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Review

Krüppel-like Factor 10 as a Prognostic and Predictive Biomarker of Radiotherapy in Pancreatic Adenocarcinoma

by
Yi-Chih Tsai
1,
Min-Chieh Hsin
1,
Rui-Jun Liu
1,
Ting-Wei Li
1 and
Hui-Ju Ch’ang
1,2,3,4,*
1
National Institute of Cancer Research, National Health Research Institutes, Miaoli 350, Taiwan
2
Department of Radiation Oncology, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
3
Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
4
Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
*
Author to whom correspondence should be addressed.
Cancers 2023, 15(21), 5212; https://doi.org/10.3390/cancers15215212
Submission received: 19 September 2023 / Revised: 17 October 2023 / Accepted: 27 October 2023 / Published: 30 October 2023
(This article belongs to the Special Issue Cancer Biomarkers: Recent Progress, Innovations and Future Clinical Implications)
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Abstract

:

Simple Summary

Despite recent improvement in chemotherapy regimens for pancreatic adenocarcinoma (PDAC), the clinical outcomes are still unsatisfactory compared to other solid tumors. Radiotherapy was demonstrated to improve locoregional control of PDAC; however, the survival benefit of radiotherapy in localized PDAC is undefined due to early distant progression in the majority of patients. Upfront chemotherapy for localized PDAC was suggested recently to avoid radical local therapy for patients of localized PDAC high risk of distant metastasis. Potential tissue biomarkers were developed to select PDAC patients who will benefit from local radiotherapy. This review summarizes potential tissue biomarkers reported to predict the efficacy and survival benefits of radiotherapy for localized PDAC including SMAD4, a biomarker validated in a prospective clinical trial to correlate with failure pattern of localized PDAC after radiotherapy. In particular, we describe Krüppel-like factor 10 (KLF10), lost in two thirds of PDAC patients, in association with distant metastasis and radio-resistance of PDAC. From tumor tissues of patients with resectable PDAC enrolled to a clinical trial, we demonstrated that the combination of KLF10 and SMAD4 expression in tumor tissues may help select those who may benefit the most from additional radiotherapy. Though promising, these potential biomarkers should be validated in prospective clinical trials.

Abstract

The prognosis of pancreatic adenocarcinoma (PDAC) remains poor, with a 5-year survival rate of 12%. Although radiotherapy is effective for the locoregional control of PDAC, it does not have survival benefits compared with systemic chemotherapy. Most patients with localized PDAC develop distant metastasis shortly after diagnosis. Upfront chemotherapy has been suggested so that patients with localized PDAC with early distant metastasis do not have to undergo radical local therapy. Several potential tissue markers have been identified for selecting patients who may benefit from local radiotherapy, thereby prolonging their survival. This review summarizes these biomarkers including SMAD4, which is significantly associated with PDAC failure patterns and survival. In particular, Krüppel-like factor 10 (KLF10) is an early response transcription factor of transforming growth factor (TGF)-β. Unlike TGF-β in advanced cancers, KLF10 loss in two-thirds of patients with PDAC was associated with rapid distant metastasis and radioresistance; thus, KLF10 can serve as a predictive and therapeutic marker for PDAC. For patients with resectable PDAC, a combination of KLF10 and SMAD4 expression in tumor tissues may help select those who may benefit the most from additional radiotherapy. Future trials should consider upfront systemic therapy or include molecular biomarker-enriched patients without early distant metastasis.

