Hyog Young Kwon

The Critical Roles of Zinc: Beyond Impact on Myocardial Signaling.

Zinc has been considered as a vital constituent of proteins, including enzymes. Mobile reactive zinc (Zn2+) is the key form of zinc involved in signal transductions, which are mainly driven by its binding to proteins or the release of zinc from proteins, possibly via a redox switch. There has been growing evidence of zincs critical role in cell signaling, due to its flexible coordination geometry and rapid shifts in protein conformation to perform biological reactions. The importance and complexity of Zn2+ activity has been presumed to parallel the degree of calciums participation in cellular processes. Whole body and cellular Zn2+ levels are largely regulated by metallothioneins (MTs), Zn2+ importers (ZIPs), and Zn2+ transporters (ZnTs). Numerous proteins involved in signaling pathways, mitochondrial metabolism, and ion channels that play a pivotal role in controlling cardiac contractility are common targets of Zn2+. However, these regulatory actions of Zn2+ are not limited to the function of the heart, but also extend to numerous other organ systems, such as the central nervous system, immune system, cardiovascular tissue, and secretory glands, such as the pancreas, prostate, and mammary glands. In this review, the regulation of cellular Zn2+ levels, Zn2+-mediated signal transduction, impacts of Zn2+ on ion channels and mitochondrial metabolism, and finally, the implications of Zn2+ in health and disease development were outlined to help widen the current understanding of the versatile and complex roles of Zn2+.

Fucoidan improves bioactivity and vasculogenic potential of mesenchymal stem cells in murine hind limb ischemia associated with chronic kidney disease

Chronic kidney disease (CKD) is a significant risk factor for cardiovascular and peripheral vascular disease. Although mesenchymal stem cell (MSC)-based therapy is a promising strategy for treatment of ischemic diseases associated with CKD, the associated pathophysiological conditions lead to low survival and proliferation of transplanted MSCs. To address these limitations, we investigated the effects of fucoidan, a sulfated polysaccharide, on the bioactivity of adipose tissue-derived MSCs and the potential of fucoidan-treated MSCs to improve neovascularization in ischemic tissues of CKD mice. Treatment of MSCs with fucoidan increased their proliferative potential and the expression of cell cycle-associated proteins, such as cyclin E, cyclin dependent kinase (CDK) 2, cyclin D1, and CDK4, via focal adhesion kinase and the phosphatidylinositol-4,5-bisphosphate 3-kinase-Akt axis. Moreover, fucoidan enhanced the immunomodulatory activity of MSCs through the ERK-IDO-1 signal cascade. Fucoidan was found to augment the proliferation, incorporation, and endothelial differentiation of transplanted MSCs at ischemic sites in CKD mice hind limbs. In addition, transplantation of fucoidan-treated MSCs enhanced the ratio of blood flow and limb salvage in CKD mice with hind limb ischemia. To our knowledge, our findings are the first to reveal that fucoidan enhances the bioactivity of MSCs and improves their neovascularization in ischemic injured tissues of CKD. In conclusion, fucoidan-treated MSCs may provide an important pathway toward therapeutic neovascularization in patients with CKD.

Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment

Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are suggested to be responsible for drug resistance and cancer relapse due in part to their ability to self-renew themselves and differentiate into heterogeneous lineages of cancer cells. Thus, it is important to understand the characteristics and mechanisms by which CSCs display resistance to therapeutic agents. In this review, we highlight the key features and mechanisms that regulate CSC function in drug resistance as well as recent breakthroughs of therapeutic approaches for targeting CSCs. This promises new insights of CSCs in drug resistance and provides better therapeutic rationales to accompany novel anticancer therapeutics.

