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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 4  |  Page : 873-880

Association between leptin level and renal cell carcinoma susceptibility and progression: A meta-analysis


1 Department of Orthopaedics, Lianyungang Clinical Medical College of Nanjing Medical University, Nanjing, 210002; Department of Orthopaedics, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, 222002, People's Republic of China
2 Department of General Surgery, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, 222002, People's Republic of China
3 Department of Pediatrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200023, People's Republic of China
4 Department of Orthopaedics, The Affiliated Nanjing Hospital of Nanjing Medical Universiy, Nanjing, 210002, People's Republic of China

Date of Web Publication27-Jun-2018

Correspondence Address:
Liming Wang
Department of Orthopaedics, The Affiliated Nanjing Hospital of Nanjing Medical Universiy, Nanjing, 210002
People's Republic of China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_848_17

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 > Abstract 


Objectives: It is well-documented that obesity participated in the development of renal cell carcinoma (RCC). Leptin is closely associated with obesity. This study is aimed to investigate the relationship between leptin level and RCC susceptibility and progression.
Methods: A meta-analysis was conducted to explore the association between leptin level and RCC susceptibility and progression. The studies were retrieved from electronic databases during January 1990–September 2017 with keywords. The qualified studies were screened with inclusion and exclusion criteria. A random effects model was applied to calculate the pooled standard mean differences and the corresponding confidence intervals.
Results: Ten studies were finally included in this meta-analysis. The serum leptin level in male RCC was significantly lower than that of in female RCC in overall populations, Asians, and Caucasians while no marked difference was noted between genders in the plasma samples. Plasma leptin level in Stage I–II RCC was significantly higher than that in the Stage III-IV. In addition, no significant difference was observed between following parameters, including RCC and non-RCC, clear and non-clear RCC, Grade I–II and Grade III-IV RCC, M0 and M1 RCC, N0 and N1 RCC, and size <4 cm and size >4 cm RCC. No evidence of publication bias was observed.
Conclusions: Our findings indicated that serum leptin level was lower in men with RCC than in women with RCC. Leptin level may not be related to the risk and progression of RCC. However, more studies should be performed in the future.

Keywords: Gender, leptin, meta-analysis, renal cell carcinoma


How to cite this article:
Zhu H, Li W, Mao S, Wang L. Association between leptin level and renal cell carcinoma susceptibility and progression: A meta-analysis. J Can Res Ther 2018;14:873-80

How to cite this URL:
Zhu H, Li W, Mao S, Wang L. Association between leptin level and renal cell carcinoma susceptibility and progression: A meta-analysis. J Can Res Ther [serial online] 2018 [cited 2019 Dec 12];14:873-80. Available from: http://www.cancerjournal.net/text.asp?2018/14/4/873/229523

Haiquan Zhu, Wei Li, and Song Mao contributed equally





 > Introduction Top


Renal cell carcinoma (RCC) has accounted for 90%–95% of all kidney malignancies,[1] with an increased incidence of 2%–4% per year worldwide for the last two decades.[2] Meanwhile, RCC has been generally resistant to radiotherapy or chemotherapy.[3] With the advances in diagnostic imaging and detection technology, it was still difficult to achieve early diagnosis.[4] The known risk factors for RCC included obesity, tobacco, hypertension, which showed a certain correlation with the development of RCC. Besides, some biomarkers were reported to be associated with carcinogenesis of RCCS, such as microRNAs,[5] thrombocytosis [6] and forkhead box M1.[7] However, the clear mechanism of nearly half cases remained unexplained.[8]

Metabolic disorders have been significant contributors to the growth and development of RCC.[9] In the United States, nearly half of RCC cases were attributable to overweight or obesity.[10] The susceptibility to RCC could be increased with obesity, through inflammation, insulin resistance and so on.[11] Obesity is regulated by several cytokines, of which adipokines were most significant. In this sense, adipokines may be associated with RCC risk. Leptin, an active polypeptide produced by adipocytes, played a critical role in the regulation of the body.[12] Congenital leptin deficiency would lead to obesity, thermogenesis dysregulation and insulin resistance,[13] which indicated that lower level of leptin may promote the carcinogenesis of RCC. The previous reports also indicated that serum level of leptin may be a biomarker in detecting the lung cancer subtypes.[14] Based on the above-mentioned evidence, we hypothesized that the risk and prognosis of RCC may be predicted with leptin level.