1. Introduction

1.1. Controversies Regarding Radiotherapy for Pancreatic Adenocarcinoma

Pancreatic adenocarcinoma (PDAC) is notoriously well known for its dismal survival outcomes. It is characterized by rapid distant metastasis or local destructive progression with a 5-year survival rate of 12% [1]. In patients with metastatic or unresectable PDAC, combination chemotherapy regimens consisting of (modified) FOLFIRINOX [2,3] and gemcitabine (GEM) plus nab-paclitaxel [4] have achieved better tumor responses (31.6% vs. 9.4% and 23% vs. 7%, both p < 0.001) and overall survival (OS) than single-agent GEM or 5-fluorouracil (11.1 vs. 6.8 months and 8.5 vs. 6.7 months, both p < 0.001). Prospective randomized trials revealed the survival benefit of adjuvant chemotherapy with FOLFIRINOX (p = 0.003) [5], GEM plus capecitabine (p = 0.032) [6], or GEM plus nab-paclitaxel (p = 0.009) [7] over single-agent GEM after PDAC resection. For borderline resectable PDAC, neoadjuvant chemotherapy achieved a better R0 resection rate (71% vs. 40%, p < 0.01) and survival (15.7 vs. 14.3 months, p = 0.025) than upfront surgery [8,9,10].
Unlike chemotherapy, the efficacy of radiotherapy as an adjuvant or curative treatment for PDAC remains controversial. The European Study Group for Pancreatic Cancer (ESPAC)-1 trial indicated no benefit of radiotherapy for resectable PDAC [11]. Our prospective randomized study to revealed that chemoradiotherapy (CRT) with adjuvant GEM for six months improved local control (GEM-CRT arm vs. GEM arm, locoregional recurrence rate: 41.4% vs. 58.1%, p = 0.039) but additional CRT had no survival benefit (GEM-CRT arm vs. GEM arm; OS: 21.5 vs. 23.5 months, p = 0.82) for patients with resescted PDAC [12]. However, long-term outcomes from the Dutch Pancreatic Cancer Group-initiated PREOPANC study revealed that in patients with (borderline) resectable PDAC receiving adjuvant GEM, neoadjuvant GEM-based CRT had a substantial advantage (5-year OS rate: 20.5% vs. 6.5%, p = 0.025) and improved locoregional control (p = 0.004) compared with upfront surgery [9,10]. The authors suggested that CRT might benefit patients with PDAC who do not have early distant metastasis. The survival benefit of neoadjuvant therapy for localized PDAC was demonstrated from the ESPAC-5 [13] and the National Clinical Trials Network cooperative groups initiated A021501 [14] trials, especially chemotherapy with FOLFIRINOX in ESPAC-5 showing the 1-year OS rate: 84% vs. 39% (p = 0.0028). Neoadjuvant capecitabine-based CRT provided a moderate survival benefit (60% vs. 39%) compared with immediate surgery despite the improved R0 resection and pathologic complete remission rates. The efficacy of neoadjuvant CRT could not be determined in the A021501 trial due to the insufficient accrual of patients after early termination due to the low R0 resection rate in the neoadjuvant CRT arm. The authors concluded that preoperative radiotherapy using other delivery approaches may benefit a subpopulation of patients. Regarding locally advanced PDAC (LAPC), the international LAP07 study identified that the addition of CRT after GEM induction therapy improved local control from 32% to 46% (p = 0.03) without survival benefit (p = 0.09), partly due to rapid distant metastasis [15]. Conversely, the Eastern Cooperative Oncology Group trial disclosed that upfront GEM-based CRT prolonged median survival duration compared with GEM alone (p = 0.017) in LAPC [16]. The conflicting results of randomized studies on localized PDAC imply a narrow therapeutic window for local radiotherapy.
Despite improved clinical outcomes with the combination chemotherapy and neoadjuvant strategy, the survival of patients with PDAC remains inferior to that of patients with other solid tumors [1]. Local recurrence remains one of the essential issues for survival and life quality of PDAC patients. One third of patients with PDAC, disclosed from rapid autopsy, died from local destructive progression without prominent distant metastasis [17]. Despite significant amelioration in recurrence with the mFOLFIRINOX regimen compared with GEM alone in patients with resectable PDAC [5], the pattern of recurrence remained unaffected with isolated locoregional recurrence accounting for 24.6% and 24% of all recurrences in patients who had undergone mFOLFIRINOX and GEM, respectively. A similar observation was noted in the ESPAC-4 study, with local recurrence rates of 53% and 46% in the GEM arm and Gem-CRT arm, respectively [6].
Using personalized radiotherapy, in 49 patients with LAPC, according to the response to induction chemotherapy of eight cycles of FOLFIRINOX and losartan, an inhibitor of thrombospondin-1-mediated activation of latent TGF-β, a phase II trial demonstrated a prominent down-staging and R0 resection rate of 61% with significantly prolonged median progression-free survival (PFS) and OS (17.5 and 31.4 months, respectively) [18]. Ablative radiotherapy following induction chemotherapy with a combination regimen revealed, in 119 patients with inoperable PDAC, safe and prolonged local control, with a median OS of 26.8 months [19]. Advancements in treatment techniques and radiotherapy strategies can be applied to current standard approaches for improving the currently unsatisfactory clinical outcomes of patients with PDAC. Modern radiotherapy provides excellent locoregional control and it should therefore be incorporated into the multimodal treatment of PDAC. Recent clinical trials, especially the PREOPAC study, have implied that administering CRT to patients with a low risk of early distant metastasis can translate local control into survival benefit [4]. Research must be conducted to find patients with PDAC who will benefit the most from CRT by using molecular biomarkers related to PDAC tumorigenesis and progression.

