Protective effects of female reproductive factors on gastric signet-ring cell carcinoma

INTRODUCTION

Gastric cancer (GC) is the fifth most common adenocarcinoma and ranks third in mortality worldwide[1]. In China, an estimated 390000 people die of GC annually, which accounts for > 50% of the global deaths and imposes a severe health burden[1-3]. Commonly, the age-standardized incidence rates of GC have shown a male predominance with the male-to-female rate of more than 2:1 in most populations around the world[1,4]. The difference, however, cannot be entirely attributed to the different prevalence of established major risk factors, such as tobacco smoking[5] and

infection[6] between the sexes. A study reported that incidence of intestinal GC after menopause increased with time, and the incidence 10 years after menopause was comparable to that of men[7]. An umbrella review including 616630 women in six observational studies showed that menopausal hormonal therapy was associated with decreased risk of GC[8]. The female reproductive factors and sex hormones may have protective effects on gastric adenocarcinoma.

Ethical approval was obtained through the Chinese Academy of Medical Science (Beijing, China).

Moreover, various reproductive factors have provided contradictory results in relation to the risk of GCs. The protective effects of female reproductive factors imply the potential role of sex hormones in carcinogenesis. Importantly, the explanation for the predominance of GSRC in young women might provide significant clues to the etiology of the tumors and pave the way for research on innovative prevention and treatment. The effect of female reproductive factors on GSRC tumorigenesis and tumor development remains unclear despite the advances in the understanding of its epidemiology and clinicopathology. The purpose of this study was to estimate the effects of female reproductive factors on the prognosis and combined modality treatment of GSRC.

The Cox proportional hazards regression model results are presented in Table 2. Overall, the menstrual women had a significantly lower risk of mortality (HR = 0.58, 95%CI: 0.42–0.82) than male patients in the multivariable model. We did not observe this protective effect in menopausal women (HR = 0.91, 95%CI: 0.72–1.14).

真正做好黨建組織保障。企業黨建高質量發展離不開制度和人才的雙重保障。海陵藥業共有員工459人，黨員39人，成立一個黨支部，兩個黨小組。在制度層面，海陵藥業將支委會研究討論、提出意見明確為管理層決策的前置程序，確保黨組織有效參與企業重大決策，真正做到黨建工作與行政工作合心、合力、合拍。在組織構架層面，由總經理兼任黨支部書記，由黨員高管兼任支部委員，配備黨務副書記和黨務專員，專職協助書記工作，組建兼具組織力和領導力的高效團隊。

MATERIALS AND METHODS

Study population and follow-up duration

Our study involved 1431 participants who were histologically confirmed with GC with signet-ring cells and underwent curative resection between January 2011 and December 2018 at the Cancer Hospital, Chinese Academy of Medical Sciences, China. Subtotal gastrectomy was performed for distal GCs, whereas total gastrectomy was conducted for proximal-third GCs. Patients with definitive signs of distant organ or peritoneal seeding metastases did not undergo gastrectomy and were referred for evaluation for chemotherapy instead. Based on the National Comprehensive Cancer Network Clinical Practice Guidelines, standard D2 lymphadenectomy was achieved in patients with curative intention[15]. All the surgical specimens were confirmed separately and independently by at least two experienced pathologists. Disagreements were resolved by discussion, especially on the proportion of signet-ring cells. The follow-up data were prospectively collected and regularly updated by surgeons every 6 mo after surgery. The overall survival was defined from the date of gastrectomy to the date of death or the end of follow-up period (April 30, 2020).

Measurements

Despite the aforementioned strengths of our study, several limitations have to be acknowledged. First, the data concerning the expression levels of ER and progesterone receptor (PR) were unavailable. Thus, we cannot conduct further analysis on the effects of ER and PR on GSRC prognosis and other molecular mechanisms. Further investigations are needed to clarify the biological role of estrogen or ER in the carcinogenesis and chemoresistance of GSRC. Second, future studies with a more specific measure of signet-ring cells in GC and more comprehensive long-term outcomes (

, the recurrence or chemoresistance, could offer more information) will be needed to verify the conclusion in this study.

