Keratin-15 high expression links with lymph node metastasis and poor survival prognosis in epithelial ovarian cancer patients

3.1 Characteristics

A total of 140 EOC patients with a mean age of 62.1 ± 9.2 years were enrolled in this study (Table 1). A respective of 102 (72.9%), 16 (11.4%), 12 (8.6%), and 10 (7.1%) patients were identified as high-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, and other types of carcinomas. Tumor size of 37 (26.4%) patients was > 10 cm. Besides, 81 (57.9%) patients were recognized as peritoneal cytology positivity, and 79 (56.4%) patients had lymph node metastasis. Additionally, 51 (36.4%) patients were at international federation of gynecology and obstetrics (FIGO) stage I-II, whereas 89 (63.6%) patients were at FIGO stage III-IV. Moreover, 122 (87.1%), 102 (72.9%), and 101 (72.1%) patients had abnormal cancer antigen 125 (CA125), cancer antigen 199 (CA199), and carcinoembryonic antigen (CEA), correspondingly. Lastly, 133 (95.0%) patients received adjuvant therapy.

Table 1 EOC patients’ characteristics3.2 Krt15 expression

The median (IQR) KRT15 IHC score was 0.0 (0.0–1.0), ranging from 0.0 to 12.0 (Fig. 1A). Among all, 36.4% of patients had positive KRT15 expression (Fig. 1B) and 15.0% of patients had a high KRT15 expression (Fig. 1C). The IHC images of negative, positive (but not high), and high KRT15 expression are showed in Fig. 1D. Besides, the characteristics between KRT15 negative group and KRT15 positive group, and between KRT15 low or no group and KRT15 high group are presented in Supplementary Table 1.

Fig. 1figure 1

KRT15 IHC score in EOC patients. The distribution of KRT15 expression in EOC patients (A). The proportion of EOC patients with positive KRT15 expression (B). The proportion of EOC patients with high KRT15 expression (C). The IHC examples of negative, positive, and high KRT15 expression tissues of EOC patients (D)

3.3 Correlation of krt15 expression with disease features

KRT15 expression was positively correlated with lymph node metastasis (P = 0.027), and exhibited a tendency to be positively correlated with FIGO stage (P = 0.052), but without statistical significance; while it was not related to age (P = 0.625), histological type (P = 0.074), tumor size (P = 0.208), peritoneal cytology (P = 0.211), abnormal CA125 (P = 0.605), abnormal CA199 (P = 0.150), abnormal CEA (P = 0.656), or adjuvant therapy (P = 0.731) (Fig. 2A–J).

Fig. 2figure 2

KRT15 expression positively linked with lymph node metastasis in EOC patients. Correlation of KRT15 expression with age (A), histological type (B), tumor size (C), peritoneal cytology (D), lymph node metastasis (E), FIGO stage (F), abnormal CA125 (G), abnormal CA199 (H), abnormal CEA (I), and adjuvant therapy (J) in EOC patients

3.4 Prognostic value of krt15 expression

Positive KRT15 expression was associated with poor DFS (P = 0.009) (Fig. 3A). Notably, high KRT15 expression was related to even worse DFS (P = 0.001) (Fig. 3B). Meanwhile, positive KRT15 expression was linked with unfavorable OS (P = 0.032) (Fig. 3C). High KRT15 expression was also correlated with worse accumulating OS (P < 0.001) (Fig. 3D).

Fig. 3figure 3

DFS and OS were shorter in EOC patients with positive (versus negative) and high (versus low or no) KRT15 expression. Comparison of DFS in EOC patients with positive versus negative KRT15 expression (A) and in patients with high versus low or no KRT15 expression (B). Comparison of OS in EOC patients with positive versus negative KRT15 expression (C) and in patients with high versus low or no KRT15 expression (D)

In addition, we screened out the high-grade serous carcinoma patients, then analyzed the correlation of KRT15 expression with prognosis in them. Positive KRT15 expression showed a tendency to be correlated with worse DFS, but did not reach the statistical significance (P = 0.063) (Supplementary Fig. 1A), while high KRT15 expression was significantly associated with unfavorable DFS (P = 0.025) (Supplementary Fig. 1B). Similarly, positive KRT15 expression showed a tendency to be correlated with worse OS, but did not reach the statistical significance (P = 0.154) (Supplementary Fig. 1C), while high KRT15 expression was significantly associated with unfavorable OS (P = 0.015) (Supplementary Fig. 1D).

3.5 Factors predicting DFS

Positive KRT15 expression (yes vs. no) (hazard ratio (HR): 1.885, P = 0.010), high KRT15 expression (yes vs. no) (HR: 2.519, P = 0.001), tumor size > 10 cm (yes vs. no) (HR: 2.043, P = 0.005), peritoneal cytology (positive vs. negative) (HR: 2.021, P = 0.009), lymph node metastasis (yes vs. no) (HR: 2.521, P = 0.001), and FIGO stage (III-IV vs. I-II) (HR: 2.316, P = 0.004) were linked with worse DFS (Fig. 4A). Further multivariable Cox’s regression analysis revealed that high KRT15 expression (yes vs. no) (HR: 2.241, P = 0.007), tumor size > 10 cm (yes vs. no) (HR: 2.072, P = 0.006), peritoneal cytology (positive vs. negative) (HR: 1.752, P = 0.042), and lymph node metastasis (yes vs. no) (HR: 2.610, P = 0.001) were independently associated with worse DFS (Fig. 4B).

Fig. 4figure 4

High KRT15 expression was independently related to poor DFS of EOC patients. Related factors of DFS by univariable Cox regression analysis (A) and independent factors of DFS by multivariable Cox regression analysis (B) in EOC patients

3.6 Factors predicting OS

Positive KRT15 expression (yes vs. no) (HR: 2.133, P = 0.036), high KRT15 expression (yes vs. no) (HR: 3.688, P = 0.001), tumor size > 10 cm (yes vs. no) (HR: 2.114, P = 0.043), were correlated with worse OS (Fig. 5).

Fig. 5figure 5

Related factors of OS by univariable Cox regression analysis in EOC patients

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