1.2. Tissue Biomarkers of Radiotherapy Responses in PDAC

The heterogeneity and aggressive biology of PDAC are classified based on epigenetic, genomic, transcriptomic, and proteomic data [20]. Several potential tissue biomarkers were identified for differentiating progression patterns in patients with PDAC (Table 1). A radiosensitivity index (RSI) for intrinsic radiosensitivity of tumors was developed from a linear regression algorithm of the surviving fraction of 48 cancer cells after 2 Gy and the expression levels of 10 genes including HDAC1, SUMO1, PKCb, c-Abl, STAT1, AR, Cdk1, c-Jun, RelA, and IRF1. In 73 patients with PDAC receiving surgery with or without radiotherapy, patients with RSI-high radioresistant tumors tended to have shorter survival (hazard ratio [HR]: 2.1, 95% confidence interval [CI]: 1.0–4.3, p = 0.054). For the 31 high-risk patients (positive lymph nodes, positive margins, or postoperative CA19-9 levels > 90 U/mL) who underwent radiotherapy, radio-sensitive patients (i.e., with a low RSI) had significantly improved survival compared with radioresistant patients (i.e., with a high RSI) (OS: 31.2 vs. 13.2 months, p = 0.04) [21]. The authors concluded that integrating the RSI with high-risk variables can refine the prognosis of patients with pancreatic cancer treated with radiotherapy. An optimal radiotherapy dose at the individual specific molecular signature level genomic-adjusted radiation dose (GARD) was obtained by combing RSI with a linear-quadratic model. Using data from the total cancer care (TCC) study, the GARD was calculated for 20 primary tumors from various sites treated with the corresponding conventional radiotherapy doses. Despite this uniformity of the radiation dose for a specific tumor type, GARD varied widely across the TCC cohort, implying that a high dose does not always result in a high therapeutic effect. The median GARD was higher in patients with oropharyngeal cancer than in those with non-oropharyngeal head and neck cancer (39.71 vs. 32.56, p = 0.042) after 70 Gy; this finding is in concordance with the observation of better efficacy of radiotherapy in patients with oropharyngeal cancer [22,23]. Among the 40 patients in the Moffitt pancreas cancer cohort, the GARD ranged between 16 and 40 and predicted OS independently to a statistically significant level (HR: 2.6, 95% CI: 1.1–6.0; p = 0.029). Higher GARDs predicted a better radiotherapeutic effect, longer time to recurrence, and longer survival; moreover, GARD enabled the individualization of the radiation dosage according to tumor radiosensitivity [22,23]. Preclinical studies have demonstrated that indoleamine 2,3 dioxygenase-2 (IDO2), a tryptophan catabolic enzyme, promotes pancreatic tumorigenesis. PDAC development reduced in IDO2−/− mice (30% vs. 10%, p < 0.05) [24]. In humans, the high prevalence of two inactivating single-nucleotide variations, rs4503083 [Exon 11] and rs10109853 [Exon 9], of IDO2 was noted. A DNA analysis of 200 patients from two pancreatic cancer cohorts (The cancer genome atlas and the Thomas Jefferson University Hospital dataset) indicated that an IDO2-deficient genotype was correlated with longer PFS in PDAC patients receiving adjuvant radiotherapy (p = 0.023). The choline phosphorylation pathway is upregulated in PDAC. From 88 patients with resectable PDAC, metabolic profile analysis demonstrated a prominent difference between good and poor responders in tumors’ choline metabolites (including N-acetylglucosamine-1-phosphate, 1-methylnicotinamide, carnitine, glucose, glutathione, N-acetylglucosamine-6-phosphate, and uridine-5″-monophosphate) regardless of whether they received neoadjuvant CRT. In patients receiving neoadjuvant CRT (n = 62), the levels of carnitine (≤130 nmol/mg), choline (≤283 nmol/mg), phosphocholine (≤749 nmol/mg), and glutathione (≤373 nmol/mg) predicted better PFS (all p < 0.05). Multivariate analysis revealed that choline levels of > 284 nmol/mg were significantly associated with recurrence. Microarray analysis confirmed significant suppression of the gene expression levels of the choline transporter CTL1-4 (SLC44A1-44A4) in pancreatic tumor tissues after neoadjuvant CRT. Thus, choline metabolism was suggested as a target and biomarker of neoadjuvant CRT for localized PDAC [25]. Another study integrated genomic profiling and clinical information to predict the radiotherapy response and noted that among 88 patients with cancer receiving radiotherapy, mutations of CHEK2 (p = 0.049), MSH2 (p = 0.014), and NOTCH1 (p = 0.031) were more frequently found in patients with a durable local control of ≥6 months (n = 47). Derangements of DNA repair pathways were associated with better local control (p = 0.014). The somatic mutation signature of smoking was observed more often in the durable local control group with a prediction probability of 0.83 for the 6-month local control [26].
SMAD4 is the only tissue biomarker validated by a prospective trial for predicting failure patterns in PDAC. Among LAPC patients, a local dominant failure pattern was noted in patients with SMAD4 expression compared to those with SMAD4 loss (73% vs. 28%, p = 0.016) [27]. A retrospective analysis of more than 600 patients with resected PDAC also demonstrated improved survival with adjuvant radiotherapy in only SMAD4-positive patients (p = 0.002). SMAD4 loss was significantly associated with metastatic recurrence (HR: 4.28, 95% CI: 2.75–6.68) [28]. SMAD4 status and expression were correlated with radiosensitivity and PDAC failure patterns in clinical and preclinical studies [17,31,32]. Further studies have demonstrated that the SMAD4 heterozygous mutation ameliorated PDAC metastatic yet increased its proliferation ability. Loss of SMAD4 heterozygosity regained PDAC metastatic competency in addition to increased proliferation. Further studies revealed that RUNX3 interacted with SMAD4 to modulate cancer cell division and dissemination. This observation implies that a combination of RUNX3 and SMAD4 levels can help clinical decision making for resectable PDAC [29].
These tissue biomarkers may optimize the integration of radiotherapy in multimodality treatment for patients with PDAC. Advances in tissue biomarkers facilitate the stratification of patients with PDAC with various potential for distant metastasis and the prediction of those who would benefit the most from additional radiotherapy. With the increasing use of neoadjuvant CRT, especially in borderline resectable PDAC, the value of potential biomarkers in specimens of biopsy, cytology, or peripheral blood should be developed in the future.
Several studies including ours have demonstrated that Krüppel-like factor (KLF) 10, a TGF-β early-response gene, contributes to radiosensitivity and cancer progression [33,34,35,36]. In the current review, we summarize recent progress in clinical studies of molecular mechanisms of KLF10 as a predictor of radiotherapy in patients with PDAC.

2. Main Text

2.1. KLFs

KLFs are of the specificity protein 1 (SP1)-like/KLF transcription factor superfamily and are characterized by the absence of a Buttonhead box, namely CXCPXC [37]. The DNA-binding domain of KLFs, located at the carboxyl terminus, contains three conserved C2H2 zinc finger structures. It enables KLFs to recognize CACCC elements or GC-boxes and to bind to regulatory regions of the target genes [38]. Eighteen unique members of the KLF family were identified, with a >65% sequence similarity for zinc finger motifs, resulting in competition for binding to promoters of target genes (Figure 1). Group 1 consists of KLF3, KLF8, and KLF12 which behave as transcriptional repressors by interacting with proteins binding to the carboxyl terminus. Group 2 includes KLF1, KLF2, KLF4, KLF5, KLF6, and KLF7 which bind to acetyltransferases and function as transcriptional activators. Group 3 comprises KLF9, KLF10, KLF11, KLF13, KLF14, and KLF16 which are transcriptional repressors and interact with switch-independent-3 family member A (Sin3A), a common transcriptional corepressor. Nowadays, KLF15, KLF17, and KLF18 remain unclassified [39]. KLFs are known to be critical regulators of many important biological processes, such as cell proliferation, differentiation, survival, cell cycle, epithelial–mesenchymal transition (EMT), invasion, metastasis, cell maturation, and organogenesis. Dysregulation of KLF function can lead to the development of cancer and other disorders [40].

