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• MUC1 expression is associated with ST3GAL2 and negatively correlated with the androgen receptor in castration‑resistant prostate cancer

  Nakanishi Shotaro, Suda Tetsuji, Tanaka Kei, Yonamine Tomoko, Numahata Kenji, Sugawa Ai, Oshiro Takuma, Oshiro Yoshinori, Saito Seiichi, Inokuchi Junichi

  Glycoconjugate Journal ( Springer )  41   381 - 394   2024.12 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Stage-specific embryonic antigen-4 (SSEA-4) is a developmentally regulated antigen, while expression level of SSEA-4 and / or its synthase ST3GAL2 is associated with prognosis in various malignancies. We have reported a prominent increase of SSEA-4 in castration-resistant prostate cancer (CRPC) and its negative correlation with the androgen receptor (AR). Meanwhile, loss of AR has increased to approximately 30% with the growing use of androgen receptor signaling inhibitor for metastatic CRPC (mCRPC). However, monitoring the progression status of AR-negative prostate cancer is a challenge because it does not produce prostate-specific antigen. Based on the negative relationship of expression between AR and SSEA-4, we hypothesized that a soluble molecule synchronized with SSEA-4 in expression could be a serum marker candidate for AR-negative prostate cancer. Thus, we investigated the molecular background of SSEA-4 expression by ST3GAL2-knockout in DU145 cells. Here we show that MUC1 is identified as a molecule associated with ST3GAL2 and expressed in AR-negative prostate cancer. A negative correlation of expression between AR and MUC1 was observed in prostate cancer cell lines and CRPC tissues. The average rate of MUC1 expression was nearly 60% in AR-negative prostate cancer cells in CRPC tissues. Level of serum CA15–3 (MUC1) was the highest in mCRPC among various stages and its higher level was associated with faster progression of mCRPC. Our results demonstrate that MUC1 is identified as a ST3GAL2-associated molecule and expressed in AR-negative CRPC cells. Furthermore, level of serum CA15–3 may reflect the progression status of mCRPC.

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• MUC1 expression is associated with ST3GAL2 and negatively correlated with the androgen receptor in castration-resistant prostate cancer

  Nakanishi, S; Suda, T; Tanaka, K; Yonamine, T; Numahata, K; Sugawa, A; Oshiro, T; Oshiro, Y; Saito, S; Inokuchi, J

  GLYCOCONJUGATE JOURNAL ( Glycoconjugate Journal )  41 ( 6 ) 381 - 394   2024.12 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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• Genome-wide association studies for pelvic organ prolapse in the Japanese population

  Matsunami, M; Imamura, M; Ashikari, A; Liu, XX; Tomizuka, K; Hikino, K; Miwa, K; Kadekawa, K; Suda, T; Matsuda, K; Miyazato, M; Terao, C; Maeda, S

  COMMUNICATIONS BIOLOGY ( Nature Research )  7 ( 1 ) 1188 - 9   2024.09 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Pelvic organ prolapse (POP) affects approximately 40% of elderly women, characterized by thedescent of the pelvic organs into the vaginal cavity. Here we present the results of a genome-wideassociation study (GWAS) for susceptibility to POP comprising 771 cases and 76,625 controls in theJapanese population. We identified a significant association of WT1 locus with POP in the Japanesepopulation; rs10742277; odds ratio (OR) = 1.48, 95% confidence interval (CI), 1.29–1.68,P = 6.72 × 10−9. Subsequent cross-ancestry GWAS meta-analysis combining the Japanese data andpreviously reported European data, including 28,857 cases and 622,916 controls, identified FGFR2locus as a novel susceptibility locus to POP (rs7072877; OR = 1.06, 95% CI, 1.04–1.08,P = 4.11 × 10−8). We also observed consistent directions of the effects for 21 out of 24 European GWASderived loci (binomial test P = 2.8 × 10−4), indicating that most of susceptibility loci for POP are sharedacross the Japanese and European populations.