During the past decades, a lot of studies were performed on investigating the relationship between leptin levels and RCC.[11],[15],[16],[17],[18],[19],[20],[21],[22],[23] On one hand, some studies showed that leptin level was inversely associated with RCC risk, whereas some showed opposite conclusion. On the other hand, some reports only focused on the relationship between leptin and RCC progression, such as the metastasis. Meta-analysis has been a good approach to pool the existing literature and provide a robust result. For the conflicting results on the association between leptin and RCC in previous studies, an improved understanding on this issue may have important clinical implications, confirming that the leptin level may be a potential indicator for RCC risk/progression.

Hence, this meta-analysis was performed to investigate the association between leptin level and RCC risk/progression. It aimed to provide a comprehensive and reliable finding on the clinical significance of this association.


 > Materials and Methods Top


Search strategy

The published studies on the association between leptin level and the risk/progression of RCC in humans were searched. The existing publications were retrieved according to the preferred reporting items for systematic reviews and meta-analysis statement,[24] from PubMed, Embase, and Cochrane databases by the date of September 2017. No restriction was imposed on search language. The applied keywords were as follows: (1) RCC, renal cancer, RCC; and (2) leptin, adiponectin, obesity, and insulin resistance. The reference list of retrieved articles and reviews were also manually reviewed. The repeated reports were removed, and the most complete analysis was included in this study.

Inclusion and exclusion criteria

Inclusion criteria

  1. A minimum of two comparison groups was included (RCC group vs control group, male group vs female group, etc.)
  2. The leptin level was reported (mean, standard deviation [SD] or median, quartiles).


Exclusion criteria

  1. Case reports, reviews and editorials were excluded
  2. Association of other cytokines with RCC was excluded
  3. Multiple publications with repeated analysis or same data were removed.


Data extraction and synthesis

Following characteristics were extracted from each study:First author's last name, year of publication, ethnicity of study population, number of cases and controls. The leptin level (mean, SD) was calculated for RCC/non-RCC groups, male/female groups, T1–2/T3–4 groups, N0/N+ groups, M0/M1 groups, G1–2/G3–4 groups, clear RCC/non-clear RCC groups, and size <4 cm/size >4 cm groups. The extracted median and quartiles were also converted to mean and SD according to previous methods.[25] The data extraction and synthesis were independently performed by two authors, and any disagreements were resolved by discussion.

Statistical analysis

STATA version 12.0 (Stata Corp, College Station, TX, USA) was applied to calculate the extracted data from each study. The pooled statistics were expressed as standard mean difference (SMD), which was applied to measure the differences of leptin level between RCC/non-RCC groups, male/female groups, T1–2/T3–4 groups, N0/N+ groups, M0/M1 groups, G1–2/G3–4 groups, clear RCC/non-clear RCC groups, and size <4 cm/size >4 cm groups. Heterogeneity of SMDs among studies was tested by with Q statistic (significance level at P < 0.10). The I2 statistics were calculated for evaluating the quantitative measure of inconsistency across studies. Pooled SMDs were calculated with a random-effects model. Furthermore, 95% confidence intervals were also calculated. Potential publication bias was assessed by Begg's test and Egger's test (significance level at P < 0.05) when the number of the included studies was more than 4. P < 0.05 was considered statistically significant, except otherwise specified.


 > Results Top


Study screening

A total of 196 studies were retrieved from the PubMed, Embase, and Cochrane databases. Thereinto, 186 publications were excluded according to the inclusion and exclusion criteria. Ten studies [11],[12],[13],[14],[15],[16],[17],[18],[19] were finally enrolled in this analysis for evaluating the association between leptin level and RCC [Figure 1]. All papers were published in English.
Figure 1: Flow chart of study selection

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The association between leptin level with RCC risk

Eight studies were identified for analyzing differences of leptin level between RCC and non-RCC groups [Table 1]. Five studies were performed in Caucasians, and three in Asians. A total of 1677 RCC and 2071 non-RCC cases were included. There were two studies on the leptin level in tissue samples, four in serum samples, and two in plasma samples.
Table 1: Characteristics of studies included in this investigation

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The differences of leptin level between male and female RCC

Five studies were enrolled for analyzing the differences of leptin level between male and female RCC cases. Three studies were performed in population of Caucasians, and two in Asians. A total of 770 male and 521 female RCC cases were enrolled. There were four studies reported the leptin level in the serum samples, and one reported the leptin level in plasma samples.