2.2. KLF10

KLF10 was identified in human fetal osteoblasts as a positive regulator of bone growth [41]. The protein homology of KLF10 among humans, Mus musculus, Bos taurus, and Liacerta agilis is as high as 81.28%, suggesting its critical role in biological processes [42]. KLF10 is an early-response mediator of TGFβ/SMAD signaling. It forms a positive feedback loop with TGF-β signaling by transcriptionally regulating SMAD2 and SMAD7 [43]. Estrogen stimulates KLF10 expression, which inhibits BAX inhibitor-1 transcription and enhances breast cancer cell apoptosis [44]. Jun B and lysine demethylase 6A may facilitate KLF10 transcription to exacerbate diabetic nephropathy [45]. Multiple long noncoding RNAs (lncRNA) and microRNAs (miRNA) were identified as upstream regulators of KLFs, thus providing essential pathways for targeting KLFs. E3 ubiquitin ligases, including seven in absentia homolog-1 (SIAH1) and FBW7, interact with KLF10 through conserved binding motifs to promote the proteasomal degradation of KLF10. The binding of KLF10 to itchy E3 ubiquitin ligase (ITCH) increases KLF10 levels and activates Foxp3 transcription in regulatory T cells [46,47]. We previously reported that KLF10 is a phosphorylated protein at Thr-93 in the N-terminal region. RAF-1 phosphorylation and PIN1 isomerization coordinately regulate KLF10 stability and tumor progression [48].

2.3. Involvement of KFL10 in Multiple Diseases

KLF10 is involved in glucose and lipid metabolism, mitochondrial structure and function, cell proliferation, and apoptosis and it plays critical roles in multiple diseases [49]. It is a clock-controlled gene that maintains the hepatic circadian rhythm which is essential for regulating hepatic glucose and lipid homeostasis [42]. Sex-dependent differences were found in the metabolic phenotypes of KLF10-knockout mice. Male mice exhibited post-prandial and fasting hyperglycaemia whereas female mice exhibited increased plasma triglyceride levels. As a circadian-clock-controlled transcription factor, KLF10 suppresses lipogenic genes of glucose and lipid metabolism in the liver and it affects gluconeogenesis, contributing to diabetes [50,51]. KLF10 alleviates hepatic steatosis and nonalcoholic-steatohepatitis by downregulating SREBP-1c involving lipogenesis [52,53]. KLF10-deficient mice exhibit reduced receptor activator of nuclear factor kappa-B ligand, increased osteoprotegerin, and delayed8 osteoclast differentiation which led to reduced bone turnover and osteopenia [49,51,54]. A study reported that male KLF-knockout mice developed cardiac hypertrophy after approximately 16 months due to the angiotensin II-induced cardiac transcription factor, GATA4, and the atrial natriuretic factor, brain natriuretic peptide [55]. KLF10 can transactivate Foxp3 promoters in regulatory T cells in response to TG-β1 to promote atherosclerosis [56,57].

2.4. KLF10 in Cancer

Many studies have demonstrated the tumor suppressor function of KLF10 in terms of cell proliferation inhibition and apoptosis induction [58,59]. KLF10 loss activates PTEN/PI3K/AKT activity in multiple myeloma and bladder cancer [60,61]. KLF10 overexpression can suppress Wnt signaling and GSK3β phosphorylation to inhibit the proliferation, migration, and drug resistance of multiple myeloma cells. Knock-down of securin, the downstream target of KLF10, can mimic the tumor suppressor role of KLF10 in multiple myeloma [62]. In advanced-stage cancer, TGF-β signaling enhances the EMT whereas KLF10 inhibits TGF-β-induced EMT. KLF10 can suppress lung and pancreatic cancer EMT and invasion by recruiting HDAC1 to suppress the SNAI2 promoter for the removal of histone acetylation (H3K9ac and H3K27ac) [63]. In oral squamous cell carcinoma, KLF10 was identified as a differentially expressed circadian-related gene that was correlated with OS (p < 0.05) and the drug response (p = 0.0014) [64]. By directly binding to the LINC00629 promoter to induce Mcl1 degradation, KLF10 exerts antitumor activity in oral squamous cell carcinoma treated with apigenin, a flavonoid [65]. KLF10 is involved in cervical cancer immunoediting by transcriptionally regulating IL6, IL25, and pregnancy-specific beta-1 glycoproteins 2 and 5 [66]. Conversely, the tumor suppressive role of KLF10 may vary depending on the tumor cells types and the microenvironments. In KLF10-knockout mice, the TGF-β-SMAD signaling pathway was activated to suppress diethylnitrosamine-induced hepatocyte proliferation in the liver cancer [67].