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• Increased level of serum leucine-rich-alpha-2-glycoprotein 1 in patients with clear cell renal cell carcinoma

  Nakanishi, S; Goya, M; Suda, T; Yonamine, T; Sugawa, A; Saito, S

  BMC UROLOGY ( BMC Urology )  24 ( 1 ) 94 - 94   2024.04 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  BACKGROUND: Currently, no useful serum markers exist for clear cell renal cell carcinoma (ccRCC), making early detection challenging as diagnosis relies solely on imaging tests. Radiation exposure is also a concern due to multiple required CT examinations during treatment. Renal cell carcinoma (RCC) histological types include ccRCC and non-clear cell RCC (non-ccRCC); however, treatment response to medications varies which necessitates accurate differentiation between the two. Therefore, we aimed to identify a novel serum marker of RCC. Increased LRG1 expression in the serum has been demonstrated in multiple cancer types. However, the expression of LRG1 expression in the serum and cancer tissues of patients with RCC has not been reported. Since ccRCC is a hypervascular tumor and LRG1 is capable of accelerating angiogenesis, we hypothesized that the LRG1 levels may be related to ccRCC. Therefore, we examined LRG1 expression in sera from patients with RCC. METHODS: Using an enzyme-linked immunosorbent assay, serum levels of leucine-rich-alpha-2-glycoprotein 1 (LRG1) were measured in 64 patients with ccRCC and 22 patients non-ccRCC who underwent radical or partial nephrectomy, as well as in 63 patients without cancer. RESULTS: Median values of serum LRG1 and their inter-quartile ranges were 63.2 (42.8-94.2) µg/mL in ccRCC, 23.4 (17.7-29.6) µg/mL in non-ccRCC, and 36.0 (23.7-56.7) µg/mL in patients without cancer, respectively (ccRCC vs. non-ccRCC or patients without cancer: P < 0.001). C-reactive protein (CRP) levels (P = 0.002), anemia (P = 0.037), hypercalcemia (P = 0.023), and grade (P = 0.031) were independent predictors of serum LRG1 levels in ccRCC. To assess diagnostic performance, the area under the receiver operating characteristic curve of serum LRG1 was utilized to differentiate ccRCC from non-cancer and non-ccRCC, with values of 0.73 (95% CI, 0.64-0.82) and 0.91 (95% CI, 0.82-0.96), respectively. CONCLUSIONS: LRG1 served as a serum marker associated with inflammation, indicated by CRP, anemia, hypercalcemia, and malignant potential in ccRCC. Clinically, serum LRG1 levels may assist in differentiating ccRCC from non-ccRCC with excellent diagnostic accuracy.

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• Increased level of serum leucine-rich-alpha-2-glycoprotein 1 in patients with clear cell renal cell carcinoma

  Nakanishi Shotaro, Goya Masato, Suda Tetsuji, Yonamine Tomoko, Sugawa Ai, Saito Seiichi

  BMC Urology ( BioMed Central )  24   1 - 7   2024.04 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Background Currently, no useful serum markers exist for clear cell renal cell carcinoma (ccRCC), making early detection challenging as diagnosis relies solely on imaging tests. Radiation exposure is also a concern due to multiple required CT examinations during treatment. Renal cell carcinoma (RCC) histological types include ccRCC and non-clear cell RCC (non-ccRCC); however, treatment response to medications varies which necessitates accurate differentiation between the two. Therefore, we aimed to identify a novel serum marker of RCC. Increased LRG1 expression in the serum has been demonstrated in multiple cancer types. However, the expression of LRG1 expression in the serum and cancer tissues of patients with RCC has not been reported. Since ccRCC is a hypervascular tumor and LRG1 is capable of accelerating angiogenesis, we hypothesized that the LRG1 levels may be related to ccRCC. Therefore, we examined LRG1 expression in sera from patients with RCC. Methods Using an enzyme-linked immunosorbent assay, serum levels of leucine-rich-alpha-2-glycoprotein 1 (LRG1) were measured in 64 patients with ccRCC and 22 patients non-ccRCC who underwent radical or partial nephrectomy, as well as in 63 patients without cancer. Results Median values of serum LRG1 and their inter-quartile ranges were 63.2 (42.8–94.2) µg/mL in ccRCC, 23.4 (17.7–29.6) µg/mL in non-ccRCC, and 36.0 (23.7–56.7) µg/mL in patients without cancer, respectively (ccRCC vs. non-ccRCC or patients without cancer: P < 0.001). C-reactive protein (CRP) levels (P = 0.002), anemia (P = 0.037), hypercalcemia (P = 0.023), and grade (P = 0.031) were independent predictors of serum LRG1 levels in ccRCC. To assess diagnostic performance, the area under the receiver operating characteristic curve of serum LRG1 was utilized to differentiate ccRCC from non-cancer and non-ccRCC, with values of 0.73 (95% CI, 0.64–0.82) and 0.91 (95% CI, 0.82–0.96), respectively. Conclusions LRG1 served as a serum marker associated with inflammation, indicated by CRP, anemia, hypercalcemia, and malignant potential in ccRCC. Clinically, serum LRG1 levels may assist in differentiating ccRCC from non-ccRCC with excellent diagnostic accuracy.