The differences of leptin level between clear RCC and non-clear RCC

Two studies were identified for analyzing the differences of leptin level between clear RCC and non-clear RCC [Table 1]. One study was performed in Caucasians, and the other in Asians. A total of 195 clear RCC and 60 non-clear RCC cases were included. The two studies reported the serum leptin level.

The differences of leptin level between Grade I–II RCC and Grade III–IV RCC

Four studies were identified for analyzing the differences of leptin level between Grade I–II RCC and Grade III–IV RCC [Table 1]. Three studies were performed in Caucasians, and one in Asians. A total of 226 Grade I–II RCC and 300 Grade III–IV cases were enrolled. Three studies were conducted to test the leptin level in serum sample, and one reported the results in plasma sample.

The differences of leptin level between Stage I–II RCC and Stage III–IV RCC

Three studies were identified for analyzing the differences of leptin level between Stage I–II RCC and Stage III–IV RCC [Table 1]. All three studies were performed in Caucasians.

A total of 190 Stage I–II RCC and 193 Stage III–IV RCC cases were enrolled. Two studies were conducted to test the leptin level in serum sample, and one reported the results in plasma sample.

The differences of leptin level between M0 RCC and M1 RCC

One study was identified for analyzing the differences of leptin level between M0 RCC and M1 RCC [Table 1]. This study was performed in Caucasians. A total of 47 M0 RCC and 10 M1 RCC cases were enrolled. This study was conducted to test the leptin level in serum samples.

The differences of leptin level between N0 RCC and N1 RCC

One study was identified for analyzing the differences of leptin level between N0 RCC and N1 RCC [Table 1]. This study was performed in Caucasians. A total of 52 N0 RCC and 5 N1 RCC cases were included. This study reported the leptin level in serum samples.

The differences of leptin level between size <4 cm RCC and size >4 cm RCC

One study was identified for analyzing the differences of leptin level between size <4 cm RCC and size >4 cm RCC [Table 1]. This study was performed in Asians. A total of 104 cases of size <4 cm RCC and 52 cases of size >4 cm RCC were enrolled. This study reported the leptin level in serum samples.

Association of leptin level with RCC risk

No significant difference was observed in leptin level between RCC and non-RCC for overall populations, Asians, and Caucasians [Table 2] and [Figure 2]. Similar results were noted in leptin levels of tissue, serum, and plasma samples.
Table 2: Meta-analysis of the association between leptin status and renal cell carcinoma

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Figure 2: Difference of leptin status between RCC and non-RCC controls

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Association of the differences of leptin level between male and female RCC

The leptin level in male RCC was significantly lower than that in female RCC in overall populations, Asians, and Caucasians [Table 2] and [Figure 3]. Similar results were noted in leptin levels of serum samples. For the plasma leptin level, no marked difference was observed between male and female RCC.
Figure 3: Difference of leptin status between male and female RCC

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Association of the differences of leptin level between clear RCC and non-clear RCC

No marked difference of leptin level was observed between clear RCC and non-clear RCC cases in overall populations, Asians and Caucasians [Table 2]. No marked difference of serum leptin level was noted between clear and non-clear RCC.

Association of the differences of leptin level between Grade I–II RCC and Grade III–IV RCC

No significant difference of leptin level was observed between Grade I–II and Grade III–IV RCC cases in overall populations, Caucasians and Asians [Table 2]. Similar results were noted in the leptin levels of serum and plasma samples.

Association of the differences of leptin level between Stage I–II RCC and Stage III–IV RCC

No significant difference of leptin level was observed between Stage I–II and Stage III-IV RCC cases in Caucasians. Similar results were noted in the serum sample. Plasma leptin level in Stage I–II was significantly higher than that in Stage III–IV RCC [Table 2].

Association of the differences of leptin level between M0 RCC and M1 RCC

No significant difference of leptin level was observed between M0 and M1 RCC cases in Caucasians [Table 2]. Similar results were noted in the serum leptin level.

Association of the differences of leptin level between N0 RCC and N1 RCC

No significant difference of leptin level was observed between N0 and N1 RCC cases in Caucasians [Table 2]. Similar results were noted in the serum leptin level.

Association of the differences of leptin level between size <4 cm RCC and size >4 cm RCC

No significant difference of leptin level was observed between size <4 cm and size >4 cm RCC case in Asians [Table 2]. Similar results were noted in the serum leptin level.