Although the incidence of GC has been decreasing, this disease remains the third cause of cancer mortality worldwide and in China. The proportion of GSRC in all GC cases has been increasing recently, especially in the young and female populations. There are obvious differences on morbidity of GSRC between the sexes. To find a new treatment and improve the overall survival of GSRC, this study has clinical significance to investigate the disparities of reproductive factors between male and female GSRC patients.

Statistical analysis

The continuous variables were expressed as mean ± SD, while categorical variables were expressed as number of observations and percentages (%). Differences in the potential covariates between the sex groups were assessed by Wilcoxon–Mann–Whitney test for continuous variables and the

test for categorical variables. The proportional hazards assumption was estimated, and the Cox multivariable model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between the sex factors and survival of GC patients with signet-ring cell carcinoma. The model was adjusted for following potential covariates: BMI, proportion of signet-ring cells, T stage, N stage, adjuvant chemotherapy, neoadjuvant chemotherapy, nerve invasion, and lymphatic vessel invasion. Subgroup analyses were conducted by (1) BMI; (2) Signet-ring cells proportion; (3) Adjuvant chemotherapy; (4) Neoadjuvant chemotherapy; (5) Nerve invasion; and (6) Lymphatic vessel invasion to explore if the impact of the sex difference was stronger in certain groups. Interaction terms between exposures and these covariates were added into the multivariable model, and Wald tests were used to examine whether the interaction terms were statistically significant. The survival curves were estimated by the Kaplan–Meier method. In the present analysis, two-sided

< 0.05 was considered to indicate statistically significant differences. All statistical analyses (and figures created) were performed with Stata 15.0 (StataCorp LLC: College Station, TX, United States).

RESULTS

Clinicopathological features of GSRC in male and female patients

Table 1 displays the distributions of the demographic and potential risk factors by sex difference. Of the 1431 GC patients with signet-ring cell carcinoma, 935 (65.3%) were male, and 496 (34.7%) were female. Overall, over one-third of the participants were aged ≥ 60 (42.0%) years, with a mean age of 56.3 (SD: 11.3) years. There were no significant differences between the sex groups in terms of histological differentiation, N stage, and adjuvant or neoadjuvant chemotherapy (

> 0.05). The female subjects were more likely to be: younger, nonsmokers and nondrinkers; with diffuse Lauren type, T1 stage and metastasis; without nerve and lymphovascular invasion; and have middle and lower tumor location, lower BMI, higher signet-ring cells proportion, and more lymph nodes removed (

< 0.05).

為患者開展醫療安全培訓，使患者的自我防護意識獲得提高，治療期間，需要對患者積極配合治療意識加以培養，為患者提供安全健康的培訓工作，充分尊重患者自身權力，同時和患者家屬保持良好的交流，使其更為詳細并且全面的掌握患者病情，提高患者的康復速度[3] 。

Subgroup analysis in the different sex groups with GSRC

Since chemoresistance is a distinct feature of GSRC, we noticed that the adjuvant chemotherapy was a protective factor in multivariate analysis. Then, we performed further subgroup analysis on adjuvant chemotherapy effects. Interestingly, protective effects exerted by female reproductive factors were observed only in the nonadjuvant chemotherapy group (HR = 0.38, 95%CI: 0.22–0.56) and the nonneoadjuvant chemotherapy group (HR = 0.53, 95%CI: 0.36–0.77). However, female reproductive factors lost their advantages and did not improve the survival after chemotherapy. It is possible that these conditions of poor survival and chemoresistance are mediated by female reproductive factors, such as ERα and ERβ, with unknown mechanism. Recently, Wang

[30] proposed that the loss of ERβ in GSRC cells might increase the potential for malignant invasion into the deep tissues easier through the mTOR signaling pathway. Therefore, ERβ might inhibit the malignancy of GSRC and can thus become a potential target in its adjuvant treatment. The investigation of Wang did not discuss the connection between ERβ and chemotherapy. We noticed that the prognostic trends are similar in all three studied groups. However, in the subgroup analysis of adjuvant chemotherapy, the mean survival time in the menstrual female group (41.4 mo) was the shortest compared to those of the male (47.6 mo) and menopausal female (45.1 mo) groups. We considered that the probable reason was the proportion of signet-ring cells in GCs. However, no association was identified between the signet-ring cell proportion and influence of female reproductive factors on the prognosis of subjects who received chemotherapy. The results of recent studies confirm the difficulties to understand the possible mechanism between sex hormones and chemoresistance in GSRC. However, more research on this topic needs to be undertaken to clearly elucidate the association between ER and chemotherapy outcomes.