Interferon-induced transmembrane protein 1 (IFITM1) is required for the progression of colorectal cancer

Interferon-induced transmembrane protein 1 (IFITM1) has been shown to be implicated in multiple cancers, yet little is known about biological significance of IFITM1 in colorectal cancer. Here, we show that IFITM1 is highly expressed in metastatic colorectal cancer cell lines as well as colorectal patient-derived tumor samples, and its expression is associated with a poor prognosis of the disease. Also, IFITM1 depletion resulted in a significant reduction in the mobility of cancer cell lines, whereas ectopic expression of IFITM1 promoted the migration of cancer cells. Epithelial-mesenchymal transition (EMT) signature was dysregulated by both loss and gain of function of IFITM1, which was partially reverted by Caveolin-1 (CAV1). Therefore, these results suggest that IFITM1 may be a prognostic marker and an attractive target to achieve better therapeutic outcomes in colorectal cancer.

Tetraspanins: Spanning from solid tumors to hematologic malignancies.

Tetraspanins (tetraspans or TM4SF) are a family of integral membrane proteins with four transmembrane helices, a small extracellular loop, and a large extracellular loop. Although tetraspanins are expressed in many types of cells, including immune cells, their biological roles are not fully defined. Nonetheless, recent studies have revealed the important roles of tetraspanins in solid tumors and hematologic malignancies, and expression of tetraspanins is associated with the malignancy of human tumors. Furthermore, genetic mouse models of tetraspanins highlight their contribution to tumorigenesis. In this review, we summarize the implication of tetraspanins in cancer with a special focus on tetraspanin 3 in myeloid leukemia. Our increasing knowledge of tetraspanins and the pathologies that alter their function will undoubtedly inform the rational design of novel cancer therapies.

Q787Q EGFR Polymorphism as a Prognostic Factor for Lung Squamous Cell Carcinoma

Objective: EGFR genetic polymorphisms have been investigated for carcinogenesis in various tumors including lung cancer. We evaluated EGFR mutations in four exons, with an emphasis on the Q787Q EGFR polymorphism in non-small-cell lung cancer. Methods: To determine the presence of the Q787Q polymorphism in patients with lung cancer, we performed direct sequencing analyses of four exons for 83 squamous cell carcinomas and 80 adenocarcinomas untreated with EGFR tyrosine kinase inhibitors. Results: The Q787Q EGFR polymorphism was more frequently detected in squamous cell carcinoma patients than in adenocarcinoma patients (24 vs. 15.9%). The group of patients with the Q787Q EGFR polymorphism included more males and heavy smokers compared with other patient groups. The presence of the Q787Q EGFR polymorphism significantly and negatively affected the overall survival rate among patients with non-small-cell carcinoma (p = 0.011), particularly those with squamous cell carcinoma (p = 0.037). Among stage I and II squamous cell carcinoma patients, those with the Q787Q EGFR polymorphism had a poor prognosis (p = 0.032). Conclusions: The Q787Q EGFR polymorphism allows stratifying lung squamous cell carcinoma patients and could be an independent prognostic marker, particularly among those in stages I and II.

RhoA is associated with invasion and poor prognosis in colorectal cancer.

Colorectal cancer is one of the most common cancers and is the fourth leading cause of cancer death in Korea. Mortality of colorectal cancer is strongly associated with the metastatic spread of the disease. As such, it is important to find and characterize signaling pathways involved in colon cancer metastasis. We investigated the functional importance of RhoA using human cell lines as well as 150 colorectal cancer patient-derived samples as it remains unclear whether RhoA functions as either an oncogene or a tumor suppressor in colon cancer. RhoA was highly expressed in metastatic cancer cell lines. Although cancer cell proliferation was only moderately impaired after depletion of RhoA, RhoA-depleted cancer cells exhibited markedly reduced migration and invasion ability in vitro. Furthermore, we found that RhoA is associated with the invasion of lymph nodes and blood vessels in the patient colorectal cancer samples. Most notably, patients with higher RhoA expression had a significantly poorer 5-year survival rate after surgery. These results suggest that RhoA is a marker of poor prognosis in colorectal cancer and may be a promising target for cancer treatment.

