupinthu, Nattapon,Yang, Ji Yeon,Gagea, Mihai (Mike),Ng, Patrick Kwok Shing,Zhang, Fan,Mills, Gordon B. American Association for Cancer Research 2017 Cancer Research Vol.77 No.7

<P>Interactions between HIPPO, YAP/TAZ, and the PI3K/AKT pathway may be therapeutically targetable, providing new approaches to treating endometrial cancers and other cancers where the HIPPO pathway is a core oncogenic driver.</P><P>The transcription regulators YAP and TAZ function as effectors of the HIPPO signaling cascade, critical for organismal development, cell growth, and cellular reprogramming, and YAP/TAZ is commonly misregulated in human cancers. The precise mechanism by which aberrant YAP/TAZ promotes tumor growth remains unclear. The HIPPO tumor suppressor pathway phosphorylates YAP and TAZ, resulting in cytosolic sequestration with subsequent degradation. Here, we report that the PI3K/AKT pathway, which is critically involved in the pathophysiology of endometrial cancer, interacts with the HIPPO pathway at multiple levels. Strikingly, coordinate knockdown of YAP and TAZ, mimicking activation of the HIPPO pathway, markedly decreased both constitutive and growth factor–induced PI3K pathway activation by decreasing levels of the GAB2 linker molecule in endometrial cancer lines. Furthermore, targeting YAP/TAZ decreased endometrial cancer tumor growth <I>in vivo</I>. In addition, YAP and TAZ total and phosphoprotein levels correlated with clinical characteristics and outcomes in endometrial cancer. Thus, YAP and TAZ, which are inhibited by the HIPPO tumor suppressor pathway, modify PI3K/AKT pathway signaling in endometrial cancer. The cross-talk between these key pathways identifies potential new biomarkers and therapeutic targets in endometrial cancer. <I>Cancer Res; 77(7); 1637–48. ©2017 AACR</I>.</P>

SPIN90 Depletion and Microtubule Acetylation Mediate Stromal Fibroblast Activation in Breast Cancer Progression

You, Eunae,Huh, Yun Hyun,Kwon, Ahreum,Kim, So Hee,Chae, In Hee,Lee, Ok-Jun,Ryu, Je-Hwang,Park, Min Ho,Kim, Ga-Eon,Lee, Ji Shin,Lee, Kun Ho,Lee, Yong-Seok,Kim, Jung-Woong,Rhee, Sangmyung,Song, Woo Keun American Association for Cancer Research 2017 Cancer Research Vol.77 No.17

<P>Disrupting expression of a determinant of microtubule acetylation may pose an effective therapeutic strategy to treat breast cancers.</P><P>Biomechanical remodeling of stroma by cancer-associated fibroblasts (CAF) in early stages of cancer is critical for cancer progression, and mechanical cues such as extracellular matrix stiffness control cell differentiation and malignant progression. However, the mechanism by which CAF activation occurs in low stiffness stroma in early stages of cancer is unclear. Here, we investigated the molecular mechanism underlying CAF regulation by SPIN90 and microtubule acetylation under conditions of mechanically soft matrices corresponding to normal stromal rigidity. SPIN90 was downregulated in breast cancer stroma but not tumor, and this low stromal expression correlated with decreased survival in breast cancer patients. <I>Spin90</I> deficiency facilitated recruitment of mDia2 and APC complex to microtubules, resulting in increased microtubule acetylation. This increased acetylation promoted nuclear localization of YAP, which upregulated expression of myofibroblast marker genes on soft matrices. <I>Spin90</I> depletion enhanced tumor progression, and blockade of microtubule acetylation in CAF significantly inhibited tumor growth in mice. Together, our data demonstrate that loss of SPIN90-mediated microtubule acetylation is a key step in CAF activation in low stiffness stroma. Moreover, correlation among these factors in human breast cancer tissue supports the clinical relevance of SPIN90 and microtubule acetylation in tumor development. <I>Cancer Res; 77(17); 4710–22. ©2017 AACR</I>.</P>

Association of Smoking History with Cancer Recurrence and Survival in Stage III–IV Male Gastric Cancer Patients