Comparison of overall survival in GSRC between the sexes

The survival curves in Figure 1 depict the survival probability based on the sex difference. Menstrual female patients had a significantly better overall survival than the male and menopausal female groups (

< 0.01). Survival analysis showed better prognosis of menstrual female patients in the non-adjuvant chemotherapy group (

< 0.01) and the inadequate survival advantages of menstrual female patients in the adjuvant chemotherapy group (

= 0.73) (Figure 2). We compared overall survival between the sexes with different levels of signet-ring cells (Figure 3). Menstrual female patients had a survival advantage compared with male and menopausal female groups; however, this advantage was not significant in the GSRC group with > 50% signet-ring cells (Supplementary Figure 1).

DISCUSSION

在工業化發展的進程中，三次產業產值在GDP中的占比呈現出一定的規律性：在前工業化階段，農業作為經濟的主導產業，GDP主要來自于農業產值；在工業化初期，農業產值在GDP中的占比仍大幅高于工業產值；在工業化中期，隨著經濟的發展和工業化的推進，農業產值在GDP中的比重有所下降，工業產值占比大幅上升，第三產業不斷涌現；在工業化后期，第三產業產值在GDP中的占比將會高于第二產業；進入發達經濟初級期和發達經濟高級期，依然是第三產業為主導產業，其產值在三次產業中的占比最大。根據庫茲涅茨對于三次產業結構和工業化發展階段關系的研究結果，得出三次產業結構指標衡量工業化發展水平的標準（見表2）。

要發揮園林綠化企業檔案管理的科學性和有效性，就要分析園林綠化企業檔案管理的主要特點，才能夠有的放矢地推進企業的檔案管理上一個更新的臺階。

In this study, we focused on the influence of the sex-specific differences on the prognosis of GSRC. Our results showed that there was a stronger positive association with overall survival in menstrual female patients with GSRC, compared to that of the male or menopause female patients. The findings of the present large patient-based retrospective study may provide valuable insights into pathways for reducing GSRC mortality in the future.

The multivariate analysis results in our study showed that being a menstrual woman was a protective factor (HR = 0.58, 95%CI: 0.42–0.82) against GSRC. A similar effect was previously reported in various types of GCs[17,18]. In a study with 758 patients, Kim

[7] proposed that female reproductive hormones might be a potentially protective factor against intestinal-type GC, and the incidence of intestinal-type GC after the menopause increased and became comparable to that in men. A Japanese study revealed that the risk of GC was lower in menstrual women (HR = 0.33, 95%CI: 0.23–0.49). Protective effects were observed in differentiated histological types (HR = 0.25, 95%CI: 0.11–0.55) and undifferentiated histological types (HR = 0.39, 95%CI: 0.23–0.63)[19]. The aforementioned consistent results demonstrate the effects of female reproductive factors in reducing the risks of different GCs. In a large Chinese prospective study with female subjects, the risks of GC increased with age of menopausal women (HR = 0.80 per 5-year increase in the menopausal age, 95%CI: 0.66–0.97)[20]. A similar finding was also obtained in a cohort study including 1 million women whose risks of GC in the menopausal age were considerably higher than those in the menstrual age (RR = 1.46, 95%CI: 1.07–2.0 and RR = 1.59, 95%CI: 1.15–2.20, respectively) from the United Kingdom[21]. Our results indicate that the effect of female reproductive factors on GSRC development is steady and robust.

Here, we hypothesize that sex hormones or their receptors, such as estrogen and estrogen receptor (ER), are the key inducers of the protective effects of female reproductive factors against GSRC. The influence of estrogen has been studied by other researchers, but the results were controversial[22]. Estrogens regulate the tissue growth, differentiation, and function, which is mediated by ER-α and ER-β. The oncological importance of estrogen and ER in carcinomas occurring in the breast and ovaries has been investigated but not in GCs. The expression of ER in the stomach is a basis on which to explore the relationship between sex hormones and survival of GC. Some researchers have demonstrated the expression of ER in gastric tissues, which provides a basis for the probable functions of estrogen in this respect[23-25]. Hess

[26] established that ERs and female sex hormones were expressed in the male reproductive tract and may have some functions. The protective effect of estrogen was discovered also in men who received hormonal therapy for prostate cancer; notably, the results showed a decrease risk of GC[27].