2.5. Role of KLF10 in PDAC Progression

Studies have revealed associations between PDAC and alterations in TGF-β receptor genes and SMAD [68,69]. However, no alterations in KLF10 expression were found in a mutation screening study of 22 human pancreatic cancer cell lines [70]. KLF10 expression in various cancer tissues has been reported to be significantly lower than that in normal tissues [63,71]. In PDAC, KLF10 expression was low in two thirds of patients and was inversely correlated with the cancer stage [36,53]. Despite alterations in the TGF-β signaling pathway components in patients with PDAC, KLF 10 could regulate TGF-β signaling and inhibit epithelial cell proliferation in pancreatic cancer cells [72]. KLF10 expression can be increased by a noncoding RNA, lncRNA FLVCR1-AS1, by acting as a competitive endogenous RNA to sequester the inhibitory effects of miR-513c-5p or miR-514b-5p. Since lncRNA FLVCR1-AS1 is a direct transcriptional target of KLF10, this FLVCR1-AS1/KLF10 positive feedback loop can suppress PDAC progression [73].
In the murine model of pancreas-specific KLF10 deletion (Pdx-1Cre KLF10L/L), no evidence of abnormal pancreas development or neoplastic lesions was noted. The synergistic effects of KLF10 inactivation-activated mutant KrasG12D in cross-breed mice led to the rapid onset of advanced PDAC with 50% penetrance. The upregulation of c-Jun and SDF-1/CXCR4 signaling after KLF10 deletion was responsible for accelerated PDAC cell growth and distant metastasis [74]. Since KLF10-knockout mice exhibited a high incidence of metabolic disorders, we previously explored sirtuin6, an NAD+-dependent deacetylase downstream of KLF10, as a key regulator of glucose homeostasis and a tumor suppressor. Our findings indicated that KLF10 transcriptionally activated sirtuin6 to modulate the EMT and glycolysis of PDAC coordinately through NFκB and HIF1α [75]. In addition to the Wnt/β-catenin signaling pathway, we demonstrated that KLF10 contributed to the cancer stemness phenotype by transcriptionally regulating Notch-3 and Notch-4 and competing with E74-like ETS transcription factor 3 (ELF3) for promoter binding. A combination of metformin, which upregulates KLF10 by phosphorylating AMP-activated protein kinase, and evodiamine, a nontoxic Notch-3 methylation stimulator, ameliorated PDAC growth through KLF10 downregulation [76] (Figure 2).

2.6. Role of KLF10 in PDAC Resistance to Radiotherapy

The KLF family regulate radiosensitivity in various cancers (Table 2). KLF2 and KLF4 are positive regulators of endothelial-protective molecules such as nitric oxide and thrombomodulin. Compared with single-dose radiation, fractionated radiation markedly reduced the ERK5/KLF2 pathway and enhanced ICAM-1 expression, leading to endothelial dysfunction [77]. KLF4 and KLF5 may prevent radiation-induced intestinal injury by inhibiting apoptosis and modulating DNA repair pathways [78,79]. KLF4 expression can predict radiotherapy resistance and poor clinical outcomes for cervical cancer. From tumor tissues of 117 patients with locally advanced cervical cancer, KLF4 was disclosed as a risk factor for radioresistance (p = 0.032), poor PFS (p = 0.001), and OS (p < 0.001) [80]. KLF5 was the predictor of poor response to CRT in rectal cancer [81]. In colon cancer cells, radiation time-dependently and dose-dependently stabilized KLF5 levels. KLF5 increased cyclin D1 and β-catenin levels to mediate cell survival. A study assessing 60 colorectal tumor tissues before radiotherapy indicated that high KLF5 expression was correlated with pathologic complete remission (p = 0.023) and radioresistance in colorectal cancer [81]. High KLF6 expression level was associated with a nearly four times higher risk of local recurrence in head and neck cancer patients after radiotherapy (p = 0.008) [82].
KLF10 gene expression can be used to discriminate between γ-radiation and α-radiation quality [83]. Radiation-induced delayed neuropsychiatric disorders was associated with biological processes, such as protein kinase activity, circadian behavior, and cell differentiation. The alteration of expression levels of six genes, including KLF10, in the chronic phase of radiation increased anxiety-like behaviors in mice [84]. Radiation-induced KLF10 upregulation was noted in many cancer cell lines and murine models [83,84,85]. KLF10 transcriptionally downregulated EGFR and modulated gemcitabine-resistance in cholangiocarcinoma [86]. In esophageal squamous cell carcinoma, exosomes secreted from hypoxic tumors after radiation expressed high levels of miR-340-5p, which suppressed KLF10 transcription. Higher miR-340-5p expression and lower KLF10 expression in plasma exosomes from patients with esophageal cancer patients were associated with poorer radiation responses and prognosis [33]. Several studies, including ours, have demonstrated that KLF10 transcriptionally suppresses the UV radiation resistance-associated gene (UVRAG) and modulates apoptosis, DNA repair, and autophagy in cancer cells. Metformin might decrease radioresistance in pancreatic and esophageal cancers by elevating KLF10 expression [33,35]. Furthermore, EMT and cancer stem cell phenotypes also contribute to radioresistance [87,88]. KLF10 modulates EMT and can lead to cancer stemness phenotypes by transcriptionally regulating sirtuin6, Notch-3, and Notch-4, respectively, and thus may cause radioresistance in PDAC [74,75,76]. Whether KLF family members share promoter binding sites on UVRAG or other signal targets and regulate the balance between radiosensitivity and radioresistance warrants further exploration.

2.7. Selection of Patients with Resectable PDAC for Radiotherapy Using KLF10 and SMAD4

To evaluate the benefits of additional CRT to standard adjuvant chemotherapy in patients with resected PDAC, we conducted a randomized clinical trial from 2009 to 2015 [12]. We enrolled 147 patients with PDAC after curative resection and randomized them to either adjuvant GEM 1000 mg/m2 infusion weekly for six cycles or adjuvant GEM for three cycles and GEM (400 mg/m2 weekly)-based CRT and another three cycles of GEM. Despite the significant locoregional benefit (p = 0.039) of additional CRT, the median recurrence-free survival and OS were of no significant difference in the two arms (HR: 0.98, p = 0.89 and HR: 1.04, p = 0.82), respectively (Figure 3A) [12]. Tumor specimens were collected from 111 patients. Immunohistochemical expression of biomarkers including KLF10, SMAD4, and RUNX3 was evaluated by pathologists using a visual grading system based on staining intensity and extent. The postoperative CA19-9 level and protein expression of KLF10 and SAMD4, were significantly associated with OS (p = 0.047, 0.013, and 0.045, respectively). High KLF10 or SMAD4 expression in patients (n = 55) receiving additional adjuvant CRT had a significantly prolonged local control time (ꚙ vs. 19.8 months, p = 0.026) and a better OS (33.0 vs. 23.0 months, p = 0.12) than those receiving GEM alone. In resected PDAC patients who had a loss of both SMAD4 and KLF10, additional adjuvant CRT caused the rapid development of distant metastasis and worse clinical outcomes (Figure 3B) [30]. The combination of KLF10 and CA19-9 levels did not reveal significant differences in survival outcomes between the treatment arms [30]. On the basis of these findings, we concluded that the chances of translating locoregional control of CRT into prolonged survival were high in patients with KLF10- or SMAD4-expressing tumors. Although these findings are promising, a prospective study is warranted to validate the results.

