The joint effects of arsenic and risk diplotypes of insulin-like growth factor binding protein-3 in renal cell carcinoma
Introduction
In 2011, kidney cancer was ranked as the 14th leading cause of cancer mortality in Taiwan in both males and females. Specifically, 644 males and 310 females were diagnosed with renal cell carcinoma (RCC), which accounted for 1.03% of all cancer patients, with a male-to-female ratio of 2.1:1 (Ministry of Health and Welfare (2014)). Arsenic is considered one of the most significant environmental hazards, and previous studies have demonstrated that arsenic may increase the risk of many cancers, including kidney cancer, in either high-arsenic or low-arsenic exposure areas (Chen et al., 1985, Huang et al., 2011a, Yuan et al., 2010). Our recent study, which demonstrated that high total levels of urinary arsenic and low estimated glomerular filtration rates was correlated with RCC in areas with low arsenic exposure (Huang et al., 2011a), we also found that P53 codon 72 Arg/Pro + Pro/Pro genotype and MDM2 309 TG + GG genotype may modify arsenic-related RCC risk (Huang et al., 2012). In addition, high levels of 8-OHdG combined with total urinary arsenic might be indicative of arsenic-associated RCC, even in a low arsenic exposure areas (Huang et al., 2011b). However, the mechanism underlying arsenic-associated RCC remains unclear.
A Korean study has reported an inverse association of urinary total arsenic concentration with the insulin secretion index HOMA2%B, leading to beta cell dysfunction and increased risk of diabetes mellitus (DM) (Rhee et al., 2013). A recent study of ours also found that the HOMA-IR value was significantly and positively related to urinary total arsenic concentrations (Lin et al., 2014). Another study has found that inorganic arsenic or trivalent methylated metabolites of inorganic arsenic exposure acted to inhibit glucose stimulated insulin secretion (Douillet et al., 2013). These results suggest that the inhibited glucose stimulated insulin secretion of inorganic arsenic exposure may be the key mechanism of inorganic arsenic-induced DM.
DM and obesity are proven risk factors for RCC, and the possible mechanism is associated with insulin resistance and hyperinsulinemia (Bonora et al., 2002, Young-Hyman et al., 2001). A recent study indicated that DM is independently associated with an increased risk of mortality among clear cell RCC (ccRCC) patients (Psutka et al., 2014). Another study showed that optimal DM and hyperlipidemia pharmacotherapy could reduce RCC risk (Rabey et al., 2014), and that DM may be an important determinant of ccRCC prognosis, especially in patients experiencing recurrence (Ha et al., 2013). These studies indicate that DM is related to the risk and prognosis of RCC. In contrast, alcohol consumption is a protective factor against RCC, possibly because moderate alcohol consumption may increase insulin sensitivity (Ley et al., 2014). It remains unclear as to whether the combined effect of arsenic exposure, alcohol consumption, and DM status affects the insulin signaling pathway and induces RCC.
Tissue responsiveness to insulin requires the insulin receptor substrate (IRS) (Dong et al., 2008). IRS-1 plays a crucial role in the insulin signaling pathway, and is expressed in insulin-sensitive tissues. The IRS-1 gene is a member of the IRS protein substrate family, and is located on chromosome 2q36. Several genetic polymorphisms of this gene and their effects on insulin action have been identified (Tang et al., 2013). The IRS-1(Gly972Arg) gene (rs1801278) is associated with a high prevalence of type 2 DM due to insulin resistance and impaired insulin secretion (Pappa et al., 2011). IRS-1 is involved in binding of the p85 regulatory subunit of phosphatidylinositide 3-kinase (PI3K), which leads to activation of this enzyme and subsequent activation of protein kinase B to enhance glucose uptake and increase glycogen and protein synthesis (Cusi et al., 2000, Grimmsmann et al., 2002). An amino acid substitution of methionine to isoleucine at codon 326 (Met326Ile) of PI3K was identified in Danish Caucasian diabetic patients, and is associated with glucose regulation (Hansen et al., 1997). Recent target therapies for RCC have also focused on the PI3K pathway (Figlin et al., 2013).
The expression of insulin-like growth factors (IGFs) plays an important role in RCC risk (Schips et al., 2004, Tavani et al., 2007). IGF-binding proteins (IGFBPs) regulate the action of IGFs. Cheng et al. (2007) demonstrated that a common genetic variation in IGFBP-3, including rs854744 (A[-202]C) and rs2132570 (C[-1590]A), may affect its circulating levels among multiethnic populations. Another study demonstrated that significantly higher IGFBP-3 serum levels were noted in carriers of the A allele of IGFBP-3 (A[-202]C) compared to carriers of the C alleles, and there was a gene dosage effect in increasing the OR of ccRCC (Safarinejad, 2011). Although high total levels of urinary arsenic, never drinking alcohol, and gene polymorphisms of insulin-related enzymes are important independent risk factors in the development of RCC, no epidemiological studies have verified their combined effects until now. In this study, we further explored the joint effect of total urinary arsenic levels, DM, alcohol consumption, and polymorphisms in insulin regulation genes (i.e., IGFBP-3, PI3K, and IRS1) on RCC in a low arsenic exposure area.
Section snippets
Study participants
Between November 2006 and December 2012, 398 prevalent cases with pathologically proven RCC and 756 age- and gender-matched controls with no evidence of RCC or any other malignancy were recruited from the Department of Urology at the National Taiwan University Hospital, Taipei Municipal Wan Fang Hospital, and Taipei Medical University Hospital (Huang et al., 2012). Pathological verification of RCC was completed by image-guided biopsy or surgical resection of renal tumors. The
Results
We continuously increased the sample size to 398 RCC patients and 756 healthy controls from our previous studies (Huang et al., 2011a, Huang et al., 2011b, Huang et al., 2012), with the mean age 58.96 ± 0.66 years and 60.15 ± 0.48 years, respectively. Due to the age- and gender-matched case-control study design, the distribution of gender and age were not significantly different between cases and controls. Frequent or occasional alcohol drinkers had a significantly lower RCC risk than
Discussion
This study showed that high total levels of urinary arsenic and history of DM and hypertension correlated with a high OR of RCC, and frequent and occasional alcohol consumption significantly correlated with a decreased OR of RCC with an increased number of study participants. These data are in accordance with our previous study, which showed that total levels of urinary arsenic significantly correlated with risk of RCC (Huang et al., 2012). In addition, participants who carried IGFBP-3
Conflict of interest statement
The authors disclosed all financial and interpersonal relationships that present a potential conflict of interest.
Acknowledgments
This study was supported by grants from the National Science Council of the Republic of China (NSC 86-2314-B-038-038, NSC 87-2314-B-038-029, NSC-88-2314-B-038-112, NSC-89-2314-B038-049, NSC-89-2320-B038-013, NSC-90-2320-B-038-021, NSC-91-3112-B-038-0019, NSC-92-3112-B-038-001, NSC-93-3112-B-038-001, NSC-94-2314-B-038-023, NSC-95-2314-B-038-007, NSC-96-2314-B038-003, NSC-97-2314-B-038-015-MY3 (1-3), NSC-97-2314-B-038-015-MY3 (2-3), NSC-97-2314-B-038-015-MY3 (3-3)), NSC 100-2314-B-038-026, NSC
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