ER has several types, including ERα, ERβ and ERγ. The biological actions of estrogen are mediated through two specific ERs, ERα and ERβ, which belong to the nuclear receptor superfamily[28]. Zhao

[25] and Matsuyama

[29] reported that both ERα, ERβ were expressed in poorly differentiated adenocarcinoma specifically in gastric signet-ring cell adenocarcinomas with characteristics of sex hormone dependency. Different effects of these two ER types were found in various studies. For example, Kameda

[27] proposed that ERα expressed in diffuse-type GC promoted the proliferation of ERα-positive GC cells. The suggested mechanism was that the activation of the ERα pathway stimulated cancer cell proliferation by activating the hedgehog pathway in a ligand-dependent but dose-independent manner

Shh induction of diffuse-type GC. ERβ is homologous to ERα, particularly in the DNA-binding domain, but it is structurally and functionally different. ERβ manifested strong cytoplasmic staining with anti-ERβ antibody in addition to the stained nuclei[29]. This result provides evidence for the potential of GSRC treatment targets. Recently, using genomic analysis, Kang

[29] identified ERγ as a potential tumor suppressor in GC. The molecular mechanisms of its action suggest that the activation of ERγ by the antagonizing Wnt signaling through DY131 could suppress GC cell growth and tumorigenesis. Studies on tumorigenesis regulated by estrogens or estrogen receptors are rare but will be urgently needed in the future.

Other variables associated with the overall survival included BMI, T stage, N stage, adjuvant or neoadjuvant chemotherapy, and lymphovascular invasion. The results of the subgroup analyses (Table 3) showed that the impact of menstruation was more significant in the female participants with lower levels of signet-ring cells (HR = 0.56, 95%CI: 0.38–0.82,

-interaction = 0.038), nerve invasion (yes

no, HR = 0.60, 95%CI: 0.40–0.89,

-interaction = 0.029), or lymphovascular invasion (yes

no, HR = 0.49, 95%CI: 0.30–0.80,

-interaction < 0.001), or without adjuvant chemotherapy (HR = 0.38, 95%CI: 0.22–0.65,

-interaction < 0.001) or neoadjuvant chemotherapy (HR = 0.53, 95%CI: 0.36–0.77,

interaction < 0.001). There was a reversal effect across the strata of BMI for menopausal women (crossover interactions).

We investigated the effects of female reproductive factors on the prognosis of the GSRC with various proportions of signet-ring cells. Being a menstrual female was a protective factor (HR = 0.56, 95%CI: 0.38–0.82) and was associated with better overall survival than that of menopausal women and men with GSRC cells < 50%. However, menstrual women lost their GSRC-associated advantages over menopausal women at a proportion of the signet-ring cells > 50%. We supposed that ERβ downregulation or ectopic expression in the cytoplasm could lead to a worse prognosis of GSRC with a higher proportion of signet-ring cells. Nevertheless, the probable mechanism remains unclear. Future studies on the topic are therefore highly recommended.

This is the first large population study focused on the relationship between female reproductive factors and GSRC with an 8-year follow-up. Our results highlight the significant effect of female reproductive factors on GSRC prognosis. The clinical importance of our present findings is critical as they have outlined the prognostic role of female reproductive factors in GSRC. Therefore, further strong evidence is provided which will increase the GSRC treatment effectiveness. In this study, we have also investigated the effect of female reproductive factors on survival in a multidimensional aspect with robust statistics such as multivariable Cox proportional hazards model and different subgroups, which could considerably diminish the impact of confounders and explore the potential effect in a specific group.