Han, Mi Ah,Kim, Young-Woo,Choi, Il Ju,Oh, Myueng Guen,Kim, Chan Gyoo,Lee, Jong Yeul,Cho, Soo-Jeong,Eom, Bang Wool,Yoon, Hong Man,Ryu, Keun Won American Association for Cancer Research 2013 Cancer epidemiology, biomarkers & prevention Vol.22 No.10

<P><B>Background:</B> Smoking and drinking alcohol are major risk factors for cancer development, and we investigated their effects on gastric cancer prognosis following initial resection.</P><P><B>Methods:</B> Data from male patients with stage III–IV gastric adenocarcinoma who underwent surgery between 2001 and 2006 were retrospectively reviewed. Patients were followed up until 2011. Kaplan–Meier plots and Cox proportional hazards regressions were applied for survival rates.</P><P><B>Results:</B> Among 238 patients, 151 (63.4%) smoked and 146 (61.3%) drank alcohol. Current smokers had an increased risk of cancer recurrence or death from any cause [adjusted HR (aHR), 1.94; 95% confidence interval (CI), 1.18–3.21], cancer recurrence (aHR, 1.89; 95% CI, 1.12–3.21), and overall mortality (aHR, 2.14; 95% CI, 1.23–3.73) compared with never-smokers. Patients with a lifetime cigarette smoking of <40 and ≥40 pack-years had increased cancer recurrence or death from any cause (aHR, 1.72 and 2.43, respectively; 95% CI, 1.03–2.86 and 1.38–4.30, respectively), cancer recurrence (aHR, 1.63 and 2.61, respectively; 95% CI, 0.95–2.79 and 1.43–4.77, respectively), and overall mortality (aHR, 1.92 and 2.75, respectively; 95% CI, 1.09–3.38 and 1.47–5.12, respectively) compared with never-smokers. However, drinking alcohol was not associated with postsurgery survival.</P><P><B>Conclusions:</B> Cigarette-smoking history at the time of diagnosis, but not drinking history, is associated with cancer recurrence and poor survival after surgery in male patients with stage III–IV gastric cancer.</P><P><B>Impact:</B> These findings encourage physicians to advise patients with gastric cancer to stop smoking to obtain a general health benefit and likely improvement in the gastric cancer course. <I>Cancer Epidemiol Biomarkers Prev; 22(10); 1805–12. ©2013 AACR</I>.</P>

Phospholipase D1 Inhibition Linked to Upregulation of ICAT Blocks Colorectal Cancer Growth Hyperactivated by Wnt/β-Catenin and PI3K/Akt Signaling

Kang, Dong Woo,Lee, Bo Hui,Suh, Young-Ah,Choi, Yong-Seok,Jang, Se Jin,Kim, Yong Man,Choi, Kang-Yell,Min, Do Sik American Association for Cancer Research 2017 Clinical Cancer research Vol.23 No.23

<P><B>Purpose:</B> Dysregulated expression of PLD1 has emerged as a hallmark feature of colorectal cancer, which remains a major cause of mortality worldwide. Aberrant activation of Wnt/β-catenin signaling is a critical event in the development of colorectal cancer. Here, we investigated molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways via inhibitor of β-catenin and T-cell factor (ICAT), a negative regulator of Wnt/β-catenin signaling. We also explored the effect of PLD1 inhibition on growth of colorectal cancer hyperactivated by Wnt/β-catenin and PI3K/Akt signaling.</P><P><B>Experimental Design:</B> Expression of ICAT via targeting of PLD1 was assessed <I>in vivo</I> in <I>Apc<SUP>Min/</SUP></I><SUP>+</SUP> mice, an AOM/DSS model, and <I>in vitro</I> using various colorectal cancer cells. The relationship between ICAT/PLD1 expression and prognostic survival value of 153 colorectal cancer patients was examined. The therapeutic efficacy of PLD1 inhibitor was determined using a patient-derived xenograft model carrying <I>APC</I> and <I>PI3K</I> mutations.</P><P><B>Results:</B> PLD1 promoted the Wnt/β-catenin signaling pathway by selectively downregulating ICAT via the PI3K/Akt-TopBP1-E2F1 signaling pathways. Low PLD1 expression and high ICAT expression were significantly associated with increased survival in colorectal cancer patients and vice versa. Furthermore, PLD1 inhibition suppressed growth of colorectal cancer activated by the Wnt/β-catenin and PI3K signaling pathways.</P><P><B>Conclusions:</B> These results suggest that PLD1 linked to ICAT mediates molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways and thus could be proposed as a novel colorectal cancer prognostic biomarker. These results may assist in the clinical development of a PLD1 inhibitor for treatment of colorectal cancer patients carrying <I>APC</I> and <I>PI3KCA</I> mutations. PLD1, a nodal modifier, acts as a potential therapeutic target for the treatment of colorectal cancer hyperactivated by the Wnt/β-catenin and PI3K/Akt signaling pathways. <I>Clin Cancer Res; 23(23); 7340–50. ©2017 AACR</I>.</P>