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• Grant-in-Aid for Scientific Research(C)

  Project Year: 2020.04  -  2023.03 

  Direct: 3,400,000 (YEN)  Overheads: 1,020,000 (YEN)  Total: 4,420,000 (YEN)

• Grant-in-Aid for Scientific Research(C)

  Project Year: 2020.04  -  2023.03 

  Direct: 3,400,000 (YEN)  Overheads: 4,420,000 (YEN)  Total: 1,020,000 (YEN)

• Research on markers expressed in high-grade prostate cancer

  Grant-in-Aid for Scientific Research(C)

  Project Year: 2016.04  -  2019.03 

  Direct: 3,700,000 (YEN)  Overheads: 1,110,000 (YEN)  Total: 4,810,000 (YEN)

  　View Summary

  We identified molecules related to the malignant potential of prostate cancer in prostate cancer cell lines. Those included enzyme protein (prostate cancer glycoprotein-enzyme: PCGP-enz), glyprotein (GP) related to glycolysis (PCGP-glyco),GP related to blood pressre (PCGP-bp), GP related to stress response (PCGP-stress), GP related to ubiquitin (PCGP-ub), GP commonly expressed in triple negative breast cancer (PCGP-br), GP commonly expressed in lung cancer (PCGP-lc), GP expressed in endoplasmic reticulum (PCGP-er), etc. Among those PCGP-lc and PCGP-er were significantly associated with higher Gleason score and PCGP-er was also significantly related to T stage using radical prostatectomy specimens. We also found stage-specific embryonic antigen-4 (SSEA-4) was significantly associated with the malignant behavior of prostate cancer using clinical samples.

• Research on markers expressed in high-grade prostate cancer

  Grant-in-Aid for Scientific Research(C)

  Project Year: 2016.04  -  2019.03 

  Investigator(s): Saito Seiichi, Miyata Yasuyoshi 

  Direct: 3,700,000 (YEN)  Overheads: 4,810,000 (YEN)  Total: 1,110,000 (YEN)

  　View Summary

  We identified molecules related to the malignant potential of prostate cancer in prostate cancer cell lines. Those included enzyme protein (prostate cancer glycoprotein-enzyme: PCGP-enz), glyprotein (GP) related to glycolysis (PCGP-glyco),GP related to blood pressre (PCGP-bp), GP related to stress response (PCGP-stress), GP related to ubiquitin (PCGP-ub), GP commonly expressed in triple negative breast cancer (PCGP-br), GP commonly expressed in lung cancer (PCGP-lc), GP expressed in endoplasmic reticulum (PCGP-er), etc. Among those PCGP-lc and PCGP-er were significantly associated with higher Gleason score and PCGP-er was also significantly related to T stage using radical prostatectomy specimens. We also found stage-specific embryonic antigen-4 (SSEA-4) was significantly associated with the malignant behavior of prostate cancer using clinical samples.

• Investigation of novel diagnostic biomarkers for prostate cancer based on RM2 antigen

  Grant-in-Aid for Young Scientists(B)

  Project Year: 2014.04  -  2017.03 

  Member: Seiichi, NAKANISHI Shotaro

  Direct: 2,900,000 (YEN)  Overheads: 870,000 (YEN)  Total: 3,770,000 (YEN)

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  Although RM2 antigen is a new histological marker for prostate cancer that may reflect the tumor stage, the target proteins carrying RM2 antigen are yet unclear. To identify the target proteins, we focused on amino acid sequence of the 50kDa protein that reacts strongly to RM2 antibody. Histological expression of several candidate proteins in prostate cancer was significantly associated with Gleason score. Among these, urine level of a candidate protein in the patients with prostate cancer decreased compared to those with benign prostate. These results suggested that these candidate proteins would be useful as a new histological or urine marker of prostate cancer.

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