The demographic characteristics included age and body mass index (BMI). We considered age as an ordinal variable (< 50, 50?60, and ≥ 60 years) to approximate tertiles. We defined BMI based on the standard cutoff points established by the Work Group on Obesity in China in categories of underweight and normal: ≤ 24 kg/m

, overweight and obese: > 24.0 kg/m

[16]. Health-related lifestyle indicators, including alcohol consumption (yes: Any alcoholic beverage consumption in the last 12 mo, or no: No alcohol consumption in the last 12 mo) and smoking (yes: Any regular tobacco consumption, or no: Never smoked), were excluded from the analysis based on the variable selection outcome of best-subset selection approach and the uneven distribution. We categorized the proportion of signet-ring cells as ≤ 10%, 10%–50%, 50%–90%, and > 90%, but we used the proportion of signet-ring cells as a dichotomous variable (≤ 50% and > 50%) in the adjustments for confounding variables and to ensure that each level had a sufficient number of observations. Clinicopathological characteristics, such as BMI, proportion of signet-ring cells, T stage, N stage, adjuvant chemotherapy, neoadjuvant chemotherapy, nerve invasion, and lymphatic vessel invasion were subjected to analysis since they were closely associated with the survival of GC patients with signet-ring cell carcinoma based on

knowledge.

CONCLUSION

Sex differences, especially female reproductive factors, might be protective against GSRC and serve as a significant prognostic factor. Further studies including more comprehensive measures will be essential to elucidate the mechanism of action of female reproductive factors on GSRC.

ARTICLE HIGHLIGHTS

FOOTNOTES

All of the authors contributed to this work; Li Y and Tian YT designed the research study and performed the research; Li Y collected the data, performed the statistical analysis, and drafted the manuscript; Li Y, Zhong YX, Xu Q, and Tian YT participated in discussion and manuscript revision; All authors have read and approve the final version of the manuscript and agreed to be accountable for all aspects of the work.

National Natural Science Foundation of China, No. 82072734.

安：謝謝你的贊揚！其實如我在訪談一開始提到的一般，這樣的能力絕非天生，而必須得益于帕內拉教授和齊科里尼教授對我的言傳身授。是他們反復為我提供這樣的解決方案，并一直告訴我，多數的所謂“技術問題”，其實大多來自對樂句音樂性的不理解。在跟隨他們學習的幾年之中，我一直讓自己保持思考，以充分吸收他們的觀點。而他們的藝術觀點解鎖了我對肢體的運用，以及我對音樂的理解。

Gastric signet-ring cell carcinoma (GSRC) is a distinct type of GC, and its incidence has been steadily increasing in Asia, Europe, and the United States, accounting for > 30% of new gastric adenocarcinoma cases[9]. GSRC belongs to the diffused, undifferentiated, and poorly differentiated types in the Laurén classification, Nakamura’s classification, and Japanese Gastric Cancer Association, respectively[10-13]. GSRC in early and advanced stages is more frequently observed in younger female patients than gastric adenocarcinoma[14]. A contradiction with the protective effect of female reproductive factors on gastric adenocarcinoma seems to exist. There is also evidence that female reproductive factors induce diffusetype GC through estrogen activity[7].

All participants gave written informed consent.

The authors declare that they have no conflict of interest.

All data included in this study are available on reasonable request from the corresponding author.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

《大學》中又寫道：為人君，止于仁；為人臣，止于敬；為人子，止于孝；為人父，止于慈；與國人交，止于信。”《尚書》中的“民為邦本，本固邦寧”，“仁者愛人”，“出入相友，守望相助。”“忠信，禮之本也；義理，禮之文也。無本不正，無文不行(《禮記·禮器》)。”“禮形于外”，“道誠于心”。以忠信、誠意按照一定的禮節規程相互表達“仁義”則“智”（意指思想道德，在今天也可延伸為科學與人文精神）成。

China

Yang Li 0000-0002-4549-1087; Yu-Xin Zhong 0000-0002-8865-3297; Quan Xu 0000-0001-6177-9503; Yan-Tao Tian 0000-0001-6479-7547.

Ma YJ

人民警察在實際執法過程中，存在著對繼續盤問、傳喚、先行拘留和拘傳等強制措施混淆適用的情形。對已經確認相對人存在著違法犯罪嫌疑的，按照法律規定應當采取傳喚、先行拘留或拘傳等強制措施，并不辨明清楚具體情形，統統以繼續盤問為由予以處置。

Kerr C

他們連滾帶爬地出現在后排。一切都恢復了人性的本源，一切都那么的順其自然，一切都開始了，沒有回頭的路徑了。往前，唯有秉持著向前的動力，沖破內心的桎梏，去尋找去探尋甚至去醉臥在銷魂蝕骨的風水寶地中。

Ma YJ

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