Assessment of publication bias

No significant publication bias was observed for overall populations (leptin level and RCC risk: Begg P = 0.621, Egger P = 0.603; leptin level between male and female: Begg P = 0.624, Egger P = 0.467) [Figure 4] and [Figure 5].
Figure 4: Publication bias for the difference of leptin status between RCC and non-RCC controls

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Figure 5: Publication bias for the difference of leptin status between male and female RCC

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 > Discussion Top


Increasing attention has been paid to the etiology of RCC. The confirmation of possible risk factors for RCC would give an insight to the therapy of RCC. Several studies have found that obesity was associated with the susceptibility to RCC.[26],[27],[28] In our meta-analysis, we investigated the potential association between obesity-related cytokine, leptin, and RCC risk/progression, which was attempted to make a more robust conclusion. Our results showed that leptin was not associated with the risk and progression of RCC and lower level of serum leptin was observed in male RCC cases compared with that in female cases.

Obesity was closely associated with an increased risk of RCC, which may be due to that overweight would lead to hyperinsulinemia and exposure to estrogen.[29] Leptin, a 16 kD protein hormone produced by adipocytes, made effects on food intake and energy expenditure.[30] Leptin also exerted effects on hematopoiesis, angiogenesis, and cell migration, which were risk factors for cancer progression. However, a null association between leptin level and RCC risk/progression was observed in our investigation; only one enrolled study showed that plasma leptin level was significantly higher in Stage I–II than that in Stage III–IV RCC. In addition, the result of plasma sample was less accurate than that of serum and tissue. More studies should be performed in the future. Our findings may be explained by several facts:First, leptin played dual roles in the cancer progression. On the one hand, leptin exerted effects on promoting inflammation, oxidative stress, and cell proliferation,[31] which contributed to the cancer susceptibility and progression. On the other hand, leptin also played a role of anticancer through NK cell proliferation and activation,[32] which contributed to the cancer cell death. Second, it considered that body weight could be lowered with leptin, leading to decreased rate of obesity, which contributed to lower risk of cancer. However, some reports also showed that leptin administration made no effects on the reduction of body weight. The reason may be than an adaptive increased level of leptin in obese cases would cause the leptin resistance, leading to final null effects on the body. Third, kidney was the main target organ responsible for leptin clearance,[33] which indicated that large amounts of leptin would be stored in the kidney, the renal inflammation and oxidative stress induced by leptin may offset the lower-obesity effects from circulating leptin. Finally, multiple factors were involved in the development of RCC. A single factor of leptin may not directly affect the risk/progression of RCC. In addition, the association between leptin level and RCC risk/progression could not be supported by current evidence. However, more studies should be performed in the future.

An interesting finding of this study was that male RCC patients show lower level of serum leptin compared with that in female cases, which may be due to the following facts: Expression of leptin could be promoted with estrogen, and more obesity was observed in the female.[34] The fat accumulation leads to the increased level of leptin in female. The previous reports showed that fasting leptin level was higher in nondiabetes women than that in men.[35] Lower circulating leptin level was found in men than that in women with comparable heart failure.[36] It speculated that men may present lower level of leptin than that in women in normal conditions. A more in-depth study should be performed to investigate the roles of gender on the prognosis of RCC.

In the past, several studies were conducted to investigate the relationship between leptin and various cancers. Kadri et al.[37] reported that lower level of leptin was associated with the risk of pancreatic cancer. Karatas et al.[14] reported that serum leptin level was not associated with weight loss and early-stage non-small cell lung cancer survival. Demiray et al.[38] reported that advanced-stage non-small cell lung cancer cases presented significantly lower serum leptin level than that of controls. Ozsoy et al.[39] reported that no significant difference of serum leptin level was observed between head/neck cancer cases and controls. All these above-mentioned evidences indicated that the association between leptin level and cancer may be affected by multiple factors, while leptin did not play a direct role in the carcinogenesis.

Although no marked publication bias for overall populations was observed, several limitations should be noted in our investigation. First, there may be heterogeneities affecting the results of our meta-analysis, even with a random-effects model. Second, the results may be affected with reporting and language bias, variable study design and different interventions. Third, the statistical power may be limited by the small sample size. Finally, the results may be influenced with differences of RCC stages and the sample of leptin. Subgroup analysis in terms of these factors should be performed in the future.

Taken together, the results of our study suggested that male RCC cases presented lower level of serum leptin compared with female cases. Leptin level was not associated with the risk and progression of RCC. However, more studies would be needed to validate our findings.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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