DR4-Ser424 <i>O</i>-GlcNAcylation Promotes Sensitization of TRAIL-Tolerant Persisters and TRAIL-Resistant Cancer Cells to Death

Lee, Hyeonjeong,Oh, Yumin,Jeon, Young-Jun,Lee, Song-Yi,Kim, Hyunjoo,Lee, Ho-June,Jung, Yong-Keun American Association for Cancer Research 2019 Cancer Research Vol.79 No.11

<P>This study reports that a novel posttranslational modification by O-GlcNAcylation of TRAIL-R1 (DR4) plays a crucial role in enabling both apoptotic and necroptotic cell death induction by TRAIL.</P><P><B></B></P><P>TNF-related apoptosis-inducing ligand (TRAIL) resistance, including nongenetically acquired tolerance in cancer persister cells, is a major obstacle to translating TRAIL therapy into patients with cancer. However, the underlying mechanisms remain to be elucidated. Here, we show that DR4/TRAIL-R1 is <I>O</I>-GlcNAcylated at Ser424 in its death domain to mediate both apoptosis and necrosis upon TRAIL ligation. We found that DR4–Ser424 mutations, identified from our cell-based functional screen using a cancer patient–derived cDNA expression library and from The Cancer Genome Atlas, caused TRAIL resistance in various human cancer cell lines. Using <I>O</I>-GlcNAc transferase knockdown cells, DR4-preferred versus DR5-preferred cancer cells, and a DR5-neutralizing antibody, we evaluated the essential role of DR4-specific <I>O</I>-GlcNAc modification in TRAIL cytotoxicity. In contrast to DR4, DR5 was not <I>O</I>-GlcNAcylated by TRAIL treatment, discriminating DR4 from DR5-mediated signaling. Apart from genetic changes in DR4-Ser424, we further classified various cancer cell lines originated from stomach, colon, lung, and glioblastoma according to their sensitivity to and receptor preference upon TRAIL death signaling and generated TRAIL-tolerant persister-derived DLD-1<SUP>PER</SUP> cells. Among these, we discovered that DR4 was not modified by <I>O</I>-GlcNAc in most of the TRAIL-resistant cancer cells and DLD-1<SUP>PER</SUP> cells. Interestingly, promoting DR4 <I>O</I>-GlcNAcylation intentionally using 2-deoxy-<SMALL>D</SMALL>-glucose or a high concentration of glucose sensitized those resistant cancer cells to TRAIL. The <I>O</I>-GlcNAcylation–defective DR4 failed to form DISC/necrosome and could not translocate to aggregated platforms for receptor clustering. Our findings demonstrate that DR4 <I>O</I>-GlcNAcylation is crucial for TRAIL death signaling, providing new opportunities for TRAIL therapy overcoming TRAIL resistance in cancers.</P><P><B>Significance:</B></P><P>This study reports that a novel posttranslational modification by <I>O</I>-GlcNAcylation of one of the two human TRAIL receptors with a death domain, TRAIL-R1 (DR4), plays a crucial role in enabling both apoptotic and necroptotic cell death induction by TRAIL.</P>