3. Conclusions

The value of radiotherapy in PDAC remains unclear due to conflicting results of clinical trials [89,90,91]. Modern radiotherapy is efficacious, resulting in a satisfactory safety profile and local control for patients with localized PDAC [18,19]. Locoregional control of the primary tumor is crucial for patients with PDAC and is increasingly possible with advancements in chemotherapy [92]. Retrospective studies have identified potential tissue biomarkers for predicting the benefits of enhanced locoregional therapy. However, most candidate biomarkers were only correlated with survival but not with failure patterns. Thus, prospective clinical trials in patients with PDAC receiving modern chemotherapy with or without up-to-date radiotherapy are required to validate the efficacy of biomarkers in selecting optimal patients for radiotherapy.
In preclinical studies, KLF10 was demonstrated to be correlated with PDAC progression and resistance and it was reported to modulate distant metastasis, cancer stemness, and radio-sensitivity. A retrospective analysis of prospective randomized trials concluded that the combination of KLF10 and SMAD4 expression can help select patients with resected PDAC who may be suitable for local radiotherapy. Current enthusiasm of upfront systemic chemotherapy for localized PDAC aims to prevent patients with rapid distant metastasis from radical local therapy including radiotherapy. Future trials evaluating the efficacy of radiotherapy in PDAC should focus on molecular biomarker-enriched patients who carry a low risk of early distant metastasis.

Author Contributions

Conceptualization, H.-J.C. and Y.-C.T.; methodology, Y.-C.T. and R.-J.L.; software, M.-C.H. and T.-W.L.; validation, Y.-C.T. and M.-C.H.; formal analysis, R.-J.L. and T.-W.L.; investigation, H.-J.C. and T.-W.L.; resources, H.-J.C.; data curation, R.-J.L. and T.-W.L.; writing—original draft preparation, Y.-C.T.; writing—review and editing, H.-J.C.; visualization, R.-J.L. and H.-J.C.; supervision, H.-J.C.; project administration, R.-J.L.; funding acquisition, H.-J.C. All authors have read and agreed to the published version of the manuscript.

Funding

National Health Research Institutes, Taiwan (CA-112-PP 14).