Karyopherin α-2 is a reliable marker for identification of patients with high-risk stage II colorectal cancer

PurposeAdjuvant chemotherapy (AC) is frequently considered in patients with high-risk stage II colorectal cancer (CRC). Among patients with stage II CRC who do not receive AC because they are not considered to be at high risk, 20–25% will develop recurrence and die from the disease. Elevated levels of KPNA2 have been observed in various cancers, and overexpression of KPNA2 is related to CRC progression.MethodsWe examined the expression of KPNA2 using 293 CRC tissues, including 118 with stage II CRC, and investigated the applicability of KPNA2 as a biomarker to predict high-risk stage II CRC. Moreover, we further investigated the role of KPNA2 as an oncogene in CRC carcinogenesis using in vitro functional studies.ResultsHigh KPNA2 expression was associated with vascular (pxa0=xa00.027) and lymphatic invasion (pxa0=xa00.009) in patients with stage II CRC. On multivariate analysis, high KPNA2 expression (HR 3.174, 95% CI 2.060–4.889; pxa0<xa00.001) was independently associated with survival in patients with CRC. The overall survival rate in patients with high KPNA2 expression was higher than that in patients with low KPNA2 expression in CRC (pxa0<xa00.001), even in patients with stage II CRC (pxa0=xa00.001). Additionally, KPNA2 was associated with tumorigenesis and cancer progression in CRC cells; high KPNA2 expression was associated with increased cell proliferation (pxa0<xa00.05), migration (pxa0=xa00.03), invasion (pxa0=xa00.001), and semisolid agar colony formation (pxa0<xa00.001).ConclusionKPNA2 expression is useful for identification of patients with high-risk stage II CRC who could benefit from AC and that KPNA2 may also be a promising therapeutic target.

Protein kinase, membrane‑associated tyrosine/threonine 1 is associated with the progression of colorectal cancer

The protein kinase, membrane‑associated tyrosine/threoninexa01 (PKMYT1) is known to inhibit precocious entry into mitosis by phosphorylating CDK1 at Thr14 and Tyr15 residues. However, the functional importance of PKMYT1 in colorectal cancer (CRC) remains unknown. Thus, it is important to elucidate whether PKYMT1 is indispensable in the tumorigenesis of CRC. To investigate the functional importance of PKMYT1 in CRC tumorigenesis, PKMYT1 was knocked down in CRC cell lines such as SW480, SW620, HCT116 and HT29 by siRNA. PKMYT1‑depleted CRC cells were analyzed to determine proliferation, migration, invasion and colony forming ability. In addition, 179xa0patient‑derived samples were used to find the correlation of the expression of PKMYT1 with the prognosis of CRC patients. By siRNA‑mediated loss of function of PKMYT1, we observed that proliferation, migration, invasion and colony forming ability of CRC cell lines were significantly impaired in the absence of PKMYT1 inxa0vitro. Furthermore, by analyzing patient‑derived samples, we revealed the association of PKMYT1 with the overall survival rate of CRC patients. These results indicated that PKMYT1 plays an essential oncogenic role in CRC and could serve as a good therapeutic target for the treatment of CRC.

Melatonin and 5-fluorouracil co-suppress colon cancer stem cells by regulating cellular prion protein-Oct4 axis

Melatonin suppresses tumor development. However, the exact relationship between melatonin and cancer stem cells (CSCs) is poorly understood. This study found that melatonin inhibits colon CSCs by regulating the PrPC‐Oct4 axis. In specimens from patients with colorectal cancer, the expressions of cellular prion protein (PrPC) and Oct4 were significantly correlated with metastasis and tumor stages. Co‐treatment with 5‐fluorouracil (5‐FU) and melatonin inhibited the stem cell markers Oct4, Nanog, Sox2, and ALDH1A1 by downregulating PrPC. In this way, tumor growth, proliferation, and tumor‐mediated angiogenesis were suppressed. In colorectal CSCs, PRNP overexpression protects Oct4 against inhibition by 5‐FU and melatonin. In contrast, Nanog, Sox2, and ALDH1A1 have no such protection. These results indicate that PrPC directly regulates Oct4, whereas it indirectly regulates Nanog, Sox2, and ALDH1A1. Taken together, our findings suggest that co‐treatment with anticancer drug and melatonin is a potential therapy for colorectal cancer. Furthermore, PrPC maintains cancer stemness during tumor progression. Therefore, targeting the PrPC‐Oct4 axis may prove instrumental in colorectal cancer therapy.