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Structure of the KLF family and KLF10. KLF isoforms can be divided into three groups. KLF10 belongs to Group 3. KLF15, 17, and 18 are not included in any of these groups.
Figure 1. Structure of the KLF family and KLF10. KLF isoforms can be divided into three groups. KLF10 belongs to Group 3. KLF15, 17, and 18 are not included in any of these groups.
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Figure 2. The role of KLF10 in cancers. KLF10 can transcriptionally regulate lnc00629 to modulate MCL1 expression in oral cancer. KLF10 inhibits multiple myeloma (MM) and bladder cancer by increasing the expression of PTEN to reduce AKT activity. In MM, miR410, which can be suppressed by lncRNAOIP5-AS1 inhibits the expression of KLF10. In bladder cancer, lncRNA00641 can suppress miR-197-3p to modulate KLF10 transcription. In cervical cancer, KLF10 regulates PSG2,5 to modulate the tumor immune environment. KLF10 can inhibit the TGFβ-induced epithelial–mesenchymal transition (EMT) to suppress cancer invasion in the lung and pancreas by recruiting HDAC1 to block the expression of SNAI2. In pancreatic adenocarcinoma, KLF10 transcriptionally suppresses the UV radiation-associated gene (UVRAG) to modulate DNA damage repair, autophagy, and the apoptosis of cancer cells. KLF10 competes with E74-like ETS transcription factor 3 (ELF3) in binding to Notch-3 and -4 promoters to suppress cancer proliferation and the stemness phenotype. KLF10 can transcriptionally activate sirtuin6 to coordinate glycolysis and EMT of pancreatic cancer via HIF1α and NFkB. Upward arrows denotes increase; downward arrows represent decrease. Lines with blunt end means inhibit. Thicker lines represent prominent increase (or decrease) and vice versa.
Figure 2. The role of KLF10 in cancers. KLF10 can transcriptionally regulate lnc00629 to modulate MCL1 expression in oral cancer. KLF10 inhibits multiple myeloma (MM) and bladder cancer by increasing the expression of PTEN to reduce AKT activity. In MM, miR410, which can be suppressed by lncRNAOIP5-AS1 inhibits the expression of KLF10. In bladder cancer, lncRNA00641 can suppress miR-197-3p to modulate KLF10 transcription. In cervical cancer, KLF10 regulates PSG2,5 to modulate the tumor immune environment. KLF10 can inhibit the TGFβ-induced epithelial–mesenchymal transition (EMT) to suppress cancer invasion in the lung and pancreas by recruiting HDAC1 to block the expression of SNAI2. In pancreatic adenocarcinoma, KLF10 transcriptionally suppresses the UV radiation-associated gene (UVRAG) to modulate DNA damage repair, autophagy, and the apoptosis of cancer cells. KLF10 competes with E74-like ETS transcription factor 3 (ELF3) in binding to Notch-3 and -4 promoters to suppress cancer proliferation and the stemness phenotype. KLF10 can transcriptionally activate sirtuin6 to coordinate glycolysis and EMT of pancreatic cancer via HIF1α and NFkB. Upward arrows denotes increase; downward arrows represent decrease. Lines with blunt end means inhibit. Thicker lines represent prominent increase (or decrease) and vice versa.
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Figure 3. PFS and OS curves of (A) 147 resectable pancreatic cancer patients randomized to adjuvant gemcitabine (GEM, n = 74) with or without additional adjuvant gemcitabine-based chemoradiotherapy (GEM-CRT, n = 73). (B) In total, 101 patients enrolled to the above mentioned clinical trial with qualified tumor tissues. The levels of KLF10 and SMAD4 were evaluated by two pathologists blinded to the clinical information. Patients with high expression of KLF10 or SMAD4 (H/H, n = 55) should receive additional adjuvant CRT than GEM only due to a significantly better PFS (NA vs. 19.8 months; p = 0.026) and a longer OS (33.0 vs. 23.0 months; p = 0.12). Conversely, adjuvant CRT after curative resection may not be suitable in those with low expression of both KLF10 and SMAD4 (LL) who develop distant metastasis rapidly.
Figure 3. PFS and OS curves of (A) 147 resectable pancreatic cancer patients randomized to adjuvant gemcitabine (GEM, n = 74) with or without additional adjuvant gemcitabine-based chemoradiotherapy (GEM-CRT, n = 73). (B) In total, 101 patients enrolled to the above mentioned clinical trial with qualified tumor tissues. The levels of KLF10 and SMAD4 were evaluated by two pathologists blinded to the clinical information. Patients with high expression of KLF10 or SMAD4 (H/H, n = 55) should receive additional adjuvant CRT than GEM only due to a significantly better PFS (NA vs. 19.8 months; p = 0.026) and a longer OS (33.0 vs. 23.0 months; p = 0.12). Conversely, adjuvant CRT after curative resection may not be suitable in those with low expression of both KLF10 and SMAD4 (LL) who develop distant metastasis rapidly.
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Table 1. Tissue biomarkers to predict radiotherapy responses in pancreatic adenocarcinoma. Representative clinical studies evaluating potential tissue biomarkers in correlation with survival or failure pattern of radiotherapy to PDAC.
Table 1. Tissue biomarkers to predict radiotherapy responses in pancreatic adenocarcinoma. Representative clinical studies evaluating potential tissue biomarkers in correlation with survival or failure pattern of radiotherapy to PDAC.
StudyStudy TypePt No.PDAC StageTissue OriginTreatmentBiomarkerEnd-PointConclusionSignificance
2015 Strom T [21]Retro-spective73resectableDNAAdjuvant GEM/5FU ± RT (n = 61) vs.
No adjuvant therapy (n = 12)		10 specific genes (RSI score)OSAmong clinical high risk irradiated patients, RSI low (radiosensitive) had significantly improved survivalRSI low vs. RSI high
OS: 31.2 vs. 13.2 months,
p = 0.04
2017 Scott JG [22]Retrospective40/8271NADNA/Moffit CohortRadiotherapy
45–54 Gy		GARDOSHigh GARD is associated with radiosensitive and better clinical outcomesHR: 2.6; p = 0.029
2019 Nevler A [24]Retro-spective129resectedDNA/TCGAWith or without radiotherapyIndoleamine 2,3 dioxygenase 2 (IDO2)RFSIDO2 inactivation associated with improved RFS in response to RTp = 0.023
2022 Wada Y [25]Retro-spective88resectedFrozen tissueResected with or without Neoadjuvant CRTCholine metabolitesRFSReduced choline metabolites correlate with better RFS especially in NA-CRT groupCholine: p = 0.0022
(in NA-CRT: p = 0.028)
Phospho-choline: p = 0.0086 (in NA-CRT p = 0.0037)
2022
Jang BS [26]		Retro-spective2/88NADNAradiotherapyCHEK2, MSH2, NOTCH1LFFSMutations of NOTCH2 and BCL were enriched in the NDLC group; Mutations of CHEK2, MSH2 and NOTCH1 were more frequently in the DLC group.Altered DNA repair pathway was associated with better LFFS (HR: 0.4; p = 0.014)
2011 Crane CH [27]Pro-spective phase II69LACytologyGEMOX + cetuximab+ capecitabine-CRTSmad4Failure patternPattern of progression may be predictable on the basis of Smad4 expressionintact Smad4 in 11/15 (73.3%) of local dominant recurrence;
Smad4 loss in 10/14 (71.4%) of distant dominant recurrence. p = 0.016
2017
Shin SH [28]		Retro-spective641resectableIHCAdjuvant 5-FU/LV or GEM;
5-FU-CRT for R1 resection 		Smad4OS, recurrence 1. Inactivation Smad4 indicate metastasis
2. In expressed Smad4, local therapy contributes to improved survival		1. HR: 4.28
2. p = 0.002
Iacobuzio Donahue 2009 JCO [17]Retrospective76Stage I/II: 22; III:18, IV:36.IHCSurgery, chemotherapy, CRTSmad4
TP53
Kras2		failure pattern: local vs. distantSmad4 loss in
2/9 (22%) LA without metastasis;
16/22 (78%) with 100–100 of metastases (p = 0.032)		Smad4 expression correlated with pattern of failure (locally destructive vs. metastatic)
p = 0.007
2015 Whittle MC [29]Retro-spective88resectableIHC/ICGC Chemotherapy with or without radiotherapySmad4, Runx3OS,
relapse pattern		Low Runx3 benefit from radiotherapy. High Runx 3 and loss of Smad4 pose the greatest challenge High Runx3 correlated with poor median survival
(p < 0.018).
2021
Pen SL [30]		Pro-spective phase III111resectableIHCAdjuvant GEM ± GEM-CRTSmad4, KLF10, Runx3OS, RFSCombining KLF10 and Smad4 may predict the benefits of adjuvant CRT in resected PDACHigh KLF10 or Smad4 (n = 55) had better local RFS (p = 0.026) and longer OS (p = 0.12) receiving adjuvant CRT than GEM alone.
Pt no.: patient number; PDAC: pancreatic adenocarcinoma; GEM: gemcitabine; 5FU: 5-fluoruracil; RT: radiotherapy; RSI: radiation sensitivity index; OS: overall survival; GARD: genomic-adjusted radiation dose; HR: hazard ratio; RFS: recurrence-free survival; NA-CRT: neoadjuvant chemoradiotherapy; LFFS: local failure free survival; NDLC: non-durable local control; DLC: durable local control; LA: locally advanced; GEMOX: gemcitabine + oxaliplatin; IHC: immunohistochemistry; LV: leucovorin; NA: not available; ICGC: International Cancer Genome Consortium; TCGA: the cancer genome atlas.
Table 2. KLFs in regulating the radiation sensitivity of cancers. Representative studies evaluating KLF family members in correlation with clinical outcomes of radiotherapy in various cancers.
Table 2. KLFs in regulating the radiation sensitivity of cancers. Representative studies evaluating KLF family members in correlation with clinical outcomes of radiotherapy in various cancers.
StudyCancer TypePatient No.TreatmentTissue CollectionAnalysisFindingsMechanisms
2021
Chen F [33]		Esophageal cancer8860 Gy (2 Gy/fx) + cisplatin and fluorouracilBlood, tumor tissueHistologic and plasma exosomal miR-340-5p and KLF10 Histologic and exosomal miR-340-5p levels correlated with tumor recurrence (p < 0.0001, p = 0.0004) and overall survival (p = 0.0026, p = 0.0076);
miR-340-5p expression negatively correlated with KLF10 		Exosomal miR-340-5p is critical for hypoxic exosomal transferred radioresistance. KLF10 was a direct target of miR-340-5p. Metformin may increase the expression of KLF10 and enhance the radiosensitivity of esophageal cancer
2017
Chang VH [35]		Pancreatic cancer20Neoadjuvant 50.4 Gy/28fx + GemcitabineTumor tissue IHCHistologic KLF10, UVRAGHigh KLF10 expression correlated with better tumor regression grade (R = −0.69, p = 0.001)
KLF10 expression was inversely correlated with UVRAG (R = −0.259, p = 0.03)		KLF10 transcriptionally suppressed UVRAG to enhance radiosensitivity via modulating apoptosis, DNA repair, and autophagy
2017
Liu HX [80]		Cervical cancer117Radical radiotherapy + brachytherapy + cisplatin-based chemotherapyTumor tissue IHCHistologic KLF4High KLF4 expression correlated with shorter PFS (p = 0.0019) and OS (p < 0.0017)High expression of KLF4 promoted radioresistance. KLF4 induces p21 leading to cell cycle arrest and suppressing BAX expression, thus reducing apoptosis
2019
Kim JY
[81]		Rectal cancer60Preoperative 50.4 Gy/28fx + 5-FU/LVTumor tissue IHCEGFR, p53, KLF5, C-ern, Ki67KLF5 expression was a significant worse factor for pCR (p = 0.012). Radiation stabilizes KLF5 protein in a time and dose dependent mannerKLF5 increased cyclin D1 and β-catenin to promote cancer cell survival. KLF5 expression depends on Kras and Braf mutations
2021 Leon X
[82]		Head and Neck cancer8370–72 Gy to primary tumor and 50 Gy on nodal areas in N0 or 70–72 Gy in N1 diseaseTumor tissue
RT-PCR		KLF6High KLF6 expression had a 3.8 times higher risk of local recurrence after radiotherapy (p = 0.008)KLF6 regulates response to cancer therapy in a p53-dependent manner and it promotes tumor progression from the transcriptional activation of TGFβ
Fx: fraction; IHC: immunohistochemistry; UVRAG: UV radiation resistance associated gene; PFS: progression-free survival; OS: overall survival; 5-FU/LV: 5-fluorouracil/leucovorin; pCR: pathologic complete remission.
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Tsai, Y.-C.; Hsin, M.-C.; Liu, R.-J.; Li, T.-W.; Ch’ang, H.-J. Krüppel-like Factor 10 as a Prognostic and Predictive Biomarker of Radiotherapy in Pancreatic Adenocarcinoma. Cancers 2023, 15, 5212. https://doi.org/10.3390/cancers15215212

AMA Style

Tsai Y-C, Hsin M-C, Liu R-J, Li T-W, Ch’ang H-J. Krüppel-like Factor 10 as a Prognostic and Predictive Biomarker of Radiotherapy in Pancreatic Adenocarcinoma. Cancers. 2023; 15(21):5212. https://doi.org/10.3390/cancers15215212

Chicago/Turabian Style

Tsai, Yi-Chih, Min-Chieh Hsin, Rui-Jun Liu, Ting-Wei Li, and Hui-Ju Ch’ang. 2023. "Krüppel-like Factor 10 as a Prognostic and Predictive Biomarker of Radiotherapy in Pancreatic Adenocarcinoma" Cancers 15, no. 21: 5212. https://doi.org/10.3390/cancers15215212

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